Anti-angiogenesis agents -
In the phase II clinical trials, fruquintinib showed a significant PFS benefit in patients with treatment-refractory mCRC [ 79 ]. Then, a randomized, double bind, phase III FRESCO trial conducted by Li et al.
laid the foundation for the approval of this drug on patients with mCRC by the CFDA in [ 80 ]. In this study, mCRC patients who had progressed after at least two lines of chemotherapy were allocated to receive either fruquintinib or placebo.
The primary end point median of OS was significantly longer in the fruquintinib group compared to placebo 9. Moreover, higher ORR and DCR were observed in patients receiving fruquintinib with a manageable safety profile.
Additionally, a phase I clinical trial is ongoing in the USA, exploring the efficacy and safety in non-Chinese populations [ 81 ]. While the approved anti-angiogenic TKIs are trying to expand their indication in other cancer types, numerous new anti-angiogenic TKIs are also being extensively explored.
Three representative TKI drugs with potential to be approved in the near future are presented. Motesanib was considered as a potent anti-tumor drug in Asian advanced NSCLC patients based on the subgroup analysis of MONET1 trial [ 83 ]. However, the results of later phase III trial MONETA were disappointing with no advantage in patients receiving motesanib plus paclitaxel and carboplatin over placebo plus paclitaxel and carboplatin [ 84 ].
Nevertheless, two phase II trials have indicated remarkable anticancer activity of motesanib among patients with advanced thyroid cancer [ 85 , 86 ]. Recently, Lubner et al. examined the efficacy of motesanib in low-grade NETs in a phase II trial [ 87 ].
The study reached its primary objective with a 4-month PFS of All in all, motesanib is as potential as a systemic targeted therapy for NETs, but its niche in the treatment of NETs still needs further study.
Though, cediranib had failed phase III clinical trials in NSCLC [ 89 ], mCRC [ 90 , 91 ], and recurrent glioblastoma [ 92 ], it showed new hope in recurrent ovarian cancer. The ICON6 trial evaluated the efficacy and safety of cediranib plus platinum-based chemotherapy and as continued maintenance treatment in patients with relapsed platinum-sensitive ovarian cancer [ 93 ].
Unfortunately, the ICON6 trail was prematurely terminated on account of the depressing results in other cancer types.
Most common side effects of grade 3—4 in arm C were neutropenia, fatigue, and hypertension during the chemotherapy phase and diarrhea, fatigue, and neutropenia during maintenance treatment. A phase I study NCT observed an acceptable safety profile and encouraging antitumor activity in patients with advanced solid tumors, particularly in NETs [ 95 ].
At present, one phase II study NCT and two phase III studies NCT, NCT conducted on advanced NETs are ongoing [ 96 ].
Immunotherapy has been changing the paradigm of oncology treatment in the recent years [ 97 , 98 , 99 ]. Whether the combination of TKIs and immunotherapy can create synthetic effect is a hot topic. The emerging evidences suggest that anti-angiogenic therapy may not only inhibit neo-vascular formation, but also regulate the immune microenvironment [ ].
This provided a theoretic basis for the combination of TKIs and immunotherapy. Subsequently, hundreds of clinical trials were designed to access the efficacy of combining TKIs with immune checkpoint blockade.
A phase Ib study JAVELIN Renal conducted by Choueiri et al. interrogated the combination therapy of axitinib plus avelumab a PD-L1 mAb in advanced RCC patients [ ]. These encouraging results supported the further study of these drug combinations. Now, the phase III JAVELIN Renal trial finished [ ].
The result showed that in patients with mRCC, the axitinib plus avelumab group showed a remarkable improvement in median PFS compared with sunitinib The combination of axitinib and avelumab would be a promising strategy for patients with mHCC based on the positive result of JAVELIN Renal Other combinations such as lenvatinib plus pembrolizumab or SHR plus apatinib in patients with HCC were also ongoing [ ].
The combination of immunotherapy with TKIs has demonstrated promising outcome in a certain type of carcinomas, but further optimized combinations are required and caution must be taken to avoid severe toxicity.
The development of anti-angiogenic agents has attracted great attention. Bevacizumab, the first clinically approved anti-VEGF targeted agents, provides a first proof of principle of anti-angiogenic treatment in cancer.
Though monotherapy with bevacizumab is largely inefficient, it really exerts therapeutic efficacy in various types of carcinoma when in combination with chemotherapy [ ]. Because tumor angiogenesis is regulated by multiple pathways, many interconnected pathways can compensate the effect of single inhibition of VEGF signaling.
It seems that multi-targeted TKIs hold a therapeutic advantage over monoclonal antibody as they can block multiple angiogenic signaling pathways simultaneously.
Indeed, TKIs have shown their efficacy in many types of cancers, mainly RCC and HCC. Although all anti-angiogenic receptor TKIs share the same mechanism of action and the similar spectrum of targeted kinases, they are different in their pharmacokinetics and substance-specific AEs.
The one possible explanation may be that the subtle difference on chemical structure leads to the variable affinity and potency to targets. Another possibility is that those TKIs may act on some unidentified targets beyond known kinases. With more and more anti-cancer agents available, it is a challenge for the oncologist to make an optimal choice in the sequence of treatment.
For instance, 12 drugs have been approved for patients with HCC, including 6 anti-angiogenic TKIs until [ ]. Though, the international guidelines have reached a global consensus for the choice of drugs in different lines. The optimal strategy and the sequence of drugs as well as the right time of the incorporation of other therapeutic methods such as surgery, radiology has not yet been resolved.
