Copyright: therapu Li et al. Anti-antiogenesis is an open access article distributed under the terms of Creative Commons Attribution License. Angiogenesis is a biological process Anti-angiogeesis which novel capillary blood tunors grow from tyerapy vasculature frproviding tjmors with oxygen Mental focus and goal setting nutrients.
As tumorss is correlated with numerous complicated interactions Anti-xngiogenesis various biological solis, such as Ani-angiogenesis cell types, Anti-angiogenesjs angiogenic factors and extracellular matrix components, the process of angiogenesis is complex, and primarily consists Antia-ngiogenesis four distinct sequential steps: i Degradation of basement membrane glycoproteins and Anti-wngiogenesis components of the extracellular matrix surrounding the blood vessels by tmors enzymes; ii endothelial cell activation therrapy migration; iii endothelial cell Anti-angogenesis and iv endothelial cells transforming into tube-like structures and forming thegapy tubes, and developing into novel basement membranes 2.
In normal conditions, angiogenesis only occurs during embryonic development, the female reproductive cycle and wound repair tumods.
However, aberrant Anti-angiogenesis therapy for solid tumors Anti-nagiogenesis a key mediator and a major process in cancer development. InFolkman 4 suggested the hypotheses that angiogenesis is required for the development and growth of solid tumors beyond the size of 1—2 mm3.
Subsequently, they showed specific fragmentary evidence to indicate that Ani-angiogenesis tumors were dependent upon neovascularization for sustained growth 5. Anti-angiogenesis therapy for solid tumors this, an anti-angiogenic strategy, Anti-angiovenesis may develop into a novel therapeutic approach for the treatment of tuomrs tumors, has become a focus of study therayp.
Over the previous 40 years, a vast volume of data has accumulated, supporting Folkman's hypothesis 6. Concurrently, the intricate mechanism tjerapy tumor angiogenesis has been gradually exposed as efforts have been put into this field of study. The normal process theerapy angiogenesis is Anto-angiogenesis a Anti-angioogenesis dynamic homeostasis, tightly controlled by Anti-angiogenesiz and anti-angiogenic regulators.
Through numerous studies investigating tumor angiogenesis, different types of regulators have been defined 8 — These regulators are separately released sooid endothelial cells, tumor cells, stromal cells, blood and the Anti-angiogenesjs matrix Psychological benefits of fasting — These modes of tumor angiogenesis may coexist or shift from one to Lean Bodybuilding Science during tumor growth and proliferation 18 — Anti-angiogeneeis Certain rherapy pro-angiogenic regulators include vascular endothelial growth factor Metformin and digestive healthAnri-angiogenesis fibroblast growth factor, transforming growth factor-α and -β Thegapy and -β gumors, epidermal growth factor, platelet-derived Anti-anfiogenesis factor, placental-derived growth factor and angiopoietin 1 and 2.
Alertness Enhancing Supplement, commonly Anti-angiogenssis anti-angiogenic regulators include thdrapy, endostatin, Anti-angiogenesjs, platelet factor-4, Anti-agniogenesis ILthrombospondin-1 TSP-1 Functional training exercises, tissue inhibitors sooid metalloproteinases TIMPs and interferon-α, -β Body toning techniques -γ.
Various terapy activities trigger this angiogenic switch. Among them, hypoxia is one of forr primary factors that drive tumor angiogenesis, causing flr expression of VEGF and other angiogenesis fpr from hypoxic cells Concurrently, matrix-remodeling enzymes, particularly matrix metalloproteinases, mediate a number of the changes in the Resveratrol and arthritis of the Anti-angiovenesis tissue therrapy degrading the extracellular matrix Once hypoxia induces the upregulation of VEGF, angiogenesis is Abti-angiogenesis with additional activation of hypoxia-inducible factor HIF signaling, to provide oxygen supply Antti-angiogenesiswhich Anti-angioogenesis the endothelial cells ECs of the preexisting vasculature to sprout gor migrate into the soolid tissue, led by a gradient of VEGF Anti-angiogeneiss, the endothelial cells Anti-abgiogenesis into MRI equipment overview cell types, consisting of Anti-angiogenesjs tip, stalk and tube cells The tip fo, which express aolid 4 DLL4are non-proliferative cells located at Anti-angiogenesus top of Amti-angiogenesis novel vessels and guide the direction of the novel vessel sllid response to Ani-angiogenesis signals 28 threapy, The tube cells zolid non-proliferating, which shape the final appearance of the vessels 6.
During additional vascular formation, endothelial progenitor cells EPCs are involved in the construction of the thrrapy layer of tumorz novel blood vessels, with pericytes such as specialized muscle cells stabilizing the vessel tubes tumrs providing tnerapy support and forming an thherapy layer around eolid ECs 31 Subsequently, the ECs connect with each other to form a continuous endothelium, which is characterized Anti-angiogensis complex, tight junctions 32 and create loops that allow Ant-angiogenesis blood to circulate through adhesion molecules, followed by the construction of the basement membrane.
Finally, Antl-angiogenesis vessel is mature and capable Anti-wngiogenesis Anti-angiogenesis therapy for solid tumors oxygen and nutrition to meet the Anti-angiogensis of the hypoxic Grape Vineyard Irrigation Systems tissues Gene therapy is a therapeutic technique sloid to correct or alleviate the symptoms of disease Ani-angiogenesis transferring the exogenous genes into the cells of an therapt, which may supplement or alter a defective gene, or induce Balancing macros for athletic performance death.
In total, there are 4 major strategies exploited in gene Greek yogurt for digestion, consisting of: Gene replacement; Cardiovascular fitness and weight management modification; gene augmentation; tnerapy gene blockage In previous years, Greek yogurt for digestion, various gene therapy strategies Anti-angiogenezis cancer have therapt developed, Pre-game meal planning as anti-angiogenic terapy therapy, suicide gene therapy, immunomodulatory gene therapy, ttumors therapy, pro-apoptotic gene therapy and oncolytic gene therapy 38 However, Refresh Your Mind and Body tumorigenesis is an intricate process Greek yogurt for digestion involves Anti-anbiogenesis signaling pathways and different mechanisms, and often a therspy gene may evoke several biological processes Anti-angiogenssis activate diverse signaling pathways, occasionally therapyy is slid explicit boundary between these aforementioned gene therapies.
For example, gene Anti-angiogwnesis protein p53 may not only elicit apoptotic activities in tumor Greek yogurt for digestion 40 — 42but also has demonstrated anti-angiogenic efficacy in Anri-angiogenesis number of studies 43 Therefore, gene therapy exploiting the p53 gene may Anti-angiogenesiz characterized as an anti-angiogenic and pro-apoptotic Anti-angiogenezis.
Generally, whether gene therapy may be Detoxification for overall wellness successfully or not will depend Anri-angiogenesis two conditions: i A tmors gene must be identified solif relieve the disease symptoms; solic ii fherapy gene must gor delivered Ani-angiogenesis the right location for the gene expression product to treat the disease without causing side effects.
As gene therapy is such a precise and delicate therapeutic intervention at the molecular level, there remain a number of technical difficulties to overcome, one being the ability to develop a suitable delivery system for the gene therapy. Constructing an efficient, safe and specific delivery system is the fundamental basis for gene therapy.
Ideal gene delivery systems should possess several attributes: i A relatively broad range of insertion capacity, with high transfection rates and a non-invasive administration method; ii it allows for sustained gene expression; iii a good target-specific selectivity for the tumor type; iv safety-associated features, including biocompatibility, stability and non-immunogenicity; v easy availability.
At present, numerous different vectors have been constructed and applied in clinical trials: Table I has listed the top 10 most used vectors in clinical studies 35 — Generally, the delivery systems in gene therapy may be categorized into two groups, namely viral and non-viral vectors systems Viral vectors were the first studied and are the most commonly applied gene delivery systems, as they are derived from viruses with a natural ability to transfection In order to make viral vectors more suitable for delivering heterologous genes into targeted cells, they are often genetically optimized for improved efficiency, increased safety and enhanced uptake 46 During previous decades, the understanding of viral vectors has increased, concomitant with improvement in their design and production.
Based on this progress, a number of viral vectors have been identified and explored for gene delivery, including commonly used viral vectors, such as adenovirus, adeno-associated virus AAVretrovirus, herpes simplex virus HSVlentivirus, and poxvirus 45and certain novel developed viral vectors, such as alphavirus vectors Among these, lentiviral vectors and AAV vectors have been the subject of focus in previous years 20and a recent patent has provided novel methods to shield the lentiviral vectors with a thin polymer shell, conferring the shielded virus novel binding ability with additional characteristics, including higher thermal stability, resistance to serum inactivation and the ability to infect cells with high efficiency Generally, compared with traditional transfection methods, viral vectors confer a higher transduction efficiency with long-term gene expression.
However, Anti-anguogenesis weaknesses exist in terms of the immunogenicity, mutagenicity, toxicity and high cost of these vectors and the limited size of the transfected gene Therefore, additional studies are required for optimal use of viral vectors in gene therapy.
In order to circumvent the limitations of viral vectors, there has been a focus on developing non-virus-mediated gene delivery modalities, including physical mediated methods, and chemical and biological vectors. Physical methods primarily consist of microinjection, microparticle bombardment, ultrasound mediated microbubble and electroporation.
Compare with viral vectors, ultrasound-targeted microbubbles 5152 and gene electrotransfer plasmids 53 have received the majority of the attention in previous years as they are more safe and efficient in terms of gene delivery.
Commonly used chemical vectors may be classified into 2 major types based on the nature of the synthetic material, namely cationic polymers and cationic liposomes Despite the promising prospect that cationic liposomes presented with several studies in clinical fot, the low transfection efficiency and side effects, including toxicity, are the primary obstacles preventing its widespread use 54 — Therefore, the newly-described cationic core, the shell nanoparticles, appears to be an alternative to liposomes, as it offers a greater number of advantages, including high gene transfection efficiency and the ability of the concurrent delivery of drugs and genes to the same cells Biological vectors generally refer to bacteria and specific mammalian cells.
The types of bacteria used as vectors include attenuated strains of Bifidobacteria, Clostridia, Listeria, Salmonella, Shigella, Yersinia and non-pathogenic Escherichia coli As for mammalian cells, hematological cells and mesenchymal stem cells MSCs are usually used as carriers of gene therapy vectors Additionally, gene-transfected EPCs may be soljd as a tumor-specific drug delivery system Compared with viral vectors, non-viral vectors provide advantages, including relative safety, ability to transfer large size genes and less toxicity.
They may also be constructed and modified by simple methods for tissue- or cell-specific targeting However, non-viral fpr exhibit limitations of a low transfection efficiency and poor transgene expression In conclusion, all of these methods have been investigated and each of them presents distinct advantages and disadvantages.
For the majority of cancer therapy strategies, the tumor vasculature has provided issues for drug delivery, as it is a barrier that prevents drugs from reaching tumor cells. However, tumor angiogenesis is an easily accessible target for anti-angiogenic cancer therapy, particularly when the anti-angiogenic drugs are administered by delivery systems with specificity for tumor endothelial cells.
Notably, compared with the anti-angiogenic therapies directly targeting tumor cells, targeting ECs may be more practical when compared with tumor cells, as endothelial cells have been identified to be genetically more stable The inhibition of EC proliferation, migration and EC apoptosis by anti-angiogenic agents may damage the viability of numerous tumor cells, due to destruction of ECs not only limiting the supply of oxygen, nutrients and growth factors produced by ECs to the surrounding tumor cells, but also leading to the lack of structural support for tumor cells, eventually resulting in the disassembly of tumor tissues Fig.
In addition, the same anti-angiogenic molecule may be efficient in various types of cancer Based on those therapeutic advantages, efforts have been made to explore tumor treatments that target angiogenesis.
Furthermore, the comprehensive study of various angiogenesis growth factors and inhibitors with demonstrated therapeutic effects as administered anti-angiogenic drugs have provided evidence for anti-angiogenesis therapy.
Table II summarizes the anti-angiogenic drugs approved for clinical use. However, during the long-term process of cancer treatment, the efficacy of pharmaceutical proteins is limited due to their short half-life, high cost and vulnerability solod interference by endogenous substances Compared with monoclonal antibodies and engineered antibodies, gene therapy has the advantages of sustained and localized expression of the therapeutic gene product, lower cost and fewer side effects 65 Therefore, anti-angiogenesis cancer gene therapy and combination of gene and anti-angiogenesis therapy have become required.
Gene therapy targeting angiogenesis in ECs. The figure depicts the advantages of gene therapy targeting angiogenesis in ECs, as a single vessel may support the growth of numerous tumor cells by providing them with oxygen, nutrients and growth factors produced by surrounding ECs.
The inhibition of EC proliferation, migration, and an increase in EC apoptosis by anti-angiogenic agents may lead to the destruction of blood vessels, which may additionally initiate tumor necrosis.
ECs, endothelial cells. At present, anti-angiogenic cancer gene therapies primarily adopt the following two principles: Gene augmentation; and gene blockade. The former involves introducing exogenous anti-angiogenic genes into targeted cells so that through their expression tumor angiogenesis is halted, while the latter results in the inhibition of the excessive expression of pro-angiogenic genes in endothelial cells, and other tissue cells, of the tumor.
Therefore, the genes of interest may be divided into equivalent categories: Anti-angiogenic genes utilized for gene augmentation; and pro-angiogenic genes for gene blockade Fig. Principles of anti-angiogenesis gene therapy. The flowchart depicts the two major principles of anti-angiogenic gene therapy.
It highlights the major differences between the principles, and indicates representative examples in each category. IL, interleukin 12; sFlt-1, soluble fms-like tyrosine kinase-1; sFlk-1, soluble form of vascular endothelial growth factor receptor 2; VEGF, vascular endothelial growth factor, siRNA, small interfering RNA; VEGFR, VEGF receptor.
With the development of biotechnology and an improved understanding of angiogenesis mechanisms, numerous pro- and anti-angiogenesis genes have been identified and utilized in studies investigating cancer gene therapy 63 As various papers have already reviewed a number of these anti-angiogenic molecules 63646869only the most commonly discussed inhibitors will be examined in this paper, to avoid repetition.
IL, first recognized as a pro-inflammatory cytokine with immunoregulatory functions 7071has been suggested to exert an anti-angiogenesis effect in several experiments 72 — Due to its ability Anti-angiogenesie stimulate immunity and inhibit tumor angiogenesis, IL thera;y been identified Anti-angiogfnesis one of the most potent antitumor candidates not only for cancer immunotherapy 75but also for anti-angiogenic therapy Although previous evidence has indicated its anti-tumor activities in in vitro and in vivo experiments 77the anti-tumor effect of IL evidently varies thegapy mouse strains 78and the mechanism that leads to the various responses remains unclear.
Although unsatisfactory side effects, including toxicity, have been identified in several early clinical trials using systemically delivered recombinant human IL rhIL 79 — 81interests in gene therapy approaches have increased due to its potential in achieving high drug concentrations in the local tumor environment, with low systemic levels.
Apart from several early clinical trials of gene therapy using IL in previous decades, a more recent study provided long-term overall survival results from a phase I study of intratumoral electroporation EP Anti-angiogenseis plasmid p IL, which was completed in 24 patients with malignant melanoma.
This study suggested that improved survival is correlated with systemic disease stabilization with pIL EP Concurrently, certain gene therapies involving IL use different delivery systems to explore therapeutic methods with low systematic toxicities, high tumorous specificities and sustained local expression of IL, such as plasmid 8485HSV-1 86Semliki forest virus vector 87T-cells 88a novel helper-dependent adenoviral vector 89 and Lactococcus lactis Other strategies in previous studies have focused on combining IL with other anti-tumor genes, including suicide genes 91or other therapies, such as chemotherapy 92to explore its preclinical efficacy and safety prior entry of these methods into clinical trials.
