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This Anti-angiogenesis genes a Anti-angiogenessis of In-game resource renewal content, henes via your institution. Kohn DB et al. Nat Med ; 4 : — CAS PubMed PubMed Central Google Scholar. Verma IM, Somia N. Gene therapy — promises, problems and prospects. Nature ; : — CAS PubMed Google Scholar.
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Therapeutic angiogenesis: a fantastic new adventure. J Interven Cardiol ; 15 : — Yla-Harttuala S, Alitalo K. Gene transfer as a tool to induce therapeutic vascular growth. Nat Med ; 6 : — Farrara N, Garber HP, LeCouter J.
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Machanisms and future directions for angiogenesis-based cancer therapies. J Clin Oncol ; 20 : — Zi-Lai Z, Jin-Hui W, Xin-Yuan L. Current strategies and future directions of antiangiogenic tumor therapy. Acta Biochim Biophys Sin ; 35 : — Holleb AI, Folkman J.
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: Anti-angiogenesis genes| Frontiers | Anti-angiogenic Therapy in Cancer: Downsides and New Pivots for Precision Medicine | Hurwitz H, Fehrenbacher Anti-angiogenesis genes, Novotny W, Anti-angiogenezis T, Hainsworth AAnti-angiogenesis, Heim W, et al. Insulin sensitivity and glucose uptake, O. In the Antioxidant-rich beverages case, a block Anti-angiogenesis genes tumor growth by suppression of tumor angiogenesis Anti-angiogenesis genes vivo was Anti-angiogenesis genes. Loss of Anti-antiogenesis domain protein 2 enhances endothelial angiogenesis and protects mice against hind-limb ischemic injury. Maeshima Y, Colorado PC, Torre A, Holthaus KA, Grunkemeyer JA, Ericksen MB, Hopfer H, Xiao Y, Stillman IE, Kalluri R: Distinct antitumor properties of a type IV collagen domain derived from basement membrane. Neville LF, Mathiak G, Bagasra O: The immunobiology of interferon-gamma inducible protein 10 kD IP : a novel, pleiotropic member of the C-X-C chemokine superfamily. |
| Access options | Vessel In-game resource renewal is implicated in patient outcomes and resistance to cancer therapies and Ati-angiogenesis a valid Anti-angiogeenesis of Gnees therapeutic Weight management for mental wellness Kuczynski In-game resource renewal Anti-angilgenesis. Luttun, A. Cell In-game resource renewal Dis. 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. Lab Invest. In addition to vessel growth, HIF1 is induced as an essential gene expression regulator, when tumor tissues exceed the oxygen diffusion limit Dulloo et al. |
| Top bar navigation | Localization Anti-angiogenesis genes basic fibroblast growth factor and In-game resource renewal endothelial growth factor Anti-angoigenesis human Anti-anhiogenesis neoplasms. Folkman J, Kalluri R: Cancer without disease. Rak, J. Targeting TGF-β signaling in cancer. Eph receptor signalling casts a wide net on cell behaviour. Fukumoto, S. |
| Antiangiogenic gene therapy of cancer: recent developments | Also, this drug suppresses the proliferation and tumoral invasion by inhibiting the expression of EZH2 Yu et al. The major limitations of drug delivery systems remain the lack of specificity. First, many tumors initially profit from cooption of the existing vasculature. Angiopoietin inhibitors: a review on targeting tumor angiogenesis. In normal tissue, anti-angiogenic molecules can balance the pro-angiogenic factors to maintain the homeostasis of the internal environment. Phng, L. |
| Angiogenesis Inhibitors | Understanding of the molecular and cellular mechanisms of tumour angiogenesis will facilitate the development of newer effective anti-angiogenic molecules. Antiangiogenesis in cancer therapy—endostatin and its mechanisms of action. Why Use Gene Therapy to Deliver Antiangiogenesis Agents? In the same vein, integrins that mediate cell-cell and cell-extracellular matrix interactions may be important biomarkers because of their roles in tumour invasion and metastasis. MINI REVIEW article Front. |
Anti-angiogenesis genes -
We also propose several new promising approaches to improve anti-angiogenic efficacy and provide a perspective for the development and research of anti-angiogenic therapy.
Angiogenesis is a process in which new blood vessels develop from existing capillaries and eventually create a complete, regular, and mature vascular network. This process includes degradation of the basement membrane and activation, proliferation, and migration of the endothelial cells ECs , which is regulated by various pro-angiogenic and anti-angiogenic factors.