Tolerance of receptor TKIs should also be taken into account. Another challenge for anti-angiogenesis TKIs is the lack of robust biomarkers to identify patients with cancer who will benefit from anti-angiogenic therapy.
Unlike RTK inhibitor, larotrectinib is special for cancer with tropomyosin receptor kinases TRK fusion-positive and has demonstrated significant efficiency in patients with different tumor histology [ ].
One of the main problems in identifying such a biomarker for anti-angiogenic therapy may come from the complex feedback loops and cross talk between signaling pathways. Currently, some biomarkers have been proposed, such as VEGF, VEGFR-2, FGF-2, or IL-8, but none of them have yet been validated for routine clinical use [ ].
Recently, a cohort study conducted by Liu et al. indicated a positive correlation between the anti-angiogenesis-related AEs and prolonged OS [ ]. It means that side effects, such as high blood pressure, hypothyroidism, or hand-foot syndrome, may associate with the anti-tumor efficacy.
Similarly, Rini et al. As there are no molecular biomarkers available for clinical use, those side effects might be helpful for clinical decision. The future of TKIs could be their positioning besides metastatic setting, such as in adjuvant therapy and neoadjuvant treatment. There were three well-known phase III clinical trials that explored the use of TKIs in RCC in adjuvant setting, namely ASSURE adjuvant sunitinib vs.
sorafenib vs. placebo , PROTECT pazopanib vs. placebo , and S-TRAC sunitinib vs. placebo [ , , ]. Only S-TRAC study showed a significant improvement by sunitinib in disease-free survival in high-risk RCC after nephrectomy [ ].
Based on the result of S-TRAC trial, sunitinib was approved by the FDA as an adjuvant therapy for RCC patents in Unfortunately, adjuvant sorafenib for HCC patients reached a negative result [ ].
The utilization of TKIs before surgery has also been studied. A phase II trial explored the safety and efficacy of the use of pazopanib prior to cytoreductive nephrectomy RCC patients, suggesting the safety, and clinical benefit could be expected [ ].
The precision role of anti-angiogenic TKI in adjuvant and neoadjuvant therapy needs further investigation. It is noted that the indication of these receptor TKIs are mainly restricted to highly vascular tumor, like RCC, HCC, NSCLC, and CRC. Their efficacy in other types of cancers needs further exploration [ 30 ].
In most case, anti-angiogenesis treatment increases the PFS of patients, while the increase in OS is unsatisfactory. Great breakthrough in immunotherapy brings new possibility for the combination of TKIs, and positive results in a certain type of carcinoma attract broad attention [ ].
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Cabozantinib in progressive medullary thyroid cancer. Priya SR, Dravid CS, Digumarti R, Dandekar M. Targeted therapy for medullary thyroid cancer: A review. Front Oncol. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Aflibercept is a fusion protein composed of the constant Fc domain of human IgG combined with the second immunoglobulin domain of VEGFR-1 and the third immunoglobulin domain of VEGFR It acts like a VEGF trap and a decoy receptor of angiogenic factors.
It targets VEGFA, VEGFB and PIGF. It is used for the treatment of metastatic colorectal cancer. In the VELOUR phase II trial of patients with advanced colorectal cancer who had failed an oxaliplatin-based regimen, patients on aflibercept showed significant improvement in overall survival and progression-free survival [ 15 ].
However, in the VITAL study, a phase III trial of aflibercept plus docetaxel vs. docetaxel alone in patients with advanced non-small-cell lung cancers NSCLC who had failed therapy with a platinum-based regimen, aflibercept did not affect overall survival though it reduced progression-free survival [ 16 ].
Ramucirumab is a human monoclonal antibody that blocks the interaction between VEGF and its receptor by binding to the extracellular domain of VEGFR2. It has high selectivity for VEGFR2. Following the RAISE study, it was approved in combination with folinic acid, 5-fluorouracil and irinotecan for the treatment of metastatic colorectal cancers that have progressed despite therapy with bevacizumab, oxaliplatin and fluoropyrimidine [ 17 ].
It is also approved as second-line therapy for gastric and NSCLC [ 18 ]. Some target VEGFRs e. sunitinib and sorafenib but they often target other pathways e. PDGFR, FGFR and c-Kit. Details of their action are shown in Table 1. These medications are susceptible to resistance when used as monotherapy.
There is also concern that they may increase the malignant potential of cancer cells. Dll4 and Notch are upregulated by VEGFA and act as negative feedback for vessel sprouting and angiogenesis under normal physiologic conditions. When Dll4 downregulation with siRNA was combined with anti-VEGF therapy, it resulted in greater tumour growth inhibition than either alone [ 19 ].
MEDI, a Dll4-Notch disrupter has shown promise in a preclinical study [ 19 ]. Demcizumab, another Dll4 inhibitor, has been trialed in pancreatic, metastatic colorectal cancers and NSCLCs [ 20 ].
After discovering the role of HIF system in the expression of different genes and proteins that are essential for tumour growth and survival, this system has become a target for newly investigated tumour therapeutics [ 21 ].
Agents have been discovered that inhibit different steps of HIF1-α signaling, from its expression to DNA binding and transcription. Jeong et al. A phase I trial has evaluated this molecule and found that the expression of HIF1-α was reduced in four out of six patients with solid tumors [ 22 ]. Despite tremendous research in this area, no drug directly tackling this system has been approved for cancer therapy yet.
This remains a promising therapeutic area. The angiopoietin-Tie axis is another important pathway in tumour angiogenesis. Both Ang1 and Ang2 are upregulated in many tumours, but each has a different effect on Tie2 signaling.