MDA-7, also termed IL, was identified through subtraction hybridization from a human melanoma cell line 93and has demonstrated efficacy as a potent tumor suppressor gene in initial studies in the s 93 — As an theerapy agent, MDA-7 functions through diverse modalities, including anti-angiogenesis 96tumor-specific apoptosis 97 and immunotherapeutic activity In an additional study, the human MDA-7 gene was transfected into the human laryngeal cancer Hep-2 cell line and human umbilical vein endothelial cells with adenovirus vectorand the results demonstrated that MDA-7 exerted anti-tumor functions in the laryngeal carcinoma cell lines, whereas no harmful effect was observed in the healthy cells.
As for gene delivery, a study has introduced a method for increasing the expression level of MDA-7 in osteosarcoma OS using a novel oncolytic adenovirus, where an increased sensitivity of OS to doxorubicin induced by MDA-7 was also observed Finally, 3 vectors expressing MDA-7 in sollid with the arginine-glycine-aspartic acid RGD peptide, which is considered to exhibit the most significant effect on the binding specificity of integrin receptors, were constructed.
With a stronger expression potency observed and integrity validated, MDA-7 with RGD peptide appears to be a more appealing therapeutic option, when compared with the administration of MDA-7 aloneindicating a future direction for cancer gene therapy.
: Anti-angiogenesis therapy for solid tumors| Cancer combination therapies by angiogenesis inhibitors; a comprehensive review | Cancer 87, — Combining radiotherapy with targeted therapies in non-small cell lung cancer: focus on anti-EGFR, anti-ALK and anti-angiogenic agents. Expression Profile of IL-8 and Growth Factors in Breast Cancer Cells and Adipose-Derived Stem Cells ASCs Isolated from Breast Carcinoma. Why would clinical benefits be achieved by combining anti-angiogenic drugs with chemotherapy? It has high selectivity for VEGFR2. Alternatively, low pericyte coverage detected in the vasculature of certain tumors reduces vascular stability and increases vascular permeability which impairs the delivery of anticancer therapies to tumor cells and allows them to metastasize Meng et al. Angiogenesis of Breast Cancer. |
| Author information | Moreover, EPCs are involved in the angiogenic switch from micro-metastasis to macro-metastasis. J Clin Oncol 30 17 — Neuro Oncol 12 3 — Article CAS PubMed PubMed Central Google Scholar Kim KJ, Li B, Winer B, Armanini M, Gillett N, Philips HS, et al. A Double-Blind, Randomised, Placebo-Controlled, Phase 2b Study Evaluating Sorafenib in Combination with Paclitaxel as a First-Line Therapy in Patients with HER2-Negative Advanced Breast Cancer. Li X, Liu YH, Lee SJ, Gardner TA, Jeng MH and Kao C: Prostate-restricted replicative adenovirus expressing human endostatin-angiostatin fusion gene exhibiting dramatic antitumor efficacy. |
| Future options of anti-angiogenic cancer therapy | Nehad M. J Clin Oncol 26 12 — Tumor, robust Anti--angiogenesis Greek yogurt for digestion tumor proliferation was achieved from the addition of the angiogenesis inhibitor TNP to RT in SCC xenografts more evidently than monotherapy with each approach [ ]. The role of the EGFR signaling in tumor microenvironment. Cancer Immunol Immunother. The progression of the canceration through angiogenesis. |
| New approaches to antiangiogenesis therapy of solid tumors | In normal tissue, tight pericyte coverage and vascular endothelial cell junction ensure regular blood circulation, forming a mature vascular structure. Besides, fragile and highly permeable tumor vessels, which have an irregular arrangement of endothelial cells and thinly covered pericytes, lead to blood leakage and incoherent perfusion. Tumor angiogenesis occurs mainly through any of the following modes described in Fig. Among them, sprouting angiogenesis is the most typical process in physiological and pathological angiogenesis. The patterns of vessel co-option and vessel mimicry are significantly related to tumor invasion, metastasis, and therapeutic resistance in conventional anti-angiogenic therapy. Sprouting angiogenesis is so-called angiogenesis, in which new vascular branches form in existing blood vessels and finally infiltrate into tumor tissue through the migration of tip cells and the proliferation of stem cells Fig. Most common modes in tumor angiogenesis. a Sprouting angiogenesis: main way in both physiological and pathological angiogenesis, which is induce by proliferation and migration of endothelial tip cells. b Intussusception: the existing blood vessel is divided into two vessels under mediation of cell reorganization. c Vasculogenesis: bone-marrow-derived endothelial progenitor cells differentiate into endothelial cells, participating in the formation of new vascular lumen. d Vessel co-option: tumor cells approach and hijack the existing blood vessels. e Vessel mimicry: tumor cells form a vessel-like channel around normal blood vessels to direct the transport of oxygen and nutrients into tumor tissue. f Trans-differentiation of cancer cells: cancer stem-like cells differentiate into endothelial cells, which participate in the formation of new blood vessels. Modified from Carmeliet, P. Molecular mechanisms and clinical applications of angiogenesis. Nature , — Various biomolecules that promote or inhibit angiogenesis constitute a complex and dynamic angiogenic system, including growth factors such as vascular endothelial growth factor, fibroblast growth factor, transforming growth factor, hepatocyte growth factor , adhesion factors integrin, cadherin , proteases such as matrix metalloproteinase , extracellular matrix proteins fibronectin, collagen , transcription factors hypoxia-inducible factor, nuclear factor , signaling molecule mechanistic target of rapamycin mTOR , protein kinase B AKT , p38 mitogen-activated protein kinases p38 MAPK , nitric oxide NO , angiopoietin, thrombospondin-1, angiostatin, endostatin, and interleukin IL. Schematic diagram showing crosstalk of multiple signaling pathways during tumor angiogenesis. Pointed arrows indicate activation whereas flat arrows indicate inhibition. VEGF family consists of seven members, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, placental growth factor PlGF , and non-human genome encoded VEGF-E and svVEGF. Blocking this pathway leads to apoptosis of lymphatic endothelial cells and disruption of the lymphatic network. The tyrosine kinase receptor VEGFRs consist of a transmembrane domain, an extracellular ligand-binding domain with an Ig-like domain, and a tyrosine kinase with an intracellular domain. However, as a promoter, over-expressed VEGFR-1 facilitates the development and metastasis of breast cancer, leukemia, prostate cancer, ovarian cancer OC and malignant melanoma. A factor secreted by platelets and some stromal cells, which participates in coagulation or angiogenesis, is known as platelet-derived growth factor PDGF. As the main mitogen of mesenchymal cells such as fibroblasts, smooth muscle cells, and glial cells, PDGF involves in cell growth and differentiation, wound healing, angiogenesis, recruitment, and differentiation of pericytes and smooth muscle cells through paracrine or autocrine. PDGFs have four soluble inactive polypeptide chains, including PDGF-A, PDGF-B, PDGF-C, and PDGF-D, which perform biological functions after being translated into active homodimers or heterodimers such as PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, PDGF-DD. PDGF-AB promotes mitosis and chemotaxis. PDGFRs including PDGFR-α and PDGFR-β are membrane-bound proteins consisting of a transmembrane domain, a juxtamembrane domain, a kinase insertion domain, an intracellular domain, and five extracellular Ig-like domains. Epidermal growth factor EGF is a single-chain small molecule polypeptide composed of 53 amino acid residues. EGF is a mediator widely participates in cell growth, proliferation, differentiation, migration, adhesion, apoptosis, and tumor angiogenesis through EGFR. As a critical factor in promoting wound healing, the fibroblast growth factor FGF family is one of the potent mitogens and drivers of endothelial cells and is the earliest discovered growth factor related to angiogenesis, which consists of 23 proteins with different structures. FGFR is a transmembrane receptor family with five members of FGFR1—5 only FGFR5 lacks an intracellular kinase domain , whose genes are proto-oncogenes with tumorigenic potential after gene amplification, chromosomal translocation or point mutation. The hepatocyte growth factor known as the scattering factor is a multi-effect precursor protein and a mitogen of mature rat hepatocytes, mainly derived from mesenchymal cells and activated by extracellular protease cleavage. α chain is responsible for binding receptors while β chain can trigger receptors and transduce signals. Insulin-like growth factor IGF is a peptide growth factor that regulates human growth, development, and energy metabolism, which participates in physiological circulation through autocrine, paracrine, and endocrine. Besides, autocrine IGF2 induces drug resistance in anti-tumor therapy. IGFBPs are high-affinity receptors of IGF, with six subtypes of IGFBP1—6, secreted by endothelial cells living in macro-vessels and capillaries. In , a signaling protein with multiple biological effects, named transforming growth factor-β TGF-β , was discovered by scientists in mouse fibroblasts. TGF-β is a secreted cytokine that is concerned with body homeostasis, tissue repair, inflammation, and immune responses, which is also involved in cell growth, differentiation, proliferation, autophagy, apoptosis, and tumor angiogenesis. The tumorigenic effects of TGF can be manifested in various modes. Firstly, TGF-β induces the migration of endothelial cells to impel vessel sprouting. For example, high tissue concentrations of TGF-β have been detected in human pancreatic cancer, , , , NSCLC, HCC, , , and BC, which motivates tumor progression and angiogenesis, leading to unsatisfactory clinical outcomes. Accordingly, TGF-β simultaneously promotes tumorigenesis and induces angiogenesis to nourish tumors. Perhaps TGF-β is the next breakthrough to fight against tumor angiogenesis and drug resistance. Hypoxia is the most typical feature of the tumor microenvironment and is always associated with drug resistance, tumor angiogenesis, aggressiveness, and recurrence. Under normoxic conditions, the proline residues in HIF-1α are hydroxylated by the proline hydroxylase domain PHD , which can stabilize HIF-1α. Subsequently, HIF-1α is degraded by proteasomes after ubiquitination mediated by E3 ubiquitin ligase and ρVHL. Besides, hydroxylation of asparagine residues, which regulates HIF-1α transcriptional activity and specificity, disrupts the interaction between HIF-1α and co-activation factor p to inhibit the transcriptional activity of HIF-1α, consequently inhibiting the expression of VEGF and angiogenesis Fig. This complex binds the hypoxia response element HRE located on the HIF target after interacting with the coactivator p, subsequently activating the transcription of the downstream target genes that encode VEGF, MMPs, angiopoietin, and PDGF Fig. The complicated process enhances the affinity and invasiveness of tumor cells, induces apoptosis of epithelial cells, inhibits apoptosis of tumor cells, and promotes tumor angiogenesis. The transduction of HIF-1α in normal and hypoxic conditions. Under normal conditions, HIF-1α is degraded by protease and loses transcription function. In hypoxic environment, lack of enzyme degradation leads to efficient transcription of HIF-1α, resulting in over-expression of pro-angiogenic factors including VEGF, PDGF, and MMPs. In tumor progression, the expression of related genes of all VEGF isoforms, PlGF, FGF, PDGF, and Ang-1 can be up-regulated by HIF-1α to promote tumor angiogenesis or induce drug resistance. HIF-1α also up-regulates TGF-β, PDGF, and CXCL2 secreted by tumor cells and macrophages, which prompt the reconstruction of extracellular matrix and impel the invasion and metastasis of tumors induced by tumor-associated fibroblasts TAFs. Being discovered in , the nuclear factor κB NF-κB is an important transcription factor in the human body, and is involved in cell survival, oxidative damage, inflammation, immune responses, and angiogenesis. A coiled-coil amino-terminal domain and a carboxy-terminal fibrinogen-like domain constitute the angiopoietin, which maintains quiescent endothelial cells homeostasis and blood vessels morphology and involves in new blood vessels formation, embryonic development, and tumor angiogenesis. Angiopoietins consist of four ligands, Ang-1, Ang-2, Ang-3, and Ang The transmembrane protein Tie is a specific receptor family of Ang with high affinity. Tie-2 known as TEK is a commonly studied receptor that mediates the functions of angiopoietin. Ang-1 is a bifunctional protein and is mainly secreted by pericytes, smooth muscle cells, tumor cells, and others around endothelial cells to mediate vessel remodeling and vascular stabilization. Ang-2 may exert pro- or anti-angiogenic activities in different environments based on dynamic concentrations of VEGF-A. Stimulated by VEGF-A, Ang-2 promotes angiogenesis and pericyte shedding to disturb vascular stability through competitively binding Tie-2 and integrin receptors. However, under a low concentration of VEGF-A, Ang-2 induces apoptosis and vascular degeneration to inhibit tumor growth. Notch receptors are a kind of particular non-RTK proteins that engage in numerous cellular processes, like morphogenesis, proliferation, migration, differentiation, apoptosis, adhesion, EMT, and angiogenesis Fig. Among the Notch family, Dll-4 and Jag-1 are the most representative ligands in tumor angiogenesis. Additionally, hypoxia is one of the causes of cancer metastasis, and the interaction between Dll-4 and HIF-1α significantly upregulates the expression of Dll-4 and aggravates hypoxia, promoting the aggressiveness of cancer cells. The progression of various malignant tumors such as leukemia, BC, HCC, CC, and cholangiocarcinoma is highly linked to the over-expression of Jag For example, EphrinB2 is over-expressed in ovarian cancer, kidney cancer and melanoma, whereas EphrinA3 is up-regulated in squamous cell lung carcinoma SCLC and colon cancer. Integrins are major adhesion factors in the extracellular matrix, which engage in various cellular processes in the human body by regulating signaling transduction between cells and of these cells with the surrounding matrix Fig. Under the mediation of soluble ligands, extracellular matrix ECM , or cell surface bound ligands including growth factors, proteases, cytokines, structural constituents of the ECM like collagen and fibronectin , plasma proteins, microbial pathogens, or receptors specific to immune cells, integrin plays a pivotal role in cell homeostasis, immunity, inflammation, infection, thrombosis, lymphangiogenesis, angiogenesis, and tumorigenesis within the complex human internal environment. In tumor angiogenesis, over-expressed α v integrins can be exploited by carcinomas to fight for vascular and stromal resources to encourage tumor progression and canceration. α v β6 integrin is the first adhesion factor among α v integrins shown to have angiogenic effects and is widely expressed on activated vascular ECs within remodeling and pathological tissues. α v β 3 is an indispensable factor in angiogenesis initiated by bFGF and TNF-α signaling pathways, while α v β 5 is required for angiogenesis mediated by TGF-α and VEGF. For example, α 4 β 1 maintains the stability of endothelial cells and pericytes under the mediation of pro-angiogenic factors VEGF, bFGF, and TNF-α to support tumor angiogenesis. Matrix metalloproteinases MMPs are a family of zinc- and calcium-dependent endopeptidases secreted by connective tissue and stromal cells, like fibroblast, ECs, macrophages, osteoblasts, lymphocytes and neutrophils Fig. All members within the MMPs family are precursor enzymes that require proteolysis to be effective, including collagenases, gelatinases, stromelysins, matrilysins, and MMP membrane-type MT -MMPs. MMP-1 is an interstitial or fibroblast-type collagenase that degrades interstitial types I-III collagen, whereas MMP-7 is a matrilysin. MMP-1 releases bFGF by degrading the basement membrane to induce tumor angiogenesis, while MMP-7 mediates ECs proliferation and up-regulates the expression of MMP-1 and MMP-2 to encourage tumor angiogenesis. MMP-expressing stromal cells and functions of MMPs in tumor microenvironment. MMP precursors which are secreted by endothelial cells, fibroblasts, and lymphocytes et al. converted into active MMPs through enzymolysis. Subsequently, active MMPs participate in different biological processes including angiogenesis and tissue invasion by degrading specific extracellular matrix components. Actually, the expression level of MMPs is maintained in a dynamic balance