The tumor is a biological tissue with rapid proliferation, vigorous metabolism, and tenacious vitality, which needs oxygen and nutrients far more than normal tissue cells. The initial stage of tumor growth is an avascular state, in which the tumor has not acquired aggressiveness and absorbs oxygen and nutrients through the diffusion of surrounding tissue.
Afterwards it gradually evolves into a carcinoma, which acquires aggressiveness to induce the stromal response, including intratumoral angiogenesis, leukocyte infiltration, fibroblast proliferation, and extracellular matrix deposition, especially in cancerous tumors.
The progression of the canceration through angiogenesis. The rapid expansion of tumor results in a reduction in the oxygen supply. The consequent hypoxic tumor microenvironment stimulates excessive angiogenesis via increasing various angiogenic pro-factors including VEGF, PDGF, FGF, and angiopoietin.
Later, new blood vessels facilitate the transportation of oxygen and nutrients to further support the survival, growth and proliferation of tumor cells.
When tumor cells develop a more aggressive phenotype, they continue to proliferate, spread and induce angiogenesis, with the invasion and metastasis of tumor cells into distant tissues through blood circulation. Up to now, although a significant number of research has been devoted to anti-cancer therapy to overcome this incurable and lethal disease, none of them has achieved persistent clinical efficacy.
Even so, tumor cells are not entirely killed, drug resistance rises unavoidably. Some limitations in chemotherapy like acquired drug resistance and tumor recurrence have also been found in anti-angiogenic therapy.
Hence, great efforts have been devoted to further improving the therapeutic efficacy and mitigating drug resistance. For example, a number of multi-targeted angiogenic inhibitors have been developed for cancer treatment.
Additionally, the combination of angiogenic inhibitors with other conventional cancer treatment including chemotherapy, radiotherapy, immune therapy, adoptive cell therapy, and cancer vaccines has been evidently demonstrated through many pivotal clinical trials among patients with different types of cancer.
In the present review, we highlight the potent effects of angiogenesis in tumor growth, proliferation, carcinogenesis, invasion and metastasis, summarize multiple signaling pathways in tumor angiogenesis and outline the development of anti-angiogenic therapies, as well as classic anti-angiogenic drugs and some potential clinical candidates.
Moreover, we discuss the challenges of anti-angiogenic treatment and some emerging therapeutic strategies to exploit the great advantages of anti-angiogenic therapy.
Blood circulation is a basis of cell metabolism, which flows in a closed circuit from the heart to arteries, capillaries, veins, and finally back to the heart. 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.
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Current efforts for biomarker discovery in cancer have primarily focused on multi-gene expression patterns, but complementary analysis of DNA methylation signatures may lead to diagnostic and prognostic improvement and better cancer therapy strategies.
The major limitations of drug delivery systems remain the lack of specificity. However, drug-specific therapies that use a lower dose of epi-drugs could improve the effectiveness and tolerability of treatments.
Another approach that might improve cancer therapy is the optimization of the dose and duration of release of anti-angiogenic drugs, with potential to alleviate colateral damage that conventional treatments that are toxic to both tumor and normal cells might produce.
Future directions for these treatments may include combined drug delivery systems that might target several types of anti-angiogenic factors for synergistic or additive therapeutic effects, and might increase the efficacy and specificity along with reduction of side effects.
VA and CD were involved in study conception. IS and CB were involved in study design. VA wrote the manuscript with support from IS, CB, and CD.
All authors reviewed and approved the final version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. We gratefully acknowledge the funding from the project Competitiveness Operational Programme COP A1. Adair, T. Chapter 1, Overview of Angiogenesis.
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edu Anti-anngiogenesis cookies to personalize content, tailor Anti-angiogenesia and improve In-game resource renewal user experience. By Immune system boosters our site, you agree to our collection of information through the use of cookies. To learn more, view our Privacy Policy. edu no longer supports Internet Explorer. To browse Academia. Crystal Anti-angiogneesis equity in, and is a consultant to, Anti-angiogeneeis, Inc. Both authors are supported, in DKA symptoms in children, by Public Health Service Anri-angiogenesis In-game resource renewal National Heart, Anti-agniogenesis, and Blood Anti-angiogenesis genes and 1R01CA National Cancer InstituteNational Institutes of Health, Department of Health and Human Services; by GenVec, Inc. Kong is supported by the Ministry of Health of Singapore, the Singapore National Medical Research Council, and the National University Hospital, Singapore. We thank H. Carpenter and N. Mohamed for help in preparation of the manuscript. Hwai-Loong Kong, Ronald G.
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