Ang1 binds to Tie2 receptor causing a reduction in vascular permeability and promotion of vessel maturation and stabilization. Ang2 antagonises Ang1 and induces neovascularization by destabilizing endothelial-pericyte junctions and promotes endothelial cells EC survival, migration and proliferation.
Thus, a higher ratio of Ang2 to Ang1 levels predicts worse clinical outcomes. The effect of Ang2 signaling appears to largely depend on other proangiogenic cytokines being present e. Ectopic Ang2 expression interferes with VEGFR2 blockade and combined inhibition of Ang2 and VEGFA produce a greater reduction in angiogenesis in laboratory models.
Regorafenib, a multi-target RTK inhibitor with VEGFR and Tie2 activity, demonstrated efficacy as third-line therapy for metastatic colorectal cancer and gastrointestinal stromal tumours GIST [ 20 ]. Trebananib is a peptide Fc fusion protein that inhibits the interaction between Ang1, Ang2 and Tie2.
It has shown promise in phase II trials. It has been combined with paclitaxel, carboplatin and liposomal doxorubicin in phase III trials [ 23 ]. A summary of anti-angiogenics in clinical use is shown in Table 1. These antiangiogenics inhibit tumour growth by blocking vascular supply, triggering degeneration of vascular networks, cellular apoptosis, stimulating tumour hypoxic death and modulating inflammatory cells and effectors.
Contrary to the initial hope about anti-angiogenics in cancer therapy, these agents only increase survival by an average of few months. Furthermore, the failure to identify and validate durable predictive markers of response, and the need to better characterize the mechanisms of tumour resistance have been the challenges limiting anti-angiogenic therapy.
Even though inhibition of VEGF pathways has anti-tumour effects in mouse cancer models, they elicit tumour adaptation, increased invasiveness and metastasis through the upregulation of alternative growth and angiogenic pathways [ 24 ]. Many patients treated with VEGF inhibitors especially when combined with chemotherapy may survive longer, but they eventually succumb to their disease.
VEGFA may be replaced by other angiogenic pathways as the disease progresses. These include VEGF upregulated pathways and other pathways mediated by other members of the VEGF family which may bind to and activate VEGFR2 after proteolytic cleavage. Investigators have identified other mechanisms of failure and resistance to anti-VEGF therapy.
The hypoxic environment of tumours while on anti-VEGF therapy results in upregulation of other chemokines and growth factors e. bFGF, PDGF, HGF, IL-1, IL-8 and ephrins which become hypoxia independent and do not respond to bevacizumab [ 25 , 26 ]. This facilitates rebound angiogenesis, tumour revascularization, escape from immune cells and tumour invasion [ 24 ].
This has been shown in patients with colorectal cancers and renal cell cancers. Moreover, hypoxia after tumour regression following VEGF blockade can lead to a switch to a more invasive nature since in some cases, cancer stem cells can become tolerant to hypoxia following the acquisition of extra mutation.
In addition, VEGF blockade may not be effective in suppressing other pathways of vascularization especially those that rely on recruitment of bone marrow-derived cells, vascular mimicry or vessel co-option.
Some tumours are also largely hypovascular e. pancreatic cancer and may not respond to anti-VEGF therapy. Furthermore, tumour vessel remodeling results in a shift to mature stabilized vessels that are less responsive to antiangiogenic therapy. It appears that signals from the stromal component of tumours play a role in acquired resistance to antiangiogenic therapy.
Moreover, EPCs are involved in the angiogenic switch from micro-metastasis to macro-metastasis. These cells are recruited into premetastatic sites in response to SDF-1 and CXCL15 gradients and promote metastasis via metalloproteinase-induced pathways [ 27 ]. Thus, targeting myeloid cells and their homing into tumour sites may break the jinx.
This behaviour of tissue EPCs and myeloid cells can be used as predictive markers of response to antiangiogenic therapy as discussed later below. Endothelial to mesenchymal transition in cancer cells contributes to increased angiogenesis, invasiveness and unresponsiveness to VEGF blockade.
Cancer-associated fibroblasts contribute to tumour angiogenesis via the release of stromal-derived factor SDF-1 which leads to the recruitment of bone marrow cells and assembly of the endothelial population in the tumour vasculature [ 28 ]. This occurs via hypoxia-induced HIF-1α activation.
SDF-1 can stimulate CXCR7 leading to proangiogenic cytokine secretion by endothelial progenitor cells. The recruitment of myeloid-derived suppressor cells leads to a weakened antitumour response. Myeloid cells of the mononuclear macrophage lineage are activated and mediate multiple pathways that lead to tumour progression and angiogenesis.
Also, there is selection pressure that leads to overgrowth of tumour cell variants that are resistant to hypoxia-mediated angiogenesis. It may also be that doses of current anti-VEGF therapies are not optimal for targeting cure. Furthermore, integrin-mediated signaling in vascular beds may provide alternative mitogenic and survival signals.
Evidence from preclinical studies has shown the interaction between integrins and receptor tyrosine kinases RTKs in tumour invasion [ 29 ]. Genetic alterations in tumours may decrease the vascular dependence of tumour cells and affect therapeutic response to antiangiogenic therapy.
In the study by Yu et al. Vessel co-option is another mechanism of tumour resistance to anti-angiogenic therapy [ 26 ]. Tumour cells can incorporate existing vasculature to accelerate their growth. This has been shown in gliomas and lung cancers and in patients with colorectal cancer treated with bevacizumab [ 31 ].
Tumour cells also use vasculogenic mimicry to evade antiangiogenic therapy. They can differentiate and gain EC-like features e. expression of VE cadherin and ephrin A2.