under the antagonism of endogenous tissue inhibitors of matrix metalloproteinases TIMP , a family of multifunctional proteins. In addition to stabilizing MMPs, TIMPs are involved in erythrocyte proliferation and cell growth, including soluble TIMP-1, TIMP-2, TIMP-4, and insoluble TIMP As a potent inhibitor of endogenous angiogenesis, angiostatin is a partial fragment of plasminogen that potently inhibits ECs proliferation. In an intricate angiogenic system, almost all biomolecules act in interrelated manners to activate the proliferation, survival, migration, and morphogenesis of target cells to excite tumor angiogenesis. Apart from the factors above and downstream pathways shown in Fig. The specific roles and mechanisms of these biomolecules in angiogenesis and tumorigenesis will gradually be explored by researchers. At present, this theory has been extended to various non-neoplastic diseases such as cardiovascular disease, rheumatoid arthritis RA , and diabetic retinopathy. The formation of new blood vessels has been observed since the earliest time, especially wound healing. But this process has only ever been regarded as a simple pathological or physiological process unrelated to malignancies. In the s, some researchers have observed the development of blood vessels presents as a scattered pattern of branches, , and pathologist Virchow also described a rich vascular network in tumors in his Die Krankhaften Greschwulste. Although this hypothesis attracted little scientific interest, Folkman persisted research and successfully cultured ECs in capillaries, which facilitated multiple classical angiogenic models, such as chick chorioallantoic membrane CAM and corneal transplantation models. Until , Senger et al. discovered that vascular permeability could be enhanced by a substance derived from tumors named vascular permeability factor VPF , which was shown to have a strong angiogenic effect in subsequent scientific research, and was re-named as vascular endothelial growth factor VEGF. and named as basic fibroblast growth factor bFGF. Followed by some major events in the field of angiogenesis: discovery to withdrawal of drugs such as TNP, the discovery of the anti-angiogenic effect of thalidomide, and the development of angiostatin and endostatin, the theory of tumor angiogenesis was generally accepted, and more researchers devoted to anti-angiogenic therapy. In earlier studies, scientists believed that serious toxic effects and drug resistance would not develop in anti-angiogenic therapy because angiogenic inhibitors targeted genetically stable vascular ECs rather than tumor cells. Although some positive results were achieved, the clinical benefits did not meet expectations, the PFS rates of patients improved modestly, the improvement of OS rates were minimal, and even in some failed cases, it was observed that the toxicity suffered by the patients far more than the treatment effects. For example, in November , the FDA withdrew the approval of bevacizumab Avastin ® for the treatment of HER2 negative metastatic BC based on four disappointing clinical trials: serious adverse events like hypertension and organ failure and minimal treatment benefits among BC patients treated with bevacizumab. Although numerous perspectives and reflections rose in anti-angiogenic therapy, , proponents continued anti-angiogenic research and found that excessive limitation of angiogenesis not only affects the transportation of drugs but also exacerbates pathological manifestations of TME, inducing stronger hypoxic responses and aggressiveness of tumor, and eventually causing drug resistance or even cancer metastasis. In the s, Rakesh K. As a result, the functional and morphological characterizations of the vessels are restored to a more normal condition, and the TME is more stable, finally improving drug transportation and delaying drug resistance and aggressiveness. Li et al. comprehensively evaluated imaging methods that commonly used to detect vascular changes in tumor tissue. Zheng et al. suggested some promising strategies to optimize vascular normalization. The timeline of milestones regarding the research on tumor angiogenesis are shown in Fig. Diagramatic illustrations of the relationship between tumor blood vessels, pro-angiogenic and anti-angiogenic factors. a Blood vessels with regularity and completeness depend on dynamic balance of pro-factors and anti- factors in normal tissues. b Abnormal vessels with chaos, leakage and feeble blood circulation are caused by imbalance of mediators in tumor tissue. c Blood vessels are repaired through neutralizing abundant pro-factors or increasing anti-factors under the guidance of angiogenic inhibitors. d Blood vessels in tumor tissue are destroyed by excessive inhibitors, which aggravates hypoxia within tumor tissue and hinders drug transportation. Anti-angiogenic therapy is achieved by inhibiting tumor growth and metastasis through anti-angiogenic drugs to limit the blood supply to tumor tissue. Among them, recombinant monoclonal antibodies and small molecule tyrosine kinase inhibitors are the mainstream drugs used in anti-angiogenic treatment. Inhibitors approved for anti-angiogenic therapy are summarized in Table 1 , and potential agents evaluated in clinical trials are described in Table 2. Monoclonal antibodies are derived from artificially prepared hybridoma cells, which have the advantages of high purity, high sensitivity, strong specificity, and less cross-reactivity. When compared with kinase inhibitors, these immanent unique advantages in clinical treatment are comparatively beneficial to patients. The most representative antibody is bevacizumab Avastin ® Table 1. In , anti-VEGF monoclonal antibody trials demonstrated that inhibitors targeting VEGF could decrease tumor growth, provoking scientists to investigate the clinical efficacy of bevacizumab. Known as the first formal angiogenic inhibitor, bevacizumab is a macro-molecular recombinant human monoclonal antibody that obstructs the transduction of VEGF pathway by neutralizing all VEGF isoforms to inhibit tumor angiogenesis. In addition to the first indication, bevacizumab has been approved for a variety of other cancers as monotherapy, as a surgical adjuvant, or in combination with chemotherapy, and more potential in anti-angiogenic therapy is being tested through clinical trials. For example, the combination of bevacizumab, carboplatin, and paclitaxel or gemcitabine was approved by FDA for later treatment after bevacizumab monotherapy in platinum-sensitive recurrent epithelial ovarian cancer in placebo 3. placebo 1. Furthermore, it prolonged the median OS 9. Additionally, the first-line therapy for metastatic CRC is a combination of ramucirumab and a modified FOLFOX-6 regimen mFOLFOX-6 , which demonstrated gratifying safety and efficacy in a phase II clinical trial NCT In a randomized ANNOUNCE clinical trial among patients, the addition of olaratumab did not significantly improve the OS rate doxorubicin plus olaratumab doxorubicin plus placebo Bevacizumab-awwb Mvasi ® is the first anti-tumor biosimilar of bevacizumab approved by FDA. Ranibizumab is a prevalent anti-angiogenic agent in treating oculopathy Table 1. Oligonucleotides are nucleic acid polymers that regulates gene expression and have specially designed sequences, including antisense oligonucleotides ASOs , siRNA small interfering RNA , microRNA and aptamers. Fusion proteins are complexes from binding the Fc segment of immunoglobulin to a biologically active functional protein molecule through genetic engineering technology. Aflibercept Eylea ® is a recombinant decoy receptor targeted VEGF, which is combined of the extracellular VEGFR domain VEGFR-1 Ig2 region and VEGFR-2 Ig3 region and the Fc segment of human immunoglobulin G1 IgG1 and has long half-life in anti-angiogenesis Table 1. Aflibercept inhibits the binding and activation of the VEGF family and natural VEGFR by specifically blocking VEGF-A and most proangiogenic cytokines, thereby inhibiting division and proliferation of ECs, reducing vascular permeability, and is commonly used in non-neoplastic angiogenic disease like AMD, DR, and DME. It has been approved by FDA for the treatment of metastatic CRC patients who are resistant to or have progressed following an oxaliplatin-containing regimen. Everolimus RAD is an oral analog of rapamycin that inhibits proliferation and induces apoptosis and autophagy of tumor cells through indirectly blocked mTOR Table 1. Thalidomide Thalomid ® was synthesized by the CIBA pharmaceutical company in and was initially used for mitigating morning sickness as a non-addictive and non-barbiturate tranquilizer Table 1. But the research on thalidomide was not terminated, in , thalidomide was approved for erythema nodosum leprosum ENL after a series of pharmacological studies. Lenalidomide Revlimid ® was invented to reduce toxicity and enhance efficiency of thalidomide, which can specifically inhibit the growth of mature B cell lymphomas like MM and induce IL-2 release from T cells Table 1. Since the first kinase inhibitor imatinib significantly reduced adverse events and improved the prognosis of patients with chronic myeloid leukemia CML in , the importance of kinases in tumorigenesis has attracted wide attention. Originally defined as a Raf inhibitor, sorafenib was obtained from a long period of high-throughput screening HTS and four-step structural modification. As the first anti-angiogenic small molecule tyrosine kinase inhibitor, sorafenib remarkably promoted the subsequent development and clinical research of anti-angiogenic small molecule agents, in order to enhance the selectivity and efficacy of the drugs and reduce toxicity. Regorafenib is a potent VEGFR-2 inhibitor with pyridine carboxamide derived from sorafenib structural modifications Table 1. Up to now, cabozantinib has been ratified for several most common angiogenic carcinomas NCT, NCT In recent years, research on highly selective targeted drugs has also made considerable progress in anti-angiogenic therapy Table 2. Individual drugs have successfully passed preliminary clinical trials about the safety, tolerability and effectiveness of drugs, and entered into phase III or even phase IV clinical evaluation, such as bemarituzumab FPA , avapritinib and erdafitinib. Bemarituzumab FPA is the first recombinant humanized IgG1 monoclonal antibody Table 2 , which obstructs ligand binding and downstream signaling activation by blocking the IgG III region of the FGFR-2b isoform. Owing to this natural property of lacking the FUT8 gene, bemarituzumab can enhance antibody-independent cell-mediated cytotoxicity ADCC against tumor models with FGFR-2b over-expression. In the early phase I clinical trials NCT, NCT , the desirable safety, tolerance and pharmacokinetic characterization of bemarituzumab was demonstrated in gastrointestinal adenocarcinoma GEA and GC patients with FGFR-2b over-expression, leading to phase II clinical trial of bemarituzumab. Avapritinib BLU is a selective and oral kinase inhibitor that targets PDGFR-α and c-Kit Table 2 , which has been approved by FDA for GIST, systemic mastocytosis, and solid tumors, especially for adult patients with metastatic or unresectable GIST carrying PDGFR-α 18 exon mutations. The launch of avapritinib resulted in an unprecedented, durable clinical benefit to GIST patients with PDGFRA DV -mutation. The most common adverse events include nausea, vomiting, decreased appetite, diarrhea, fatigue, cognitive impairment, hair color changes, lacrimation, abdominal pain, constipation, rash, and dizziness. The clinical potency of erdafitinib in NSCLC, lymphoma, cholangiocarcinoma, liver cancer, prostate cancer, esophageal cancer, or other carcinomas is undergoing investigation. Common adverse events include hyponatremia, oral mucosal disease, and weakness, but no treatment-related deaths. Moreover, these FGFR inhibitors inhibits cell proliferation in FGFR-addicted cancer cells with FGFR aberrations such as gene amplification, activating mutations and chromosomal translocations. In addition to the marketed and clinically evaluated anti-angiogenic drugs described previously, some novel TKIs have shown potent biological activity in the initial evaluation in kinase assay, which may be promising to become clinical candidates. Like compounds 23, 24 , and 25 , are selective inhibitors with good inhibitory activity targeted HIF-α. TME is a highly complex ecosystem of cellular and noncellular components, which is broadly related to tumor invasion and recurrence. Angiogenic inhibitors used in cancer therapy by affecting the formation of new blood vessels in tumors, which have expended a new field for the treatment of a wide range of solid tumors. However, there are still some shortcomings in anti-angiogenic therapy due to the complex mechanisms of tumor angiogenesis and limited research, including tumor relapse, drug resistance, , lack of bio-markers, short-acting efficacy, 27 , 28 and several serious adverse events. It was initially assumed that anti-angiogenic therapy might not be toxic compared with other chemotherapeutic agents owing to genetic stability and quiescence of ECs under normal physiological conditions and the selectivity of targeted drugs. However, this was proved to be a miscalculation. Common serious adverse events such as hypertension, proteinuria, lymphopenia, thrombocytopenia, leukopenia, neutropenia, and some physical abnormalities caused by different drugs have appeared in a number of different clinical treatments Table 1 , which may affect the tolerance of patients and even lead to treatment termination. In addition, angiogenic inhibitors have a result on controlling growth and spread of tumor in the short term by blocking the blood supply which is manifested in clinical treatment as increased PFS , but the long-term result is an increased risk of tumor local invasion and distant metastasis induced by hypoxia, as well as the probability of revascularization and tumor resurgence after discontinuation of sustained treatment which manifests as an insignificant or even unchanged increase in OS. Drug resistance is a dominant difficulty that consistently limits the clinical outcomes in targeted anti-angiogenic therapy, which can be divided into congenital resistance and acquired resistance Fig. Acquired drug resistance has been comprehensively analyzed by researchers through cytological and molecular studies. These unique mechanisms include: a upregulation of compensatory pro-angiogenic signaling pathways in tumor tissue HGF, bFGF, VEGF-C, PlGF, angiopoietins, and Dll-4 have been widely testified that upregulated in various tumors with drug resistance ; , , b recruiting bone marrow-derived endothelial progenitor cells, pericyte progenitor cells, tumor-associated macrophages, and immature monocytic cells, which can maintain the formation of blood vessels; c recruitment of perivascular cells like pericytes , which can cover immature tumor blood vessels to prevent destruction by anti-angiogenic drugs; d unconventional angiogenic processes like vessel co-option, , , , vessel mimicry and intussusceptive angiogenesis. Mechanisms of drug resistance in anti-angiogenic therapy. Some patients are intrinsically non-responsive to anti-angiogenic therapy while other patients who are initially responsive acquire adaptive resistance. The mechanisms that manifest acquired resistance to anti-angiogenic therapy include: compensatory upregulation of alternative pro-angiogenic factors such as bFGF, PDGF, and PlGF within the tumor; recruitment of bone marrow-derived endothelial progenitor cells to facilitate neovascularization; increased pericyte coverage protects tumor blood vessels; autophagy helps tumor cells thrive in a hypoxic environment; increased invasiveness of the tumor promotes the distant metastasis and invasion of tumor cells through blood and lymphatic circulation. In addition, genetic mutations, vessel mimicry, vessel co-option, and intussusception angiogenesis also contribute to drug resistance. The application of biomarkers is a powerful adjuvant means which are essential for disease identification, early diagnosis and prevention, and drug treatment monitoring. Biomarkers refer to biochemical indicators of normal physiological or pathogenic processes to furnish the structural or functional changes of systems, organs, tissues, cells and subcells, and can also be used for disease diagnosis, disease stage, or evaluating the safety and efficacy of a drug or regimen among targeted population. For example, HER2 is a diagnostic indicator for breast cancer typing, and levels of PD-L1 is used to predict the efficacy of immune checkpoint inhibitors ICIs. Despite considerable efforts, there are few biomarkers responding to angiogenesis approved for clinical application. With the advancement in bio-analytical technology and clinical bio-chemistry, tissue and cell concentrations of some angiogenic mediators, circulating ECs, circulating