This is important for invasion and metastasis. An interesting concept in anti-angiogenic therapy is vascular normalization and re-distribution of flow in tumour vascular bed when anti-angiogenics are combined with the conventional chemotherapy regimen [ 32 ].
It has been suggested that normalising the tumour vasculature would diminish endothelial and perivascular cells, decrease the high interstitial pressures in solid tumours, enhance oxygenation and chemotherapy delivery into tumour cells [ 11 ].
Antiangiogenic agents do not achieve enough efficacy when they destroy tumour vascular networks as monotherapy but rather, by pruning tumour vascular networks when administered with other chemotherapeutics, they reduce vascular hydrostatic pressure, tumour-associated oedema and temporarily improve tumour hypoxia, thus improving delivery and activity of chemotherapeutics which can then effectively destroy tumour cells.
This has been demonstrated in colorectal cancers and glioblastoma multiforme [ 32 , 33 ]. Recently, a combination of bevacizumab with paclitaxel and carboplatin in patients with non-small cell lung cancer NSCLC has also shown improved survival [ 11 ].
In tumours, molecules involved in immune checkpoint e. PD-1 interacts with its ligand, PD-L1 in immune and cancer stromal cells to inhibit the proliferation and survival of T cells which are important in immune surveillance of tumours [ 33 ].
Hijacking of PD-PD-L1 pathway activation by solid tumours leads to T cell exhaustion and increased expression of FoxP3 by regulatory T cells Tregs with resultant immunosuppression and tumour resistance.
The combination of low-dose VEGFR2 blockade and a cancer vaccine also led to an increased immune response to tumour cells, vascular normalisation and improved survival in mice models of breast cancer and colon cancer [ 34 , 35 ]. There are now ongoing trials investigating the role of dual anti-angiogenic therapy and immunotherapy using bevacizumab with atezolizumab e.
in advanced renal cell cancers NCT [ 33 ]. Triple therapy using a combination of anti-angiogenic agents, immunotherapy and conventional chemotherapy are also being trialed in metastatic solid tumours NCT, NCT [ 33 ].
These trials have a high potential for overcoming of tumour resistance to anti-angiogenic molecules in future. Reliable biomarkers of tumour response to antiangiogenic therapy have become a focus of attention given the risk of tumour resistance and adverse events. However, most of the studies have been inconsistent.
Circulating VEGF levels have been investigated as a predictive biomarker of response to anti-VEGF therapy. In the study by Hillan et al.
In the TARGET trial which investigated sorafenib in advanced renal cell carcinoma, serum VEGF levels had an inverse relationship with progression-free survival and overall survival [ 37 ]. Taken together, it seems that while VEGF has prognostic value, it is not a reliable predictor of response to therapy.
Vascular endothelial cadherin is another potential biomarker [ 38 ]. It is important in maintaining EC contact. It also plays important role in regulating cell proliferation, apoptosis and modulates VEGFR2 function.
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. Nanoparticles bearing αvβ3 integrins are being investigated for molecular tumour imaging.
Circulating levels of HGF, IL-6, IL-8, osteopontin and TIMP1 have been shown to identify patients who had greater overall survival benefit from treatment in pazopanib-treated patients with metastatic renal cell cancers in one study [ 41 ].
Challenges with the use of circulating biomarkers include the absence of standardization of measurements across centres and the absence of accepted cut-off levels for these circulating biomarkers.
Moreover, circulating factors tend to fluctuate in disease settings and disease stage. Mast cells and miRNAs are increasingly being investigated as diagnostic and prognostic biomarkers in tumours like colorectal cancers and are potential therapeutic targets [ 42 ].
High mast cells density is correlated with the advanced stage of colorectal cancer and tumour progression. Recently, mast cell tryptase inhibitors e. gabexalate mesylate and nafamostat mesylate have been studied in metastatic gastric cancers with encouraging result [ 43 ].
There has been an interest in non-coding miRNAs in colorectal cancer progression. miRNA and miRNA are oncogenic miRNAs seen at all stages of colorectal cancer progression [ 42 ].
Their levels in tumour tissues have been correlated with survival in individuals with colorectal cancers. miRNA has been shown to confer tumour resistance to 5-fluoro uracil by downregulating MutS homologue-2 while high levels of miRNA have been correlated with oxaliplatin resistance [ 42 ].
The development of drugs which target the secretion or action of these miRNAs holds great promise for the prevention and treatment of tumour resistance in patients on anti-angiogenic treatment and conventional chemotherapy.
Microvascular density in serial tumour biopsies has been proposed as a reliable biomarker of response along with the measurement of circulating angiogenic markers and adhesion molecules [ 44 ]. A meta-analysis showed that micro-vessel density predicted survival in non-small cell lung cancer NSCLC [ 45 ].
Anti-angiogenics may not only affect tumour vessels but also the normal vasculature; thus, healthy tissue in tumours may be used to monitor antiangiogenic therapy in tumours. Vessel density and intra-tumour blood supply may be estimated using imaging methods like contrast-enhanced MRI or PET.
In one clinical trial of metastatic colon cancer, epithelial and stromal VEGF expression and micro-vessel density were not predictive of the benefit of the addition of bevacizumab to 5-fluorouracil based therapy [ 46 ].
Vascular imaging using ultrasound, CT, MRI or PET is another predictive marker that can be used to assess response to treatment as shown by the use of MRI in monitoring response to antiangiogenic therapy in patients with glioblastoma multiforme GBM [ 47 ].