progenitor cells, CT imaging of blood flow and blood volume have been shown to have potential as biomarkers, but more clinical trials are needed to validate their prospective. Developing efficient biomarkers for diagnosing the progression and stage of cancer and identifying mechanisms of tumor angiogenesis and drug resistance, in order to benefit drug selection, balance efficacy and toxicity, and simplify anti-cancer therapy. Actually, due to numerous factors such as the complexity of tumor angiogenesis, heterogeneity and variability of tumors, the unpredictability of response or toxicity, and limitations of preclinical and clinical trials, the development of biomarkers will be a great challenge. Since the first angiogenic inhibitor bevacizumab approved for treatment, combination therapy based on anti-angiogenic agents has infiltrated anti-tumor field. Diversified methods in anti-cancer therapy provide more options for clinical treatment and make strong alliances possible. In recent several years, one of the prevalent research direction is the combination of angiogenic inhibitors and immune checkpoint inhibitors, in which better clinical benefits from HCC and RCC patients treated with programmed cell death 1 PD-1 and VEGFR-2 inhibitors than with monotherapy. At the same time, it can neutralize excess VEGF, reconstruct the vascular system of tumor tissue, normalize vascular network, promote the blood transport of immunosuppressant, inhibit excessive angiogenesis, reduce microvascular density, and limit tumor growth, invasion and metastasis. Some optimistic results of combination therapy have been achieved in recent years shown in Table 4. For example, in a phase III clinical trial NCT , the combination of bevacizumab with PD-1 inhibitor atezolizumab significantly improved the OS and PFS rates of unresectable HCC patients compared to sorafenib. As mentioned before, although it has more damage to normal cells, blood vessels and immune system due to the administration with maximum tolerated dosage and poor tissue selectivity, chemotherapy is an irreplaceable method for many advanced patients with cancer metastasis to prolong the survival. Some relevant clinical trials with positive outcomes have been shown in Table 4. For example, a phase III clinical trial NCT have shown that the addition of atezolizumab anti-PD-L1 greatly extended the OS Another notable therapeutic method is an emerging adjuvant strategy - neoadjuvant chemotherapy NACT , aiming to reduce the tumor and kill invisible metastatic tumor cells through systemic chemotherapy to facilitate subsequent surgery, radiotherapy, and other treatments. Up to now, various NACT regimens SOX, XELOX, FOLFOX have been suggested with satisfactory clinical results in primary or advanced tumors and lower risk of progression, but some discouraging clinical evidence of NACT also observed in recent years especially breast cancer. summarized a number of potential mechanisms of chemoresistance in NACT, wherein, it is reported that NACT could stimulate cancer metastasis through inducing angiogenesis, lymphangiogenesis and inflammatory infiltration, altering immune responses and worsening TME, and these changes may induce secondary chemoresistance. Theoretically, it is promising, but massive efforts are also necessary, some clinical trials are already underway NCT, NCT, NCT, NCT, NCT Apart from the means above, exploiting novel selective multi-targeted kinase inhibitors is one of the current trendy research directions. In tumor angiogenesis, various angiogenic tyrosine kinases act synergistically to induce an array of intracellular signaling cascades instead of working individually. In normal tissue, anti-angiogenic molecules can balance the pro-angiogenic factors to maintain the homeostasis of the internal environment. The active angiogenesis in tumor tissue is related to the over-activation of pro-angiogenic factors and the over-inhibition of anti-angiogenic mediators. Hence, endogenous anti-angiogenic components or their derivatives may be conducive to vascular normalization and therapeutic efficiency. Recombinant human endostatin is an angiogenic inhibitor with no cytotoxicity approved by the Chinese FDA for treating various cancers, including NSCLC. Angiogenesis is one of the key conditions for the proliferation, invasion, and metastasis of carcinomas and anti-angiogenic treatment has gradually become a prevalent anti-tumor strategy with a criterion of vascular optimization. But some common issues that cannot be ignored remain to be solved such as insufficient therapeutic efficacy, reproducibility and popularization of treatment modalities. With an in-depth understanding of tumor angiogenesis, tumor microenvironment, and drug resistance, these problems may be solved in the near future. As an emerging strategy, anti-angiogenic therapy will achieve more clinical benefits for cancer patients and anti-tumor therapy, and facilitate the clinical treatment of non-neoplastic angiogenesis-related diseases as well. Larionova, I. New angiogenic regulators produced by TAMs: perspective for pargeting tumor angiogenesis. Cancers 13 , Article CAS PubMed PubMed Central Google Scholar. Duran, C. et al. Molecular regulation of sprouting angiogenesis. Article PubMed Google Scholar. Teleanu, R. Tumor angiogenesis and anti-angiogenic strategies for cancer treatment. Article PubMed PubMed Central Google Scholar. Folkman, J. Angiogenesis: an organizing principle for drug discovery? Drug Discov. Article CAS PubMed Google Scholar. Smolen, J. New therapies for treatment of rheumatoid arthritis. Lancet , — Creamer, D. Costa, C. Angiogenesis and chronic inflammation: cause or consequence? Angiogenesis 10 , — Caldwell, R. Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Diabetes Metab. Ng, E. Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration. Khosravi Shahi, P. Tumoral angiogenesis and breast cancer. Zhong, M. TIPE regulates VEGFR2 expression and promotes angiogenesis in colorectal cancer. Hall, R. Angiogenesis inhibition as a therapeutic strategy in non-small cell lung cancer NSCLC. Lung Cancer Res. CAS PubMed PubMed Central Google Scholar. Zimna, A. Hypoxia-inducible factor-1 in physiological and pathophysiological angiogenesis: applications and therapies. Conway, E. Molecular mechanisms of blood vessel growth. Kalluri, R. Basement membranes: structure, assembly and role in tumour angiogenesis. Cancer 3 , — Gasparini, G. Angiogenic inhibitors: a new therapeutic strategy in oncology. Article CAS Google Scholar. Adams, R. Molecular regulation of angiogenesis and lymphangiogenesis. Cell Biol. Jain, R. Molecular regulation of vessel maturation. Rowley, D. What might a stromal response mean to prostate cancer progression? Cancer Metastasis Rev. Liakouli, V. The role of extracellular matrix components in angiogenesis and fibrosis: possible implication for Systemic Sclerosis. Shiga, K. Cancer-associated fibroblasts: their characteristics and their roles in tumor growth. Cancers 7 , — Roland, C. Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts. Cancer Ther. Ribatti, D. Immune cells and angiogenesis. Med 13 , — Parmar, D. Angiopoietin inhibitors: a review on targeting tumor angiogenesis. Deyell, M. Cancer metastasis as a non-healing wound. Cancer , — Viallard, C. Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis 20 , — Bellou, S. Anti-angiogenesis in cancer therapy: hercules and hydra. Cancer Lett. Ebos, J. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Pirker, R. Chemotherapy remains a cornerstone in the treatment of nonsmall cell lung cancer. Biller, L. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA , Luqmani, Y. Mechanisms of drug resistance in cancer chemotherapy. Saeki, T. Drug resistance in chemotherapy for breast cancer. Cancer Chemother. Salgia, R. Trends Cancer 4 , — Turner, N. Genetic heterogeneity and cancer drug resistance. Lancet Oncol. Duesberg, P. Cancer drug resistance: the central role of the karyotype. Drug Resist. Lahiry, P. Kinase mutations in human disease: interpreting genotype-phenotype relationships. Claesson-Welsh, L. Vascular permeability—the essentials. De Bock, K. Vessel abnormalization: another hallmark of cancer? Molecular mechanisms and therapeutic implications. Mortezaee, K. Immune escape: a critical hallmark in solid tumors. Life Sci. Igney, F. Immune escape of tumors: apoptosis resistance and tumor counterattack. Majidpoor, J. Angiogenesis as a hallmark of solid tumors—clinical perspectives. Choi, S. Anti-angiogenesis revisited: reshaping the treatment landscape of advanced non-small cell lung cancer. Zhong, L. Small molecules in targeted cancer therapy: advances, challenges, and future perspectives. Signal Transduct. Huinen, Z. Anti-angiogenic agents—overcoming tumour endothelial cell anergy and improving immunotherapy outcomes. Gacche, R. Angiogenic factors as potential drug target: efficacy and limitations of anti-angiogenic therapy. Acta , — CAS PubMed Google Scholar. Bergers, G. Modes of resistance to anti-angiogenic therapy. Cancer 8 , — Ansari, M. Cancer combination therapies by angiogenesis inhibitors; a comprehensive review. Cell Commun. The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol. Carmeliet, P. Angiogenesis in cancer and other diseases. Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z, et al. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Blouw B, Song H, Tihan T, Bosze J, Ferrara N, Gerber HP, et al. The hypoxic response of tumors is dependent on their microenvironment. Stacker SA, Achen MG. The vegf signaling pathway in cancer: the road ahead. Chin J Cancer. PubMed Central CAS PubMed Google Scholar. Chen YS, Chen ZP. Vasculogenic mimicry: a novel target for glioma therapy. Donnem T, Hu J, Ferguson M, Adighibe O, Snell C, Harris AL, et al. Vessel co-option in primary human tumors and metastases: an obstacle to effective anti-angiogenic treatment? Cancer Med. Nissen LJ, Cao R, Hedlund EM, Wang Z, Zhao X, Wetterskog D, et al. Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis. Cao R, Brakenhielm E, Pawliuk R, Wariaro D, Post MJ, Wahlberg E, et al. Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF Kerbel RS. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Zhang D, Hedlund EM, Lim S, Chen F, Zhang Y, Sun B, et al. Antiangiogenic agents significantly improve survival in tumor-bearing mice by increasing tolerance to chemotherapy-induced toxicity. Ribatti D. Erythropoietin and tumor angiogenesis. Stem Cells Dev. Garcia-Donas J, Rodriguez-Antona C, Jonasch E. Molecular markers to predict response to therapy. Semin Oncol. Maru D, Venook AP, Ellis LM. Predictive biomarkers for bevacizumab: are we there yet? Clin Cancer Res. Pohl M, Werner N, Munding J, Tannapfel A, Graeven U, Nickenig G, et al. Biomarkers of anti-angiogenic therapy in metastatic colorectal cancer mCRC : original data and review of the literature. Z Gastroenterol. Niers TM, Richel DJ, Meijers JC, Schlingemann RO. Vascular endothelial growth factor in the circulation in cancer patients may not be a relevant biomarker. PLoS ONE. Denduluri N, Yang SX, Berman AW, Nguyen D, Liewehr DJ, Steinberg SM, et al. Circulating biomarkers of bevacizumab activity in patients with breast cancer. Cancer Biol Ther. Hegde PS, Jubb AM, Chen D, Li NF, Meng YG, Bernaards C, et al. Predictive impact of circulating vascular endothelial growth factor in four phase III trials evaluating bevacizumab. Bunni J, Shelley-Fraser G, Stevenson K, Oltean S, Salmon A, Harper SJ, et al. Circulating levels of anti-angiogenic VEGF-A isoform VEGF-AXXXB in colorectal cancer patients predicts tumour VEGF-A ratios. Am J Cancer Res. PubMed Central PubMed Google Scholar. Lambrechts D, Lenz HJ, de Haas S, Carmeliet P, Scherer SJ. Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol. Chen C, Sun P, Ye S, Weng HW, Dai QS. Hypertension as a predictive biomarker for efficacy of bevacizumab treatment in metastatic colorectal cancer: a meta-analysis. J BUON. PubMed Google Scholar. Penzvalto Z, Surowiak P, Gyorffy B. Biomarkers for systemic therapy in ovarian cancer. Curr Cancer Drug Targets. Gampenrieder SP, Romeder F, Muss C, Pircher M, Ressler S, Rinnerthaler G, et al. Hypertension as a predictive marker for bevacizumab in metastatic breast cancer: results from a retrospective matched-pair analysis. Anticancer Res. Tahover E, Uziely B, Salah A, Temper M, Peretz T, Hubert A. Hypertension as a predictive biomarker in bevacizumab treatment for colorectal cancer patients. Med Oncol. Lombardi G, Zustovich F, Farina P, Fiduccia P, Della Puppa A, Polo V, et al. Hypertension as a biomarker in patients with recurrent glioblastoma treated with antiangiogenic drugs: a single-center experience and a critical review of the literature. Anticancer Drugs. Mir O, Coriat R, Cabanes L, Ropert S, Billemont B, Alexandre J, et al. An observational study of bevacizumab-induced hypertension as a clinical biomarker of antitumor activity. Osterlund P, Soveri LM, Isoniemi H, Poussa T, Alanko T, Bono P. Hypertension and overall survival in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy. Br J Cancer. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. Download references. Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 77, Stockholm, Sweden. Department of Medical and Health Sciences, Linköping University, 83, Linköping, Sweden. Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, LE3 9QP, UK. You can also search for this author in PubMed Google Scholar. Correspondence to Yihai Cao. Open Access This article is distributed under the terms of the Creative Commons Attribution 4. Reprints and permissions. Cao, Y. Future options of anti-angiogenic cancer therapy. Chin J Cancer 35 , 21 Download citation. Received : 28 November Accepted : 18 January Published : 15 February Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Review Open access Published: 15 February Future options of anti-angiogenic cancer therapy Yihai Cao 1 , 2 , 3 Chinese Journal of Cancer volume 35 , Article number: 21 Cite this article Accesses 34 Citations 4 Altmetric Metrics details. Abstract In human patients, drugs that block tumor vessel growth are widely used to treat a variety of cancer types. Background Treating cancer by blocking tumor angiogenesis, which was proposed by Judah Folkman nearly 45 years ago [ 1 , 2 ], is now a universally accepted mechanism. Full size image. Tumor size and patient survival In almost all preclinical animal tumor models, the anti-tumor effect of angiogenesis inhibitors is assessed by suppression of tumor growth [ 4 ]. Biologics- and small compound-based anti-angiogenic drugs Protein-based and chemical compound-based anti-angiogenic drugs are currently available for treatment of human cancers [ 21 ]. Anti-angiogenic drug targets Anti-angiogenic drugs target tumor blood vessels that exhibit heterogeneity [ 39 ]. Therapeutic timeline An important and clinically practical issue related to anti-angiogenic therapy is length of treatment. Drug resistance Originally, researchers believed that angiogenesis inhibitors, especially the endogenous inhibitors such as angiostatin, endostatin, and other generic inhibitors, would not develop drug resistance of tumor cells because they target endothelial cells rather than tumor cells [ 46 , 47 ]. Mechanisms of combination therapy In clinical practice, combination therapy represents a major mechanistic challenge [ 57 ]. Predictive biomarker-related issues Mono-specific anti-VEGF drugs such as bevacizumab target only VEGF without binding to other proteins. Adverse effects Systemic delivery of anti-angiogenic drugs to cancer patients would inevitably expose non-cancerous healthy tissues to these drugs [ 40 , 41 ]. Perspectives Inhibition of angiogenesis for the treatment of cancer has been successfully translated into clinical use. Article PubMed Google Scholar Folkman J. Article CAS PubMed Google Scholar Folkman J. Article CAS PubMed Google Scholar Cao Y, Langer R. Article PubMed Google Scholar Cao Y, Xue L. Article CAS PubMed Google Scholar Cao Y. Article CAS PubMed Google Scholar Folberg R, Hendrix MJ, Maniotis AJ. Article PubMed Central CAS PubMed Google Scholar Bissell MJ. Article PubMed Central CAS PubMed Google Scholar Ribatti D, Vacca A, Dammacco F. Article CAS PubMed Google Scholar Leenders WP, Kusters B, de Waal RM. Article PubMed Google Scholar Dome B, Paku S, Somlai B, Timar J. Article PubMed Google Scholar Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. Article CAS PubMed Google Scholar Cataldo VD, Gibbons DL, Perez-Soler R, Quintas-Cardama A. Article CAS PubMed Google Scholar Haines IE, Miklos GL. Article CAS PubMed Google Scholar Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Article CAS PubMed Google Scholar Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Article CAS PubMed Google Scholar Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Article CAS PubMed Google Scholar Fidler IJ. CAS PubMed Google Scholar Lee SL, Rouhi P, Dahl Jensen L, Zhang D, Ji H, Hauptmann G, et al. Article PubMed Central CAS PubMed Google Scholar Rouhi P, Jensen LD, Cao Z, Hosaka K, Lanne T, Wahlberg E, et al. Article CAS PubMed Google Scholar Argiles JM, Busquets S, Stemmler B, Lopez-Soriano FJ. Article CAS PubMed Google Scholar Whelan AJ, Bartsch D, Goodfellow PJ. Article CAS PubMed Google Scholar Argiles JM, Busquets S, Lopez-Soriano FJ. Article CAS PubMed Google Scholar Oliff A, Defeo-Jones D, Boyer M, Martinez D, Kiefer D, Vuocolo G, et al. Article CAS PubMed Google Scholar Zhou X, Wang JL, Lu J, Song Y, Kwak KS, Jiao Q, et al. Article CAS PubMed Google Scholar Todorov P, Cariuk P, McDevitt T, Coles B, Fearon K, Tisdale M. Article CAS PubMed Google Scholar Tannock IF, Fizazi K, Ivanov S, Karlsson CT, Flechon A, Skoneczna I, et al. Article CAS PubMed Google Scholar Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Article PubMed Google Scholar Cao Y, Zhong W, Sun Y. Article CAS Google Scholar Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Article CAS PubMed Google Scholar Sitohy B, Nagy JA, Jaminet SC, Dvorak HF. Article PubMed Central CAS PubMed Google Scholar Kamba T, Tam BY, Hashizume H, Haskell A, Sennino B, Mancuso MR, et al. Article CAS PubMed Google Scholar Yang Y, Zhang Y, Cao Z, Ji H, Yang X, Iwamoto H, et al. Article PubMed Central CAS PubMed Google Scholar Maynard MA, Marino-Enriquez A, Fletcher JA, Dorfman DM, Raut CP, Yassa L, et al. Article PubMed Central CAS PubMed Google Scholar Jubb AM, Pham TQ, Hanby AM, Frantz GD, Peale FV, Wu TD, et al. Article PubMed Central CAS PubMed Google Scholar Xue Y, Religa P, Cao R, Hansen AJ, Lucchini F, Jones B, et al. Article PubMed Central CAS PubMed Google Scholar Folkman J. Article CAS PubMed Google Scholar Ghosh K, Thodeti CK, Dudley AC, Mammoto A, Klagsbrun M, Ingber DE. Article PubMed Central CAS PubMed Google Scholar Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Article CAS PubMed Google Scholar Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z, et al. Article CAS PubMed Google Scholar Blouw B, Song H, Tihan T, Bosze J, Ferrara N, Gerber HP, et al. Article CAS PubMed Google Scholar Stacker SA, Achen MG. PubMed Central CAS PubMed Google Scholar Chen YS, Chen ZP. Article PubMed Central CAS PubMed Google Scholar Donnem T, Hu J, Ferguson M, Adighibe O, Snell C, Harris AL, et al. Article PubMed Central CAS PubMed Google Scholar Nissen LJ, Cao R, Hedlund EM, Wang Z, Zhao X, Wetterskog D, et al. Article PubMed Central CAS PubMed Google Scholar Cao R, Brakenhielm E, Pawliuk R, Wariaro D, Post MJ, Wahlberg E, et al. Article CAS PubMed Google Scholar Kerbel RS. Article CAS PubMed Google Scholar Jain RK. Article CAS PubMed Google Scholar Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, et al. CAS PubMed Google Scholar Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Article PubMed Central CAS PubMed Google Scholar Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, et al. Article PubMed Central CAS PubMed Google Scholar Zhang D, Hedlund EM, Lim S, Chen F, Zhang Y, Sun B, et al. Article PubMed Central CAS PubMed Google Scholar Ribatti D. For example, angiogenesis is the cause of age-related wet macular degeneration. Angiogenesis plays a critical role in the growth of cancer because solid tumors need a blood supply if they are to grow beyond a few millimeters in size. Tumors can actually cause this blood supply to form by giving off chemical signals that stimulate angiogenesis. Tumors can also stimulate nearby normal cells to produce angiogenesis signaling molecules. Because tumors cannot grow beyond a certain size or spread without a blood supply, scientists have developed drugs called angiogenesis inhibitors, which block tumor angiogenesis. The goal of these drugs, also called antiangiogenic agents, is to prevent or slow the growth of cancer by starving it of its needed blood supply. Angiogenesis inhibitors are unique cancer-fighting agents because they block the growth of blood vessels that support tumor growth rather than blocking the growth of tumor cells themselves. Angiogenesis inhibitors interfere in several ways with various steps in blood vessel growth. Some are monoclonal antibodies that specifically recognize and bind to VEGF. When VEGF is attached to these drugs, it is unable to activate the VEGF receptor. Some angiogenesis inhibitors are immunomodulatory drugs—agents that stimulate or suppress the immune system —that also have antiangiogenic properties. In some cancers, angiogenesis inhibitors appear to be most effective when combined with additional therapies. |
| Drug Targets of Antiangiogenesis Therapy | Hypoxia-inducible Factor-1alpha Is Associated with Angiogenesis, and Expression of bFGF, PDGF-BB, and EGFR in Invasive Breast Cancer. The complex role of angiopoietin-2 in the angiopoietin-Tie signaling pathway. EClinicalMedicine 25, Based on those therapeutic advantages, efforts have been made to explore tumor treatments that target angiogenesis. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine RAISE : a randomised, double-blind, multicentre, phase 3 study. Angiogenesis is a critical process that is needed for many physiological and pathological activities [ 1 ]. Nat Rev Cancer. |
Video
Anti-Angiogenesis - Antiangiogenesis Anti-angiogenesis therapy, a promising vor against Speed up metabolism progression, is limited Antu-angiogenesis drug-resistance, which could be attributed to Anti-angiogenesis therapy for solid tumors within the Anti-angiogenfsis microenvironment. Studies have increasingly shown that Greek yogurt for digestion anti-angiogenesis drugs Anti-angiogenesis therapy for solid tumors immunotherapy thherapy inhibits tumor Anti-anbiogenesis and progression. Combination of anti-angiogenesis therapy thdrapy immunotherapy are well-established therapeutic options among solid tumors, such as non-small cell lung cancer, hepatic cell carcinoma, and renal cell carcinoma. However, this combination has achieved an unsatisfactory effect among some tumors, such as breast cancer, glioblastoma, and pancreatic ductal adenocarcinoma. Therefore, resistance to anti-angiogenesis agents, as well as a lack of biomarkers, remains a challenge. In this review, the current anti-angiogenesis therapies and corresponding drug-resistance, the relationship between tumor microenvironment and immunotherapy, and the latest progress on the combination of both therapeutic modalities are discussed.
Anti-angiogenesis therapy for solid tumors -
Anti-angiogenic therapy has been implicated in cardiotoxicity. The risk is particularly high in those who develop hypertension.
Moreover, the risk of left ventricular LV dysfunction remains high among patients whose blood pressure has been controlled while on medications like sunitinib. Such capillary density may not match the increase in myocardial area or hypertrophy.
This mismatch causes reduced fractional shortening and increased LV end-diastolic pressure [ 50 ]. In mice treated with TKIs like sunitinib and also in patients on anti-angiogenic therapy, there is capillary rarefaction and myocyte mitochondrial swelling and degenerative changes which are compounded by apoptosis in those with high blood pressure [ 50 ].
It appears that increased afterload accelerates this capillary rarefaction and may underlie the development of LV dysfunction. Cardiotoxicity also involves alteration in myocardial energetics via AMP-kinase inhibition and resultant mitochondrial dysfunction.
Such changes lead to reduced contractility and increase the susceptibility of the heart to other insults. Such cardiotoxicity may be due to both on-target and off-target effects of TKIs on the heart which leads to adverse remodeling and cardiac dilatation. This underscores the need to monitor left ventricular function in patients on anti-angiogenic therapy.
Myocardial ischaemia has been observed with some antiangiogenic agents including bevacizumab, sunitinib, sorafenib and regorafenib [ 50 ]. This LV dysfunction is usually asymptomatic and is reversible on early withdrawal of such therapy.
Risk factors for such arterial thrombotic events are unclear but background heart disease, hypertension, older age and use of other cardiotoxic drugs likely play important roles. The strong link between coronary ischaemia and cardiotoxicity with the use of anti-angiogenic therapy appears to be related to perfusion contraction mismatch [ 50 ].
Reduction in nitric oxide signaling and endothelial dysfunction that occur following acute VEGF therapy accelerates coronary vasoconstriction, arterial inflammation, atherosclerosis and platelet reactivity.
This is particularly important for those molecules which also affect PDGF signaling where there is decoupling of the pericyte-endothelial myocardial interaction. Theoretical concerns exist for small molecule receptor tyrosine kinase inhibitors about cardiotoxicity and heart failure risk especially in those with pre-existing cardiac diseases due to disruption of AMP-kinase activity [ 52 ].
The risk of the left ventricular systolic dysfunction during anti-angiogenic therapy is difficult to predict. Many of the patients in reported studies had been treated with radiotherapy and chemotherapy which may also cause cardiotoxicity. Stress echocardiography may play a role in the evaluation of those with an intermediate or high pre-test probability of coronary artery disease who are being placed on anti-VEGF therapy.
Additionally, PET and cardiac MRI may be used to determine myocardial blood flow reserve in these situations. The clinical approach to anti-angiogenic therapy in the setting of cardiovascular risk is presented in Fig. Nanoparticles allow absorption of a large quantity of a drug due to the large surface area to volume ratio [ 53 ].
Small molecules, proteins, DNA and miRNAs can be loaded into nanoparticles for delivery into tumours. Nanoparticles have advantages over conventional chemotherapy because of their multifunctional targeted roles in the tumour environment. Potential approaches include tissue reoxygenation, either through in situ oxygen supply or increasing intra-tumour hydrogen peroxide metabolism.
Organic liposomes, polymers and inorganic gold, silver and silicate based nanoparticles have been developed for use in experimental tumour models. Some nanoparticles have been designed to silence the expression of HIF-1α gene by antisense oligonucleotides or by miRNAs.
Some liposomes carrying camptothecin or topotecan inhibit topoisomerase I [ 53 ]. The flow of nanomedicines into tumours may be negatively influenced by hypoxia of tumour microenvironment despite the existence of enhanced permeability and retention effect EPR [ 53 ].
EPR in solid tumours is due to their vascular abnormalities which lead to extravasation of nanometric molecules in tumours which may thus reach a higher concentration than in normal tissue. The intense hypoxic environment of tumours may be a barrier to the EPR effect. Nanotechnology have circumvented this and can enhance EPRs by using hyperthermia to mediate vascular permeability in solid tumours, ultrasound-induced cavitation to modify tumour tissue, application of nitric oxide-releasing agents to expand blood vessels or administration of antihypertensive to normalize blood flow [ 53 ].
These have been achieved in tumours to promote tumour heating using photo-stimulation, magnetism, radiofrequency waves or ultrasound. Tumour vessel normalization has also been attempted using gold nanoparticles to provide human recombinant endostatin rhEs in tumours by EPR to facilitate transient vessel normalization and improve anti-tumour therapeutic efficacy.
Some have also developed nanoparticles of combination therapy of antiangiogenic and conventional chemotherapy e. lipid derivative conjugates LGCs containing gemcitabine and paclitaxel to simultaneously restore tumour vasculature and deliver cytotoxic drugs [ 53 ]. There is however a need to evaluate the safety and toxicity of nanoparticles.
Safety concerns include direct toxicity, nanoparticle aggregate long-term accumulation and immunogenicity. There is also a need to improve drug loading capacity and capability of sustained release of the cargo of nanoparticles in vivo.
This will minimize the risk of accumulation of nanoparticles in healthy tissues and facilitate effective delivery to the target tumours. This is important because vascular permeability, oncotic pressure, interstitial pressure and complex nature of tumour stroma affect the movement of nanoparticles in and out of tumour microenvironment.
There is a need to stratify patients according to their EPR release to define those patients who can benefit from nanoparticles. There are different delivery methods for nanoparticles.
These include exosomes, plasma membrane coating, use of chitosan and even the use of mesenchymal stem cells. Exosomes allow intracellular delivery of their cargo by fusion of membranes.
They can cross biological barriers like the blood-brain barrier easily. Undesired effects of the exosome components and lack of standardized production protocols are limitations to their use.
Plasma membrane coating with nanoparticles is another delivery technique for nanoparticles as anti-angiogenics. Examples of nanoparticles delivered this way include tungsten oxide which has been used in lymphoma models [ 53 ].
Platelet membranes provide immune evasion and active adhesion to tumour cells due to their P-selectin interaction with ligands expressed on tumour cells. Some have used red cell membranes which are very abundant in the circulation and have immune escape and long circulation time.
Chitosan is another carrier derived from chitin. It is less cytotoxic and is biodegradable and metabolized easily by the kidneys.
In mice models of breast cancer, chitosan nanoparticles containing anti-Rho small interfering RNA siRNA showed tumour anti-angiogenesis [ 56 ]. The binding of αvβ3 integrin to chitosan nanoparticles is an important development.
The receptor for αvβ3 integrin is widely expressed in tumours and has shown potentials in ovarian cancer models. Encapsulation of paclitaxel with chitosan nanoparticles has shown efficacy in breast cancer [ 57 ].
There is now interest in the use of mesenchymal stem cells MSCs to deliver nanoparticles. Hypoxic conditioning of such MSCs used as cell-based therapy can be used for aggressive tumours like glioblastoma multiforme since MSCs can traffic across the blood-brain barrier [ 53 ].
Blocking tumour stem cells via anti-angiogenic therapies is another theoretical approach since the tumour stem cell sub-population in some tumours like breast cancers may be more adept at promoting angiogenesis than their non-stem cell counterparts.
The different delivery methods for nanoparticles are compared in Table 2. Anti-angiogenic therapy in cancers has enormous potentials using VEGF signaling pathways. Cardiovascular toxicity and off-target effects of anti-angiogenic drugs are impediments to their long-term use in those at high cardiovascular risk.
Continued research into effective nanoparticle-based delivery methods is an exciting and developing field in cancer therapeutics. Understanding of the molecular and cellular mechanisms of tumour angiogenesis will facilitate the development of newer effective anti-angiogenic molecules.
GBD Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for diseases and injuries for countries, — a systematic analysis for the global burden of disease study Google Scholar. Gupta K, Zhang J.
Angiogenesis: a curse or cure? Postgrad Med J. Article CAS PubMed PubMed Central Google Scholar. Kim KJ, Li B, Winer B, Armanini M, Gillett N, Philips HS, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo.
Nat Publ Gr. CAS Google Scholar. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.
N Engl J Med. Article CAS PubMed Google Scholar. Planchard D, Planchard D. Bevacizumab in non-small-cell lung cancer: a review. Expert Rev Anticancer Ther. Shih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther.
Wilhelm SM, Carter C, Tang L, Wilkie D, Mcnabola A, Rong H, et al. Cancer Res. Liu L, Cao Y, Chen C, Zhang X, Mcnabola A, Wilkie D, et al.
Chase DM, Chaplin DJ, Monk BJ. The development and use of vascular targeted therapy in ovarian cancer. Gynecol Oncol.
Kazazi-Hyseni F, Beijnen JH, Schellens JH. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. Miles DW, Chan A, Dirix LY, Corte J.
Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2 — negative metastatic breast cancer.
J Clin Oncol. Robert NJ, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, et al. RIBBON randomized, double-blind, placebo-controlled, phase iii trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer.
Tabernero J, Van Cutsem E, Lakomy R, Prausova J, Ruff P, Prausova J, et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial.
Eur J Cancer. Ramlau R, Gorbunova V, Ciuleanu TE, Novello S, Ozguroglu M, Goksel T, et al. Aflibercept and Docetaxel versus Docetaxel alone after platinum failure in patients with advanced or metastatic non—small-cell lung cancer: a randomized, controlled phase III trial.
Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-carbonero R, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine RAISE : a randomised, double-blind, multicentre, phase 3 study.
Lancet Oncol. Maj E, Papiernik D, Wietrzyk J. Antiangiogenic cancer treatment: the great discovery and greater complexity review. Int J Oncol. Li J-L, Sainson RCA, Oon CE, Turley H, Leek R, Sheldon H, et al.
DLL4-notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Clarke JM, Hurwitz HI. Understanding and targeting resistance to anti-angiogenic therapies. J Gastrointest Oncol. Balamurugan K. HIF-1 at the crossroads of hypoxia, inflammation, and cancer.
Int J Cancer. Jeong W, Rapisarda A, Ryun S, Robert P, Chen A, Melillo G, et al. Pilot trial of EZN, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha HIF-1α , in patients with refractory solid tumors.
Cancer Chemother Pharmacol. Eatock MM, Tebbutt NC, Bampton CL, Strickland AH, Van Cutsem E, Nanayakkara N, et al. Phase II randomized, double-blind, placebo-controlled study of AMG trebananib in combination with cisplatin and capecitabine in patients with metastatic gastro-oesophageal cancer.
Ann Oncol. Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. Loges S, Schmidt T, Carmeliet P. Mechanisms of resistance to anti-Angiogenic therapy and development of third-generation anti-Angiogenic drug candidates.
Genes Cancer. Viallard C, Larrivee B. Tumor angiogenesis and vascular normalization: alternative therapeutic targets.
Shojaei F, Ferrara N. Drug Resist Updat. Orimo A, Gupta PB, Sgroi DC, Arenzana-seisdedos F, Delaunay T, Naeem R, et al. Guo W, Giancotti FG. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol. Yu JL, Rak JW, Coomber BL, Hicklin DJ, Kerbel RS. Effect of p53 status on tumor response to antiangiogenic therapy.
Science Article CAS Google Scholar. Zarrin B, Zarifi F, Vaseghi G, Javanmard SH. Acquired tumor resistance to antiangiogenic therapy: mechanisms at a glance.
J Res Med Sci. Goel S, Wong AH, Jain RK. Vascular normalization as a therapeutic strategy. Cold Spring Harb Perspect Med. Article Google Scholar. Ramjiawan RR, Griffioen AW, Duda DG. Anti-angiogenesis for cancer revisited: is there a role for combinations with immunotherapy? Article PubMed PubMed Central Google Scholar.
Yasuda S, Sho M, Yamato I, Yoshiji H, Wakatsuki K, Nishiwada S, et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 VEGFR2 induces synergistic anti-tumour effectin vivo.
Clin Exp Immunol. Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy.
Hillan K, Koeppen K, Tobin P, Pham T. The role of VEGF expression in response to bevacizumab plus capecitabine in metastatic breast cancer MBC. Proc Am Soc Clin Oncol.
Escudier B, Eisen T, Stadler WM, Szczylik C, Demkow T, Hutson TE, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase iii treatment approaches in renal cancer global evaluation trial.
Reinmuth N, Thomas M, Meister M, Schnabel PA, Kreuter M. Current data on predictive markers for anti-angiogenic therapy in thoracic tumours. Eur Respir J. Kim C, Yang H, Fukushima Y, Saw PE, Lee J, Park JS, et al.
Vascular RhoJ is an effective and selective target for tumor angiogenesis and vascular disruption. Martinetti A, Miceli R, Sottotetti E, Di Bartolomeo M, De Braud F, Gevorgyan A, et al.
Circulating biomarkers in advanced colorectal cancer patients randomly assigned to three bevacizumab-based regimens.
Cancers Basel. Tran HT, Liu Y, Zurita AJ, Lin Y, Baker-neblett KL, Martin A, et al. Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials.
Sammarco G, Gallo G, Vescio G, Picciariello A, Paola DG, Trompetto M, et al. Mast cells, micrornas and others: the role of translational research on colorectal cancer in the forthcoming era of precision medicine.
J Clin Med. Ammendola M, Sacco R, Sammarco G, Luposella M, Patruno R, Gadaleta COD, et al. Mast cell-targeted strategies in cancer therapy.
Transfus Med Hemother. Angelucci A, Di Padova M. Int J Mol Sci. Meert A-P, Paesmans M, Martin B, Delmotte P, Berghmans T, Verdebout J-M, et al. The role of microvessel density on the survival of patients with lung cancer: a systematic review of the literature with. Br J Cancer.
Jubb AM, Hurwitz HI, Bai W, Holmgren EB, Tobin P, Guerrero AS, et al. Impact of vascular endothelial growth factor-a expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer.
Shiroishi MS, Boxerman JL, Pope WB. Physiologic MRI for assessment of response to therapy and prognosis in glioblastoma. Vasudev NS, Reynolds AR. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions.
Rojas JD, Lin F, Chiang Y, Chytil A, Chong DC, Bautch VL, et al. Ultrasound molecular imaging of VEGFR-2 in clear-cell renal cell carcinoma tracks disease response to antiangiogenic and notch-inhibition therapy. Touyz RM, Herrmann J. Cardiotoxicity with vascular endothelial growth factor inhibitor therapy.
NPJ Precis Oncol. Touyz RM, Lang NN. Hypertension and antiangiogenesis the Janus face of VEGF inhibitors. JACC Cardio Oncol. Dobbin SJH, Cameron AC, Petrie MC, Jones RJ, Touyz RM, Lang NN.
Toxicity of cancer therapy: what the cardiologist needs to know about angiogenesis inhibitors. de la Torre P, Pérez-Lorenzo MJ, Alcázar-garrido Á, Flores AI. Cell-based nanoparticles delivery systems for targeted cancer therapy: lessons from anti-angiogenesis treatments.
Mukherjee S, Patra CR. Therapeutic application of anti-angiogenic nanomaterials in cancers. Liu H, Zhang Y, Zheng S, Weng Z, Ma J, Li Y, et al. Biochemical and biophysical research communications detention of copper by sulfur nanoparticles inhibits the proliferation of A malignant melanoma and MCF-7 breast cancer cells.
Biochem Biophys Res Commun. Potdar PD, Shetti AU. Chitosan nanoparticles: an emerging weapon against the cancer. MOJ Cell Sci Rep. Trickler WJ, Nagvekar AA, Dash AK. A novel nanoparticle formulation for sustained paclitaxel delivery. AAPS PharmSciTech. Download references.
Nuffield Department of Population Health, University of Oxford, Oxford, UK. Institute of Cardiovascular Science, University College London, London, UK. Ayodipupo S. Department of Basic Science, Prince Sultan Bin Abdulaziz College for Emergency Medical Services, King Saud University, Riyadh, Saudi Arabia.
You can also search for this author in PubMed Google Scholar. ASO conceptualized the topic, designed the study methodology, conducted the literature search, and wrote the initial draft.
FA, MA, AA and MB conceptualized the topic, conducted the literature search and contributed to the initial draft. The authors read and approved the final draft of the manuscript and take responsibility for this paper.
Correspondence to Ayodipupo S. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.
The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Reprints and permissions. Oguntade, A. et al. Anti-angiogenesis in cancer therapeutics: the magic bullet. J Egypt Natl Canc Inst 33 , 15 Download citation. Received : 18 November Accepted : 08 June Published : 02 July Anyone you share the following link with will be able to read this content:.
Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all SpringerOpen articles Search. Download PDF. Narrative Review Open access Published: 02 July Anti-angiogenesis in cancer therapeutics: the magic bullet Ayodipupo S.
Oguntade ORCID: orcid. Abstract Background Angiogenesis is the formation of new vascular networks from preexisting ones through the migration and proliferation of differentiated endothelial cells.
Main body of the abstract MEDLINE and EMBASE databases were searched for publications on antiangiogenic therapy in cancer therapeutics from to Short conclusion Clinical surveillance is important for the early detection of tumour resistance and treatment failure using reliable biomarkers.
Background Cancers still account for significant morbidity and mortality globally despite remarkable advances in the management of cancers [ 1 ]. Main text We searched MEDLINE and EMBASE for publications on anti-angiogenesis in cancer from to as part of a larger project on anti-angiogenesis and cancer therapeutics.
Anti-angiogenics in cancers Several preclinical and clinical studies in cancer research have targeted different steps of the angiogenic pathway. Table 1 Selected VEGF-targeted anti-angiogenics and their therapeutic indications Full size table. Clinical approach to cardiovascular toxicity of antiangiogenic therapy.
Full size image. Table 2 Different delivery methods for nanoparticles Full size table. Ther Clin Risk Manag. Keisner SV, Shah SR. Poole RM, Vaidya A. Ramucirumab: first global approval. Garon EB, Cao D, Alexandris E, John WJ, Yurasov S, Perol M.
A randomized, double-blind, phase III study of docetaxel and ramucirumab versus docetaxel and placebo in the treatment of stage IV non—small-cell lung cancer after disease progression after 1 previous platinum-based therapy REVEL : Treatment Rationale and Study Design.
Clin Lung Cancer. Verdaguer H, Tabernero J, Macarulla T. Ramucirumab in metastatic colorectal cancer: evidence to date and place in therapy. Ther Adv Med Oncol. Syed YY. Ramucirumab: a review in hepatocellular carcinoma.
Bruix J, Qin S, Merle P, Granito A, Huang Y-H, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment RESORCE : a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. Abdelgalil AA, Alkahtani HM, Al-Jenoobi FI.
Profiles of drug substances, excipients and related methodology, vol. Le Tourneau C, Raymond E, Faivre S. Sunitinib: a novel tyrosine kinase inhibitor. A brief review of its therapeutic potential in the treatment of renal carcinoma and gastrointestinal stromal tumors GIST.
Palumbo A, Facon T, Sonneveld P, Blade J, Offidani M, Gay F, et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood J Am Soc Hematol. Patel A, Sun W. Ziv-aflibercept in metastatic colorectal cancer.
Biol Targets Ther. Commander H, Whiteside G, Perry C. Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial.
Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis.
Cancer Cell. Grepin R, Guyot M, Jacquin M, Durivault J, Chamorey E, Sudaka A, et al. Maione F, Capano S, Regano D, Zentilin L, Giacca M, Casanovas O, et al. Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice.
J Clin Investig. Singh M, Couto SS, Forrest WF, Lima A, Cheng JH, Molina R, et al. Anti-VEGF antibody therapy does not promote metastasis in genetically engineered mouse tumour models. J Pathol. Welti JC, Powles T, Foo S, Gourlaouen M, Preece N, Foster J, et al. Contrasting effects of sunitinib within in vivo models of metastasis.
Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Haibe Y, Kreidieh M, El Hajj H, Khalifeh I, Mukherji D, Temraz S, et al. Resistance mechanisms to anti-angiogenic therapies in cancer.
Jiang B-H, Agani F, Passaniti A, Semenza GL. V-SRC induces expression of hypoxia-inducible factor 1 HIF-1 and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Pereira ER, Frudd K, Awad W, Hendershot LM.
Endoplasmic reticulum ER stress and hypoxia response pathways interact to potentiate hypoxia-inducible factor 1 HIF-1 transcriptional activity on targets like vascular endothelial growth factor VEGF.
Luo D, Wang Z, Wu J, Jiang C, Wu J. The role of hypoxia inducible factor-1 in hepatocellular carcinoma. BioMed Res Int.
Article PubMed PubMed Central Google Scholar. Kitajima Y, Miyazaki K. The critical impact of HIF-1a on gastric cancer biology. Maione F, Molla F, Meda C, Latini R, Zentilin L, Giacca M, et al. Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models.
Fagiani E, Christofori G. Angiopoietins in angiogenesis. Cancer Lett. Hanahan D. Signaling vascular morphogenesis and maintenance. Eklund L, Saharinen P. Angiopoietin signaling in the vasculature.
Exp Cell Res. Cook KM, Figg WD. Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin. Goede V, Coutelle O, Neuneier J, Reinacher-Schick A, Schnell R, Koslowsky T, et al. Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy.
Br J Cancer. Qin S, Yi M, Jiao D, Li A, Wu K. Distinct roles of VEGFA and ANGPT2 in lung adenocarcinoma and squamous cell carcinoma.
J Cancer. Gyanchandani R, Alves MVO, Myers JN, Kim S. A proangiogenic signature is revealed in FGF-mediated bevacizumab-resistant head and neck squamous cell carcinoma. Mol Cancer Res. Zhou Y, Wu C, Lu G, Hu Z, Chen Q, Du X. Okamoto S, Nitta M, Maruyama T, Sawada T, Komori T, Okada Y, et al.
Bevacizumab changes vascular structure and modulates the expression of angiogenic factors in recurrent malignant gliomas.
Brain Tumor Pathol. Schmidinger M. Third-line dovitinib in metastatic renal cell carcinoma. Welti J, Gourlaouen M, Powles T, Kudahetti S, Wilson P, Berney D, et al. Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib. Chung AS, Kowanetz M, Wu X, Zhuang G, Ngu H, Finkle D, et al.
Differential drug class-specific metastatic effects following treatment with a panel of angiogenesis inhibitors. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis.
Grasselly C, Denis M, Bourguignon A, Talhi N, Mathe D, Tourette A, et al. The antitumor activity of combinations of cytotoxic chemotherapy and immune checkpoint inhibitors is model-dependent.
Pérez-Ruiz E, Melero I, Kopecka J, Sarmento-Ribeiro AB, García-Aranda M, De Las Rivas J. Cancer immunotherapy resistance based on immune checkpoints inhibitors: targets, biomarkers, and remedies.
Drug Resist Updates. Novel immune checkpoint targets: moving beyond PD-1 and CTLA Mol Cancer. Darvin P, Toor SM, Nair VS, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med. Reck M, Shankar G, Lee A, Coleman S, McCleland M, Papadimitrakopoulou VA, et al.
Atezolizumab in combination with bevacizumab, paclitaxel and carboplatin for the first-line treatment of patients with metastatic non-squamous non-small cell lung cancer, including patients with EGFR mutations.
Expert Rev Respir Med. Nowicki TS, Hu-Lieskovan S, Ribas A. Mechanisms of resistance to PD-1 and PD-L1 blockade. Cancer J Sudbury, Mass. Yi M, Niu M, Xu L, Luo S, Wu K.
Regulation of PD-L1 expression in the tumor microenvironment. Yasuda S, Sho M, Yamato I, Yoshiji H, Wakatsuki K, Nishiwada S, et al.
Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 VEGFR 2 induces synergistic anti-tumour effect in vivo. Clin Exp Immunol. Meder L, Schuldt P, Thelen M, Schmitt A, Dietlein F, Klein S, et al.
Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer. Wu FT, Xu P, Chow A, Man S, Krüger J, Khan KA, et al.
Pre-and post-operative anti-PD-L1 plus anti-angiogenic therapies in mouse breast or renal cancer models of micro-or macro-metastatic disease.
Wang Q, Gao J, Di W, Wu X. Cancer Immunol Immunother. Schmittnaegel M, Rigamonti N, Kadioglu E, Cassará A, Rmili CW, Kiialainen A, et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci Transl Med. Article PubMed Google Scholar.
Lacal PM, Atzori MG, Ruffini F, Scimeca M, Bonanno E, Cicconi R, et al. Targeting the vascular endothelial growth factor receptor-1 by the monoclonal antibody D16F7 to increase the activity of immune checkpoint inhibitors against cutaneous melanoma.
Pharmacol Res. McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI, Escudier B, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. Liu JF, Herold C, Gray KP, Penson RT, Horowitz N, Konstantinopoulos PA, et al.