High levels of vascular perfusion on vascular imaging predicted response and outcome in patients with metastatic renal cell cancers who were treated with TKIs [ 48 ]. A recent study by Rojas et al. Challenges with using these imaging modalities include marked variability in methodologies used to assess imaging biomarkers across studies and the need for standardization of tumour molecular imaging.
Different types of biomarkers e. circulating and imaging may have to be combined to yield a composite biomarker for more robust predictors of response to antiangiogenic therapy.
The cardiovascular adverse effects of antiangiogenic therapy are worthy of mention. Some of the reported side effects are hypertension, cardiac dysfunction and myocardial ischaemia. These agents act by reducing nitric oxide expression which leads to vasoconstriction and elevation of blood pressure [ 50 ].
Other pathophysiologic pathways for hypertension include increased expression of endothelin-1, microvascular rarefaction, activation of the renin-angiotensin-aldosterone axis, oxidative stress, pressure natriuresis and arterial stiffness. VEGF signaling pathway inhibitors cause an increase in blood pressure with 7.
Blood pressure elevation occurs rapidly within hours or days of starting anti-VEGF therapy and is commensurate with effective VEGF signaling inhibition. It remains unclear whether blood pressure goals in such patients should be the same as for the general population even though current hypertension guidelines do not discriminate between these patients and the general population.
The risk of hypertensive target organ damage is increased in these patients. The National Cancer Institute recommends formal cardiovascular assessment before commencing anti-angiogenic therapy, and antihypertensives should be commenced in such patients once there is a more than 20mmHg rise in diastolic blood pressure from baseline even if blood pressure remains in the normotensive range [ 51 ].
There is a need to clarify the blood pressure threshold at which anti-angiogenic dose reduction or termination should be considered.
The preferred classes of antihypertensives in such instances are also a matter of debate. It is better to avoid non-dihydropyridine calcium channel blockers since they inhibit the CYP3A4 which is responsible for the metabolism of antiangiogenic medications and can thus elevate plasma levels of anti-angiogenics with resultant worsening of hypertension.
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. For example, a correlation between high circulating levels of VEGF-A and survival benefit in metastatic breast and gastric cancer patients treated with bevacizumab has been reported [ — ].
A large phase III trial MERiDIAN will prospectively test the utility of high circulating VEGF-A levels as a potential biomarker of response to bevacizumab in HER2-negative metastatic breast cancer [ ].
Biomarker signatures, composed of multiple circulating factors, may also have potential value as predictive biomarkers. In pazopanib-treated mRCC patients for example, circulating levels of six serum cytokines and angiogenesis factors CAF HGF, interleukin 6, interleukin 8, osteopontin, VEGF, and TIMP1 were able to identify a sub-set of patients that derived significantly greater overall survival benefit from treatment [ ].
Moreover, a serum-based protein signature composed of mesothelin, FLT4, AGP and CA has recently been shown to identify patients with ovarian cancer more likely to benefit from bevacizumab [ ]. However, there are several challenges associated with taking circulating factors forward as a prospective marker.
Firstly, measurement of circulating markers can be difficult to standardise across centres, due to technical issues associated with sample handling [ ]. Secondly, deciding on a predefined cut-off for high versus low levels of circulating factors is challenging because it may vary with geography and disease setting [ ].
Baseline predictive markers that are binary in nature i. a mutation or gene amplification are attractive because they may be easier to measure and apply prospectively than biomarkers based on the measurement of circulating factors.
A large study that examined data from two phase III trials of bevacizumab in metastatic pancreatic adenocarcinoma AViTA and mRCC AVOREN recently reported that a SNP in VEGFR1 was significantly associated with poor outcome in patients treated with bevacizumab [ ].
The same SNP has subsequently been associated with poor outcome in mRCC patients treated with sunitinib [ ]. Fine mapping of this SNP to tyrosine 1, of VEGFR1 shows that mutation at this site leads to increased expression and signalling of VEGFR1, providing a plausible explanation as to why VEGF-targeted therapy is less effective in patients bearing this SNP [ ].
Therefore, this work identifies a negative biomarker that might be used prospectively to exclude patients who are less likely to benefit from VEGF-targeted therapy. Functional imaging of the tumour vasculature, using CT, MRI or PET, is a potentially attractive approach for predicting response and outcome, as reviewed in [ ].
Imaging permits inspection of various parameters, such as tumour morphology and blood flow, which may provide important predictive information. There are studies showing that baseline features of tumours, such as the level of vascular perfusion, can predict response or outcome in patients treated with anti-angiogenic agents.
For example, at least 4 published studies demonstrate that a high level of vascular perfusion predicts for response or outcome in mRCC patients treated with TKIs [ — ]. Early changes in vascular characteristics detected on imaging after the initiation of therapy have also been shown to correlate with response or outcome.
For example, many studies performed in mRCC patients treated with TKIs show that a reduction in vascular perfusion on therapy provides extra predictive information regarding response or outcome than using criteria based on change in lesion size alone [ , — ].
Moreover, in patients with colorectal liver metastases treated with bevacizumab and chemotherapy, changes in tumour morphology on CT were shown to associate more significantly with overall survival than the use of RECIST criteria [ ].
Although these studies suggest a promising role for imaging as a predictive marker in certain settings, many challenges remain. For example, we have an incomplete understanding of how features detected on imaging correlate with the underlying tumour biology [ ].
Also, methodologies used to assess imaging biomarkers vary considerably between studies and require standardisation for their prospective application across multiple study centres [ ].
Therefore, biomarkers that predict response or outcome for VEGF-targeted therapy are emerging, but they require further standardisation and validation before they are incorporated into clinical practice.