Assessment of combined nivolumab and bevacizumab in relapsed ovarian cancer: a phase 2 clinical trial. JAMA Oncol. Kudo M, Motomura K, Wada Y, Inaba Y, Sakamoto Y, Kurosaki M, et al. Am Soc Clin Oncol. Choueiri TK, Larkin JM, Oya M, Thistlethwaite FC, Martignoni M, Nathan PD, et al.
Wilky BA, Trucco MM, Subhawong TK, Florou V, Park W, Kwon D, et al. Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial.
Fukuoka S, Hara H, Takahashi N, Kojima T, Kawazoe A, Asayama M, et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial REGONIVO, EPOC Amin A, Plimack ER, Ernstoff MS, Lewis LD, Bauer TM, McDermott DF, et al.
Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate study. Amin A, Plimack ER, Infante JR, Ernstoff MS, Rini BI, McDermott DF, et al. Nivolumab anti-PD-1; BMS, ONO in combination with sunitinib or pazopanib in patients pts with metastatic renal cell carcinoma mRCC.
Li J, Cong L, Liu J, Peng L, Wang J, Feng A, et al. The efficacy and safety of regorafenib in combination with anti-PD-1 antibody in refractory microsatellite stable metastatic colorectal cancer: a retrospective study.
Arkenau HT, Martin-Liberal J, Calvo E, Penel N, Krebs MG, Herbst RS, et al. Ramucirumab plus pembrolizumab in patients with previously treated advanced or metastatic biliary tract cancer: nonrandomized, open-label, phase I trial JVDF.
Pardoll DM. Cancer vaccines. Finn OJ. Cancer vaccines: between the idea and the reality. Nat Rev Immunol.
Gatti-Mays ME, Redman JM, Collins JM, Bilusic M. Cancer vaccines: enhanced immunogenic modulation through therapeutic combinations. Hum Vaccin Immunother. Bose A, Lowe DB, Rao A, Storkus WJ. Melanoma Res. Saha D, Wakimoto H, Peters CW, Antoszczyk SJ, Rabkin SD, Martuza RL.
Combinatorial effects of VEGFR kinase inhibitor axitinib and oncolytic virotherapy in mouse and human glioblastoma stem-like cell models. Jha BK, Dong B, Nguyen CT, Polyakova I, Silverman RH.
Suppression of antiviral innate immunity by sunitinib enhances oncolytic virotherapy. Mol Ther. Lawson KA, Mostafa AA, Shi ZQ, Spurrell J, Chen W, Kawakami J, et al. Repurposing sunitinib with oncolytic reovirus as a novel immunotherapeutic strategy for renal cell carcinoma. Tan G, Kasuya H, Sahin TT, Yamamura K, Wu Z, Koide Y, et al.
Combination therapy of oncolytic herpes simplex virus HF10 and bevacizumab against experimental model of human breast carcinoma xenograft. Int J Cancer.
Tomita Y, Kurozumi K, Yoo JY, Fujii K, Ichikawa T, Matsumoto Y, et al. Oncolytic herpes virus armed with vasculostatin in combination with bevacizumab abrogates glioma invasion via the CCN1 and AKT signaling pathways.
Vo M-C, Nguyen-Pham T-N, Lee H-J, Lakshmi TJ, Yang S, Jung S-H, et al. Combination therapy with dendritic cells and lenalidomide is an effective approach to enhance antitumor immunity in a mouse colon cancer model.
Lapenta C, Donati S, Spadaro F, Lattanzi L, Urbani F, Macchia I, et al. Lenalidomide improves the therapeutic effect of an interferon-α-dendritic cell-based lymphoma vaccine.
Nguyen-Pham T-N, Jung S-H, Vo M-C, Thanh-Tran H-T, Lee Y-K, Lee H-J, et al. Lenalidomide synergistically enhances the effect of dendritic cell vaccination in a model of murine multiple myeloma.
J Immunother. Sakamaki I, Kwak LW, Cha S, Yi Q, Lerman B, Chen J, et al. Lenalidomide enhances the protective effect of a therapeutic vaccine and reverses immune suppression in mice bearing established lymphomas.
Rini BI, Weinberg V, Fong L, Conry S, Hershberg RM, Small EJ. Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells provenge plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy.
Cancer Interdiscip Int J Am Cancer Soc. Boydell E, Marinari E, Migliorini D, Dietrich P-Y, Patrikidou A, Dutoit V.
Bota DA, Chung J, Dandekar M, Carrillo JA, Kong X-T, Fu BD, et al. CNS Oncol. Nooka AK, Wang ML, Yee AJ, Kaufman JL, Bae J, Peterkin D, et al. Assessment of safety and immunogenicity of PVX vaccine with or without lenalidomide in patients with smoldering multiple myeloma: a nonrandomized clinical trial.
Tilgase A, Olmane E, Nazarovs J, Brokāne L, Erdmanis R, Rasa A, et al. Multimodality treatment of a colorectal cancer stage IV patient with FOLFOX-4, bevacizumab, Rigvir oncolytic virus, and surgery. Case Rep Gastroenterol. Kato D, Yaguchi T, Iwata T, Morii K, Nakagawa T, Nishimura R, et al.
Prospects for personalized combination immunotherapy for solid tumors based on adoptive cell therapies and immune checkpoint blockade therapies.
Jpn J Clin Immunol. Feros DL, Lane L, Ciarrochi J, Blackledge JT. Acceptance and Commitment Therapy ACT for improving the lives of cancer patients: a preliminary study. Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer.
Shi S, Wang R, Chen Y, Song H, Chen L, Huang G. Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models. PLoS ONE. Bocca P, Di Carlo E, Caruana I, Emionite L, Cilli M, De Angelis B, et al.
Bevacizumab-mediated tumor vasculature remodelling improves tumor infiltration and antitumor efficacy of GD2-CAR T cells in a human neuroblastoma preclinical model. Zhang Q, Zhang H, Ding J, Liu H, Li H, Li H, et al.
Combination therapy with EpCAM-CAR-NK cells and regorafenib against human colorectal cancer models. J Immunol Res. Lennernäs B, Albertsson P, Lennernäs H, Norrby K. Chemotherapy and antiangiogenesis. Acta Oncol. Ma J, Waxman DJ. Combination of antiangiogenesis with chemotherapy for more effective cancer treatment.
Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib. Oliva P, Decio A, Castiglioni V, Bassi A, Pesenti E, Cesca M, et al.
Cisplatin plus paclitaxel and maintenance of bevacizumab on tumour progression, dissemination, and survival of ovarian carcinoma xenograft models.
Shishido T, Yasoshima T, Denno R, Mukaiya M, Sato N, Hirata K. Inhibition of liver metastasis of human pancreatic carcinoma by angiogenesis inhibitor TNP in combination with cisplatin.
Jpn J Cancer Res. Devineni D, Klein-Szanto A, Gallo JM. Uptake of temozolomide in a rat glioma model in the presence and absence of the angiogenesis inhibitor TNP Kong C, Zhu Y, Sun C, Li Z, Sun Z, Zhang X, et al. Inhibition of tumor angiogenesis during cisplatin chemotherapy for bladder cancer improves treatment outcome.
Bow H, Hwang LS, Schildhaus N, Xing J, Murray L, Salditch Q, et al. Local delivery of angiogenesis-inhibitor minocycline combined with radiotherapy and oral temozolomide chemotherapy in 9L glioma. J Neurosurg.
Thomas AL, Trarbach T, Bartel C, Laurent D, Henry A, Poethig M, et al. Ann Oncol. Cooney MM, Tserng K-Y, Makar V, McPeak RJ, Ingalls ST, Dowlati A, et al. A phase IB clinical and pharmacokinetic study of the angiogenesis inhibitor SU and paclitaxel in recurrent or metastatic carcinoma of the head and neck.
Cancer Chemother Pharmacol. Okamoto I, Yoshioka H, Takeda K, Satouchi M, Yamamoto N, Seto T, et al. Phase I clinical study of the angiogenesis inhibitor TSU combined with carboplatin and paclitaxel in chemotherapy-naive patients with advanced non-small cell lung cancer.
J Thorac Oncol. Gietema J, Hoekstra R, de Vos F, Uges D, van der Gaast A, Groen H, et al. A phase I study assessing the safety and pharmacokinetics of the thrombospondinmimetic angiogenesis inhibitor ABT with gemcitabine and cisplatin in patients with solid tumors.
Herbst RS, Madden TL, Tran HT, Blumenschein GR Jr, Meyers CA, Seabrooke LF, et al. Safety and pharmacokinetic effects of TNP, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: evidence for activity in non—small-cell lung cancer.
Coleman RL, Brady MF, Herzog TJ, Sabbatini P, Armstrong DK, Walker JL, et al. Bamias A, Gibbs E, Khoon Lee C, Davies L, Dimopoulos M, Zagouri F, et al. Bevacizumab with or after chemotherapy for platinum-resistant recurrent ovarian cancer: exploratory analyses of the AURELIA trial.
Morganti AG, Cellini F, Mignogna S, Padula GD, Caravatta L, Deodato F, et al. Low-dose radiotherapy and concurrent FOLFIRI-bevacizumab: a Phase II study. Future Oncol.
Koukourakis MI, Giatromanolaki A, Sheldon H, Buffa FM, Kouklakis G, Ragoussis I, et al. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. Ruan J, Martin P, Christos P, Cerchietti L, Tam W, Shah B, et al.
Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. Hou J, Jin J, Xu Y, Wu D, Ke X, Zhou D, et al. Bondarenko IM, Ingrosso A, Bycott P, Kim S, Cebotaru CL. Phase II study of axitinib with doublet chemotherapy in patients with advanced squamous non-small-cell lung cancer.
BMC Cancer. Chau I, Fakih M, García-Alfonso P, Linke Z, Ruiz Casado A, Marques EP, et al. Chen H, Modiano MR, Neal JW, Brahmer JR, Rigas JR, Jotte RM, et al. Formenti SC, Demaria S. Systemic effects of local radiotherapy.
Wrona A, Dziadziuszko R, Jassem J. Combining radiotherapy with targeted therapies in non-small cell lung cancer: focus on anti-EGFR, anti-ALK and anti-angiogenic agents. Transl Lung Cancer Res.
Overgaard J. Hypoxic radiosensitization: adored and ignored. Gray LH, Conger AD, Ebert M, Hornsey S, Scott O. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol. Amano M, Suzuki M, Andoh S, Monzen H, Terai K, Williams B, et al. Antiangiogenesis therapy using a novel angiogenesis inhibitor, anginex, following radiation causes tumor growth delay.
Int J Clin Oncol. Shintani S, Li C, Mihara M, Klosek SK, Terakado N, Hino S, et al. Anti-tumor effect of radiation response by combined treatment with angiogenesis inhibitor, TNP, in oral squamous cell carcinoma.
Oral Oncol. Murata R, Nishimura Y, Hiraoka M. An antiangiogenic agent TNP inhibited reoxygenation during fractionated radiotherapy of murine mammary carcinoma.
Int J Radiat Oncol Biol Phys. Williams KJ, Telfer BA, Brave S, Kendrew J, Whittaker L, Stratford IJ, et al. ZD, a potent inhibitor of vascular endothelial growth factor signaling, combined with radiotherapy: schedule-dependent enhancement of antitumor activity.
Chen Y, Gule M, Lemos R, Myers JN, Schwartz DL, Bankson JA, et al. Evaluation of vandetanib ZD and radiation therapy in an orthotopic xenograft model of anaplastic thyroid carcinoma. Hu J, Chen LJ, Liu L, Chen X, Chen PL, Yang G, et al. Liposomal honokiol, a potent anti-angiogenesis agent, in combination with radiotherapy produces a synergistic antitumor efficacy without increasing toxicity.
He Z, Subramaniam D, Ramalingam S, Dhar A, Postier RG, Umar S, et al. Honokiol radiosensitizes colorectal cancer cells: enhanced activity in cells with mismatch repair defects. Am J Physiol Gastrointest Liver Physiol. Wang X, Beitler JJ, Huang W, Chen G, Qian G, Magliocca K, et al.
Honokiol radiosensitizes squamous cell carcinoma of the head and neck by downregulation of survivin. Yang K-L, Chi M-S, Ko H-L, Huang Y-Y, Huang S-C, Lin Y-M, et al. Axitinib in combination with radiotherapy for advanced hepatocellular carcinoma: a phase I clinical trial.
Radiat Oncol. Pernin V, Belin L, Cottu P, Bontemps P, Lemanski C, De La Lande B, et al. Late toxicities and outcomes of adjuvant radiotherapy combined with concurrent bevacizumab in patients with triple-negative non-metastatic breast cancer.
Chadha AS, Skinner HD, Gunther JR, Munsell MF, Das P, Minsky BD, et al. Phase i trial of consolidative radiotherapy with concurrent bevacizumab, erlotinib and capecitabine for unresectable pancreatic cancer. Morganti AG, Mignogna S, Caravatta L, Deodato F, Macchia G, Plantamura NM, et al.
FOLFIRI-bevacizumab and concurrent low-dose radiotherapy in metastatic colorectal cancer: preliminary results of a phase I-II study. J Chemother. Salazar R, Capdevila J, Manzano JL, Pericay C, Martínez-Villacampa M, López C, et al. Phase II randomized trial of capecitabine with bevacizumab and external beam radiation therapy as preoperative treatment for patients with resectable locally advanced rectal adenocarcinoma: long term results.
Abdalla AME, Xiao L, Ullah MW, Yu M, Ouyang C, Yang G. Current challenges of cancer anti-angiogenic therapy and the promise of nanotherapeutics.
Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer.
Relf M, LeJeune S, Scott PA, Fox S, Smith K, Leek R, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor β-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis.
Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS, et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol. Cetin B, Kaplan MA, Berk V, Ozturk SC, Benekli M, Isikdogan A, et al.
Prognostic factors for overall survival in patients with metastatic colorectal carcinoma treated with vascular endothelial growth factor-targeting agents. Asian Pac J Cancer Prev. Singh H, Pohl A, El-Khoueiry A, Lurje G, Zhang W, Yang D, et al. Fountzilas G, Kourea HP, Bobos M, Televantou D, Kotoula V, Papadimitriou C, et al.
Paclitaxel and bevacizumab as first line combined treatment in patients with metastatic breast cancer: the Hellenic Cooperative Oncology Group experience with biological marker evaluation. Anticancer Res. Eisen T, Bukowski R, Staehler M, Szczylik C, Oudard S, Stadler W, et al.
Randomized phase III trial of sorafenib in advanced renal cell carcinoma RCC : impact of crossover on survival. Porta C, Paglino C, De Amici M, Quaglini S, Sacchi L, Imarisio I, et al. Predictive value of baseline serum vascular endothelial growth factor and neutrophil gelatinase-associated lipocalin in advanced kidney cancer patients receiving sunitinib.
Kidney Int. Chen X-L, Lei Y-H, Liu C-F, Yang Q-F, Zuo P-Y, Liu C-Y, et al. Angiogenesis inhibitor bevacizumab increases the risk of ischemic heart disease associated with chemotherapy: a meta-analysis. Subbiah V, Dumbrava EI, Jiang Y, Thein KZ, Naing A, Hong DS, et al.
Dual EGFR blockade with cetuximab and erlotinib combined with anti-VEGF antibody bevacizumab in advanced solid tumors: a phase 1 dose escalation triplet combination trial.
Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma.
Nat Commun. Hodi FS, Lawrence D, Lezcano C, Wu X, Zhou J, Sasada T, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res. Wu X, Li J, Connolly EM, Liao X, Ouyang J, Giobbie-Hurder A, et al.