Resistance to anti-angiogenic therapy is a prominent issue that likely explains the variable results obtained in the clinic with this approach.
Resistance can broadly be classified into intrinsic resistance where tumours fail to respond from the outset of treatment and acquired resistance where tumours initially respond and then progress whilst still on treatment [ ]. Since anti-angiogenic therapy targets tumour cells indirectly by acting on tumour blood vessels, mechanisms that determine response and resistance are likely to stem from a complex interaction between tumour cells and stroma.
Insight into this tumour-stromal relationship in the setting of intrinsic resistance can be gained from studies in mRCC patients, which examined both change in tumour blood flow and change in lesion size in clinically detectable tumours upon treatment with single agent anti-angiogenic therapy [ — ].
In some cases, a strong vascular response may be observed, which is accompanied by significant tumour shrinkage Fig. Tumours undergoing this type of response probably fulfil two important conditions: a the growth and survival of the vasculature is very sensitive to the agent, and b tumour cell survival is highly dependent on the vascular supply.
In the second instance, despite a strong vascular response, tumour growth is only stabilised Fig. In this scenario, tumour cells may be adapted to survive, despite a reduction in vascular supply. In the third instance, the targeted agent results in minimal or insignificant suppression of the tumour vascular supply, resulting in stabilisation of disease or tumour progression Fig.
In this scenario, the growth and survival of the vasculature is apparently poorly sensitive to the agent. Response and resistance to anti-angiogenic therapy. Tumours may respond initially to anti-angiogenic therapy in different ways. a Therapy results in a strong vascular response a significant reduction in the amount of perfused tumour vessels and significant tumour shrinkage.
b Therapy results in a strong vascular response, but only stabilisation of disease is achieved. c Therapy results in a poor vascular response minimal reduction in the amount of perfused tumour vessels and tumour stabilises or progresses.
d , e After a period of response, acquired resistance can occur. This may be due to the activation of alternative angiogenic pathways d or because tumour cells adapt to the lack of a vascular supply via various potential mechanisms e. Longitudinal assessment of mRCC patients treated with these agents demonstrates that acquired resistance to therapy can also arise following a period of initial disease control [ — ].
Acquired resistance may conceivably occur because the tumour finds alternative means to drive tumour vascularisation which are insensitive to the therapy Fig 3 d or because tumour cells become adapted so that they can grow despite the reduced vascular supply Fig 3 e [ ].
Evidence for specific cellular and molecular mechanisms that may underlie intrinsic or acquired resistance to anti-angiogenic therapy are discussed below. The tumour vasculature is heterogeneous with respect to its response to anti-angiogenic therapy, with some vessels being sensitive whilst others are resistant Fig.
In preclinical studies, VEGF-targeted therapy suppresses the growth of newly formed tumour vessels, but is less effective against more established tumour vasculature [ — ].
One aspect of vessel maturation is the recruitment of pericytes to tumour vessels, mediated by platelet-derived growth factors PDGFs. It has been demonstrated that inhibition of PDGF-mediated pericyte recruitment improves the efficacy of VEGF-targeted therapy [ , ].
Of interest, many clinically approved anti-angiogenic TKIs are potent inhibitors of both VEGF and PDGF receptors e. sunitinib, sorafenib, pazopanib and may therefore target pericyte recruitment. However, paradoxically, in xenograft models TKIs have been shown to result in either decreased or increased pericyte coverage, dependent on the study [ — ].
Therefore, whilst mature tumour vessels may be resistant to VEGF-targeted therapy, it is not currently clear how these tumour vessels can be effectively targeted. Potential mechanisms involved in resistance to VEGF-targeted therapy.
a Tumours present with a mixture of therapy-sensitive and therapy-insensitive vessels. The top vessel is destroyed by the therapy depicted in grey , whilst the bottom one remains depicted in red.
b Alternative signalling pathways can regulate the sensitivity of vessels to therapy. In the panel, the tumour cells in blue have up-regulated an alternative pro-angiogenic growth factor in order to drive blood vessel growth and survival. c Stromal cells, such as immature myeloid cells black or fibroblasts green infiltrate the tumour and mediate resistance either by releasing pro-angiogenic growth factors or by physically incorporating into vessels.
d Tumour cells can survive conditions of stress. Some tumour cells depicted in blue have survived the loss of a vascular supply, because they are adapted to survive conditions of hypoxia or nutrient shortage. e Tumours may use alternative mechanisms of vascularisation besides sprouting angiogenesis.
In intussusceptive microvascular growth new vessels are generated by the fission of existing vessels. Glomeruloid angiogenesis is characterised by tight nests of vessels that resmemble the renal glomerulus. In vasculogenic mimicry, tumour cells directly form vascular channels blue cells that are perfused via connection to the host vasculature red cells.
In looping angiogenesis, contractile myofibroblasts green pull host vessels out of the normal surrounding tissue pink region.
In vessel co-option tumour cells engulf host vessels in the normal surrounding tissue pink region as the tumour invades.
f Increased tumour aggressiveness i. Other pro-angiogenic signalling pathways can stimulate blood vessel growth and blood vessel survival even when the VEGF-pathway is blocked Fig.
Pre-clinical studies have identified numerous candidates including angiopoietins [ ], Bv8; Bombina variagata peptide 8 [ ], EGF; epidermal growth factor [ ], the Delta-Notch pathway [ ], FGF1 and FGF2; fibroblast growth factors 1 and 2 [ , ], HGF; hepatocyte growth factor [ ], IL-8; interleukin 8, [ ], PDGF-C; platelet derived growth factor-C [ , ] and PLGF; placental growth factor [ 26 ].