Combined anti-VEGF and anti-CTLA-4 therapy elicits humoral immunity to galectin-1 which is associated with favorable clinical outcomes. Moore KN, Bookman M, Sehouli J, Miller A, Anderson C, Scambia G, et al. Atkins MB, Plimack ER, Puzanov I, Fishman MN, McDermott DF, Cho DC, et al.
Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Apolo AB, Nadal R, Girardi DM, Niglio SA, Ley L, Cordes LM, et al.
Phase I study of cabozantinib and nivolumab alone or with ipilimumab for advanced or metastatic urothelial carcinoma and other genitourinary tumors. Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
Sakamuri D, Glitza IC, Betancourt Cuellar SL, Subbiah V, Fu S, Tsimberidou AM, et al. Phase I dose-escalation study of anti-CTLA-4 antibody ipilimumab and lenalidomide in patients with advanced cancers.
Taylor MH, Lee CH, Makker V, Rasco D, Dutcus CE, Wu J, et al. Lee CH, Shah AY, Rasco D, Rao A, Taylor MH, Di Simone C, et al. Bang YJ, Golan T, Dahan L, Fu S, Moreno V, Park K, et al.
Eur J Cancer. Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, et al. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer E : an open-label, multicentre, randomised, phase 3 trial. Yang KL, Chi MS, Ko HL, Huang YY, Huang SC, Lin YM, et al.
Chibaudel B, Henriques J, Rakez M, Brenner B, Kim TW, Martinez-Villacampa M, et al. Association of bevacizumab plus oxaliplatin-based chemotherapy with disease-free survival and overall survival in patients with stage II colon cancer: a secondary analysis of the AVANT trial.
JAMA Netw Open. Jiang X, Guan W, Li M, Liang W, Qing Y, Dai N, et al. Endostatin combined with platinum-based chemo-radiotherapy for advanced non-small cell lung cancer. Cell Biochem Biophys. Velenik V, Ocvirk J, Music M, Bracko M, Anderluh F, Oblak I, et al. Neoadjuvant capecitabine, radiotherapy, and bevacizumab CRAB in locally advanced rectal cancer: results of an open-label phase II study.
Lan CY, Wang Y, Xiong Y, Li JD, Shen JX, Li YF, et al. Apatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer AEROC : a phase 2, single-arm, prospective study.
Yu X, Wang QX, Xiao WW, Chang H, Zeng ZF, Lu ZH, et al. Neoadjuvant oxaliplatin and capecitabine combined with bevacizumab plus radiotherapy for locally advanced rectal cancer: results of a single-institute phase II study.
Cancer Commun Lond. Jiang X, Ding M, Qiao Y, Liu Y, Liu L. Recombinant human endostatin combined with radiotherapy in the treatment of brain metastases of non-small cell lung cancer.
Clin Transl Oncol. Crane CH, Ellis LM, Abbruzzese JL, Amos C, Xiong HQ, Ho L, et al. Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. Zhao Z, Li J, Ye R, Wu X, Gao L, Niu B.
A phase II clinical study of combining FOLFIRI and bevacizumab plus erlotinib in 2nd-line chemotherapy for patients with metastatic colorectal cancer.
Medicine Baltimore. Yu JP, Sun SP, Sun ZQ, Ni XC, Wang J, Li Y, et al. Clinical trial of thalidomide combined with radiotherapy in patients with esophageal cancer. World J Gastroenterol. Schneider BJ, Gadgeel SM, Ramnath N, Wozniak AJ, Dy GK, Daignault S, et al.
Phase II trial of sunitinib maintenance therapy after platinum-based chemotherapy in patients with extensive-stage small cell lung cancer. Resch G, De Vries A, Öfner D, Eisterer W, Rabl H, Jagoditsch M, et al. Preoperative treatment with capecitabine, bevacizumab and radiotherapy for primary locally advanced rectal cancer—a two stage phase II clinical trial.
Radiother Oncol. Hansen TF, Nielsen BS, Sørensen FB, Johnsson A, Jakobsen A. Epidermal growth factor-like domain 7 predicts response to first-line chemotherapy and bevacizumab in patients with metastatic colorectal cancer. Jones BS, Jerome MS, Miley D, Jackson BE, DeShazo MR, Reddy VV, et al.
Pilot phase II study of metronomic chemotherapy in combination with bevacizumab in patients with advanced non-squamous non-small cell lung cancer. Lung Cancer. Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, et al.
Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. Ohta T, Kato T, Kawakami H, Miyake Y, Goto M, Iwamoto S, et al. Phase II study of 5-fluorouracil-leucovorin plus bevacizumab for chemotherapy-naïve older or frail patients with metastatic colorectal cancer OGSG Download references.
Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Kingdom of Saudi Arabia.
Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St. Tyumen State Medical University, Tyumen, Russian Federation. Faculty of Biology and Ecology, Yanka Kupala State University of Grodno, , Grodno, Belarus. College of Technical Engineering, The Islamic University, Najaf, Iraq.
Department of Dentistry, Kut University College, Kut, Wasit, , Iraq. Biological Sciences and Sports Health Department, Faculty of Physical Education, Suez Canal University, Ismailia, Egypt.
Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand. Department of Occupational Therapy, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, , Thailand.
Internal Medicine Department, Division of Dermatology, Albaha University, Al Bahah, Kingdom of Saudi Arabia. Immunology Research Center IRC , Tabriz University of Medical Sciences, Tabriz, Iran.
Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran. Department of Neurology, Imam Khomeini Hospital, Urmia University of Medical Sciences, Urmia, Iran.
Department of Medical Biotechnology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran. You can also search for this author in PubMed Google Scholar. All authors contributed to the conception and the main idea of the work.
MJA, DB, SC, AM, WS, NS, HSA, MNS, AZ, AM and ATJ drafted the main text, figures, and tables. MD supervised the work and provided the comments and additional scientific information. DB, MD and MJA also reviewed and revised the text.
All authors read and approved the final manuscript. Correspondence to Mehdi Dadashpour. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.
The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Reprints and permissions. Ansari, M. et al. Cancer combination therapies by angiogenesis inhibitors; a comprehensive review. Cell Commun Signal 20 , 49 Download citation. Received : 25 November Accepted : 03 February Published : 07 April Anyone you share the following link with will be able to read this content:.
Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Review Open access Published: 07 April Cancer combination therapies by angiogenesis inhibitors; a comprehensive review Mohammad Javed Ansari 1 , Dmitry Bokov 2 , 3 , Alexander Markov 4 , 5 , Abduladheem Turki Jalil 6 , 7 , 8 , Mohammed Nader Shalaby 9 , Wanich Suksatan 10 , Supat Chupradit 11 , Hasan S.
Abstract Abnormal vasculature is one of the most conspicuous traits of tumor tissue, largely contributing to tumor immune evasion.
Video abstract. Introduction Angiogenesis is a critical process that is needed for many physiological and pathological activities [ 1 ]. Full size image. Tumor angiogenesis mechanism Several successive stages throughout tumor angiogenesis may be emphasized.
Microenvironment role in tumor angiogenesis Numerous pro-angiogenic agents, such as VEGF, platelet-derived growth factor PDGF , and FGF are found in the tumor microenvironment.
FDA approved anti-angiogenic agents Upon successful preclinical studies Table 1 , a myriad of clinical trials have been accomplished or are ongoing to determine the safety, feasibility, and efficacy of anti-angiogenic agents therapy in cancer patients alone or in combination with other therapeutic means Table 2.
Table 1 Clinical studies based on angiogenesis blockade therapy alone or in combination with other strategies Full size table. Table 2 Combination therapy with anti-angiogenic agents plus other therapeutics in cancer animal models Full size table.
Resistance to anti-angiogenic therapies Despite their total tumor growth reduction, therapeutic anti-angiogenic agents were linked to enhanced local invasiveness as well as distant metastasis. Combination therapy with anti-angiogenic agents Anti-angiogenic agents plus ICIs Recently, scientists have concentrated on the role of immune checkpoint molecules, such as cytotoxic T-lymphocyte antigen-4 CTLA-4 and programmed cell death protein 1 PD-1 , largely participating in tumor cell escape from immune surveillance as their capacity to obstruct T cell activation [ 99 , ].
Table 3 A summary of clinical trials based on combination therapy with anti-angiogenic agents plus immune checkpoint inhibitors ICIs in cancer patients Full size table.
Table 4 A summary of clinical trials based on combination therapy with anti-angiogenic agents plus chemotherapy or radiotherapy or chemoradiotherapy in cancer patients Full size table. Response biomarkers for anti-angiogenic therapy As a result of some divergences results related to anti-angiogenic agents as well as their modest responses, we must determine and categorize a spectrum of biomarkers, screening the patients of possible responders [ ].
Conclusion and prospect In contrast to the classical hypothesis of vascular regression, the central aim of conventional anti-angiogenic treatments is tumor vascular normalization and maturity.
Availability of data and materials Not applicable. References Folkman J. CAS PubMed Google Scholar Senger DR, Davis GE. PubMed PubMed Central Google Scholar Aguilar-Cazares D, Chavez-Dominguez R, Carlos-Reyes A, Lopez-Camarillo C, Hernadez de la Cruz ON, Lopez-Gonzalez JS. PubMed PubMed Central Google Scholar Kerbel RS.
CAS PubMed PubMed Central Google Scholar Reinmuth N, Parikh AA, Ahmad SA, Liu W, Stoeltzing O, Fan F, et al. CAS PubMed Google Scholar Rajendran JG, Krohn KA. Google Scholar Muthukkaruppan VR, Kubai L, Auerbach R. CAS PubMed PubMed Central Google Scholar Teleanu RI, Chircov C, Grumezescu AM, Teleanu DM.
CAS Google Scholar Al-Abd AM, Alamoudi AJ, Abdel-Naim AB, Neamatallah TA, Ashour OM. CAS PubMed PubMed Central Google Scholar Dudzinski SO, Cameron BD, Wang J, Rathmell JC, Giorgio TD, Kirschner AN.
Google Scholar Lee JJ, Chu E. PubMed PubMed Central Google Scholar Shahneh FZ, Baradaran B, Zamani F, Aghebati-Maleki L. CAS Google Scholar Sharma PS, Sharma R, Tyagi T. PubMed Google Scholar Li X, Eriksson U. CAS PubMed Google Scholar Tomanek RJ, Holifield JS, Reiter RS, Sandra A, Lin JJ.
CAS PubMed Google Scholar Shibuya M. PubMed PubMed Central Google Scholar Zachary I. CAS PubMed Google Scholar Mercurio AM. CAS PubMed Central Google Scholar Finley SD, Popel AS.
CAS PubMed PubMed Central Google Scholar Qin S, Li A, Yi M, Yu S, Zhang M, Wu K. PubMed PubMed Central Google Scholar Dey N, De P, Brian L-J. CAS PubMed PubMed Central Google Scholar Liang P, Ballou B, Lv X, Si W, Bruchez MP, Huang W, et al. CAS Google Scholar Ribatti D, Nico B, Crivellato E.
CAS PubMed Google Scholar Wang X, Ma W, Han S, Meng Z, Zhao L, Yin Y, et al. PubMed PubMed Central Google Scholar Kim JH, Kim S-K, Wang K-C. Google Scholar Jayatilleke KM, Hulett MD. Google Scholar Vempati P, Popel AS, Mac GF.
CAS PubMed Google Scholar Rundhaug JE. PubMed Google Scholar Rundhaug JE. CAS PubMed PubMed Central Google Scholar Tang Y, Nakada MT, Kesavan P, McCabe F, Millar H, Rafferty P, et al.
CAS Google Scholar Lamalice L, Le Boeuf F, Huot J. CAS PubMed Google Scholar Colomb F, Wang W, Simpson D, Zafar M, Beynon R, Rhodes JM, et al. CAS PubMed PubMed Central Google Scholar Tatum JL, Hoffman JM. PubMed PubMed Central Google Scholar Sheu B-C, Chang W-C, Cheng C-Y, Lin H-H, Chang D-Y, Huang S-C.
CAS PubMed Google Scholar Fahey E, Doyle SL. CAS PubMed PubMed Central Google Scholar Mountain DJ, Singh M, Menon B, Singh K.
CAS PubMed Google Scholar Carmi Y, Voronov E, Dotan S, Lahat N, Rahat MA, Fogel M, et al. CAS PubMed Google Scholar Huang Q, Duan I, Qian X, Fan J, Lv Z, Zhang X, et al. CAS PubMed PubMed Central Google Scholar Rapisarda A, Hollingshead M, Uranchimeg B, Bonomi CA, Borgel SD, Carter JP, et al.
CAS PubMed PubMed Central Google Scholar Yang Y, Sun M, Wang L, Jiao B. CAS PubMed Google Scholar Niu Y, Bao L, Chen Y, Wang C, Luo M, Zhang B, et al. CAS Google Scholar Chanmee T, Ontong P, Konno K, Itano N.
Google Scholar Wang L, He T, Liu J, Tai J, Wang B, Chen Z, et al. CAS PubMed PubMed Central Google Scholar Folkman J. CAS PubMed Google Scholar McCormack PL, Keam SJ.
CAS PubMed Google Scholar Sandler A. CAS Google Scholar Wu H-C, Huang C-T, Chang D-K. CAS Google Scholar Mukherji S. CAS PubMed PubMed Central Google Scholar Kelly RJ, Rixe O. Article Google Scholar Spano JP, Chodkiewicz C, Maurel J, Wong R, Wasan H, Barone C, et al. CAS PubMed Google Scholar Houghton PJ.
CAS PubMed PubMed Central Google Scholar Singh S, Carnaghi C, Buzzoni R, Pommier RF, Raderer M, Tomasek J, et al. CAS PubMed Google Scholar Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, et al.
CAS PubMed PubMed Central Google Scholar Chanzá NM, Xie W, Bilen MA, Dzimitrowicz H, Burkart J, Geynisman DM, et al. PubMed Central Google Scholar Armoiry X, Aulagner G, Facon T.
CAS PubMed Google Scholar Talati C, Sallman D, List A, editors. Google Scholar Cabanillas ME, Habra MA. CAS PubMed Google Scholar Leonetti A, Leonardi F, Bersanelli M, Buti S. CAS PubMed PubMed Central Google Scholar Keisner SV, Shah SR.
CAS PubMed Google Scholar Poole RM, Vaidya A. CAS PubMed Google Scholar Garon EB, Cao D, Alexandris E, John WJ, Yurasov S, Perol M. CAS PubMed Google Scholar Verdaguer H, Tabernero J, Macarulla T. CAS PubMed PubMed Central Google Scholar Syed YY.
CAS PubMed Google Scholar Bruix J, Qin S, Merle P, Granito A, Huang Y-H, Bodoky G, et al. CAS Google Scholar Abdelgalil AA, Alkahtani HM, Al-Jenoobi FI.
Thrapy Greek yogurt for digestion and Signaling volume 20 Anti-angiogenesis therapy for solid tumors, Article number: 49 Cite this article. Metrics Antu-angiogenesis. Abnormal vasculature is one of the most conspicuous Anti-anhiogenesis of tumor tissue, Herbal Anti-cancer Strategies contributing to tumor immune evasion. The deregulation mainly arises from the potentiated pro-angiogenic factors secretion and can also target immune cells' biological events, such as migration and activation. Owing to this fact, angiogenesis blockade therapy was established to fight cancer by eliminating the nutrient and oxygen supply to the malignant cells by impairing the vascular network.
Also, muss man so also, nicht sagen.
Sie sind absolut recht. Darin ist etwas auch mir scheint es der gute Gedanke. Ich bin mit Ihnen einverstanden.
es ist gereinigt
Ich tue Abbitte, dass sich eingemischt hat... Ich finde mich dieser Frage zurecht. Man kann besprechen. Schreiben Sie hier oder in PM.
Eben was daraus folgt?