Most of these studies also show that co-targeting of VEGF and the candidate factor improves therapeutic response.
Therefore, therapies that target signalling by multiple pro-angiogenic growth factors may be necessary to achieve efficient and durable suppression of tumour angiogenesis and tumour growth. There is also clinical evidence showing that circulating levels of certain pro-angiogenic factors, including FGF2, HGF, PLGF and SDF-1α can become elevated in patients just prior to progression on anti-angiogenic therapy, providing potential evidence that these factors are indeed related to the development of acquired resistance [ , ].
However, the concept that these alternative growth factor and cytokine signalling pathways mediate resistance to anti-angiogenic therapy has yet to be truly validated clinically. The majority of TKIs used to treat patients including brivanib, cediranib, dovitinib, sunitinib, sorafenib, vatalanib and many others are multitargeted in nature and can suppress the signalling of multiple pro-angiogenic signalling pathways, including VEGF, FGF and PDGF.
And yet, despite this, tumours have been shown to progress through treatment with these agents in many indications, including metastatic breast cancer [ 44 — 47 ], glioblastoma [ 75 ], hepatocellular carcinoma [ , ] and mRCC [ ].
This is in contrast to preclinical studies demonstrating a role for alternative growth factor signalling pathways and questions the relevance of alternative pro-angiogenic growth factors in mediating resistance to anti-angiogenic therapy in patients.
It is now well established that tumours are a community composed of both transformed tumour cells and distinct stromal cell types.
These stromal cells include fibroblasts and many different kinds of immune cell such as lymphocytes, granulocytes and macrophages as well as the cells that make up the vasculature endothelial cells and pericytes.
The roles played by these different stromal cell types in tumour progression have been extensively reviewed [ — ]. Importantly, the tumour stroma can promote tumour progression and therapy resistance, including resistance to anti-angiogenic therapies [ — ]. Preclinical studies have demonstrated that infiltration of tumours by various stromal cell types, including immature myeloid cells [ , ], endothelial progenitor cells [ ] or fibroblasts [ ] can all mediate resistance to VEGF-targeted agents in preclinical models Fig.
Alternatively, there is evidence that immature myeloid cells and endothelial progenitor cells may promote resistance to therapy by physically incorporating into tumour vessels [ — ]. Inhibition of tumour vascularisation should reduce the supply of oxygen and nutrients to tumours and slow tumour growth.
However, preclinical work shows that tumour cells can be adapted to survive, even when the vascular supply is significantly reduced.
These survival mechanisms include a reduced propensity for certain tumour cells to die under conditions of stress and may be driven by genetic aberrations such as loss of p53 function [ , ].
Tumours treated with anti-angiogenic agents may also adapt to survive under conditions of nutrient withdrawal and hypoxia, by adapting their metabolism or through autophagy [ , — ].
Pre-adaptation or reactive adaptation to stress may therefore play a key role in determining whether tumours respond to VEGF-targeted therapies Fig. Despite a prevailing dogma that tumours utilise mainly VEGF-dependent sprouting angiogenesis Fig.
IMG is a process that generates two new vessels via the fission of an existing vessel Fig. It has been observed in human primary melanoma and glioblastoma [ , ]. Glomeruloid angiogenesis results in tight nests of tumour vessels known as a glomeruloid bodies Fig.
Glomeruloid bodies have been reported in a wide range of malignancies, including glioblastoma, melanoma, breast, endometrial and prostate cancer [ ].
In vasculogenic mimicry, tumour cells organise into vessel-like structures that are perfused via connection to the host vasculature Fig. It has been reported in many human cancers, including melanoma, breast, ovarian, prostate and sarcoma [ ].
Recent pre-clinical studies suggest that tumour stem cells can directly differentiate into endothelial cells or pericytes, which may be a mechanism for vasculogenic mimicry [ — ]. In looping angiogenesis, vessels are extracted from normal surrounding tissue by the action of contractile myofibroblasts [ ] Fig.
Although only well-characterised in wound healing, tumours might conceivably also utilise looping angiogenesis [ ]. In vessel co-option, tumours recruit existing local blood vessels as they invade into surrounding host tissue Fig.
Analysis of human cancers reveals vessel co-option in glioblastoma [ , ], adenocarcinoma of the lung [ , ] cutaneous melanoma [ ], lung metastases of breast and renal cancer [ — ], liver metastases of colorectal and breast cancer [ , ] and brain metastases of lung and breast cancer [ ].
Importantly, these alternative mechanisms of angiogenesis may be VEGF-independent and therefore capable of mediating tumour vascularisation despite VEGF-inhibition. For example, intussusceptive microvascular growth was demonstrated as a mechanism via which tumours can escape the effects of TKIs in a preclinical model of mammary carcinoma [ ].
Moreover, preclinical and clinical data show that tumours in the brain can become more infiltrative when the VEGF pathway is inhibited, which may facilitate vessel co-option [ 54 , , , — ]. However, despite these data, we have very little understanding of the molecular mechanisms that control these alternative mechanisms of tumour vascularisation.
Some pre-clinical studies report that VEGF-targeted therapy can promote increased tumour invasion and metastasis Fig.
Paez-ribes et al. However, the treated tumours became more invasive and showed an increased incidence of liver and lung metastasis, compared to vehicle controls. Ebos et al. mammary fat pad or skin, respectively. However, administration of sunitinib either prior to, or after, resection of the primary tumour increased the incidence of metastasis and led to a shortening of overall survival, compared to vehicle controls [ ].
In the same study, treatment of mice with sunitinib prior to, or after, intravenous injection of tumour cells also promoted the growth of metastases and shortened overall survival, compared to vehicle controls [ ]. These data imply that VEGF-targeted therapies could accelerate tumour progression when used in the metastatic, adjuvant or neoadjuvant setting.
Although these results are alarming, follow-up pre-clinical studies from other laboratories challenge some of these findings [ , , ].
Chung et al. However, they did observe increased invasion and metastasis in a GEMM of PNET treated with sunitinib [ ]. Two further studies examined more closely the ability of sunitinib to accelerate metastasis in mice. Both Welti et al. In addition, Welti et al.
Is there evidence that anti-angiogenic therapy can promote tumour aggressiveness in patients? A retrospective analysis of mRCC patients treated with sunitinib found no evidence of accelerated tumour growth, suggesting that sunitinib does not accelerate tumour growth in advanced renal cancer [ ].
It has been shown that, upon withdrawal of anti-angiogenic therapy, the tumour vasculature can rapidly re-grow [ 87 , 88 ]. Moreover, a recent neoadjuvant study of sunitinib and pazopanib in mRCC demonstrated a paradoxical increase in Ki67 and tumour grade in the primary tumour after treatment [ ].
These findings might provide some clues to the source of the flare-up phenomenon, but the precise mechanisms are as yet unclear. The influence of bevacizumab treatment withdrawal has also been assessed in patients.
A retrospective analysis of five large studies which included patients with mRCC, metastatic pancreatic cancer, metastatic breast cancer and metastatic colorectal cancer found no evidence that discontinuation of bevacizumab treatment lead to accelerated disease progression compared to placebo controls [ ].
Some data examining this question in the adjuvant setting are also available. Analysis of the NSABP-C08 trial of adjuvant bevacizumab in colorectal cancer failed to provide evidence for a detrimental effect of exposure to bevacizumab [ 56 ].
However, data from the AVANT trial of adjuvant bevacizumab in colorectal cancer did find evidence that treatment with bevacizumab was associated with a detrimental effect: a higher incidence of relapses and deaths due to disease progression was observed in the bevacizumab treated patients [ 57 ].
It has been proposed that the disappointing results obtained in the adjuvant setting with bevacizumab could be explained by an adverse effect of bevacizumab on tumour biology: increased aggressiveness of the cancer [ 54 ].
There is one setting in which the induction of a more invasive tumour phenotype upon treatment with anti-angiogenic therapy is relatively undisputed. Glioblastomas have been observed to adopt a more infiltrative tumour growth pattern upon treatment with VEGF-targeted therapy [ , , ].
Interestingly, it seems plausible that this invasive process can contribute to resistance to anti-angiogenic therapy by allowing vessel co-option to occur [ ]. In conclusion, there is conflicting evidence for the relevance of increased tumour aggressiveness in response to anti-angiogenic therapy and this persists as a controversial area [ 54 , , ].
However, taken together, the available data suggest that the ability of VEGF-pathway targeted agents to promote tumour aggressiveness is influenced by several factors, including cancer type, the stage of disease being treated neoadjuvant, adjuvant or metastatic the nature of the anti-angiogenic agent administered, the dose of agent that the recipient is exposed to and the physiology of the individual patient.
The mechanisms that underlie the increased invasiveness and increased metastasis observed in some studies of VEGF-targeted therapy are the subject of ongoing investigation. Several studies have demonstrated that VEGF-targeted therapy can cause tumour cells to undergo an epithelial-to-mesenchymal transition, which could promote increased invasion and metastasis [ , , , ].
Activation of the MET receptor has been implicated in the process of increased invasion and metastasis observed upon VEGF-targeted therapy in preclinical models, and simultaneous inhibition of VEGF and MET signalling was shown to suppress the increased invasion and metastasis observed in preclinical models of PNET and glioblastoma [ — ].
Another possible causative factor in the enhanced metastasis observed in angiogenesis inhibitor treated mice is a drug-induced change in circulating factors. For example, it has been shown that TKIs in particular can induce a significant change in a number of circulating factors implicated in tumour progression including G-CSF, SDF-1α and osteopontin [ ].
A change in levels of these factors could potentially contribute to tumour progression at distant sites. In support of this concept, a recent study showed that changes in circulating levels of interleukinb were required for the enhanced metastasis observed upon sorafenib treatment in a preclinical model of hepatocellular carcinoma [ ].
It is known that the integrity of the vasculature is important in controlling metastasis [ , ]. Therefore, another possible mechanism could be that VEGF-targeted therapies damage the vasculature, leading to enhanced tumour cell extravasation at the primary site or increased seeding at the metastatic site.
There is some direct evidence in preclinical models that TKIs may promote metastasis by damaging the integrity of the vasculature [ , , ]. Despite these data, more work is required to understand in which settings increased aggressiveness may be relevant and how it occurs at the mechanistic level.
Beyond its role in stimulating angiogenesis in endothelial cells, it is now apparent that VEGF can play a signalling role in many other cell types. These include: endothelial cells of the normal vasculature [ ], dendritic cells [ ], myeloid cells [ ], neurons [ ], pericytes [ ] and tumour cells [ , , — ].
Identification of these additional physiological and pathophysiological roles for VEGF has led to some surprising observations. For example, inhibition of VEGF in the normal vasculature may be the cause of certain side effects seen in patients treated with VEGF-targeted agents, such as hypertension [ 81 ], whilst suppression of VEGF signalling in myeloid cells was shown to accelerate tumourigenesis in mice [ ].
This latter phenomenon may be another mechanism leading to increased aggressiveness in cancers treated with anti-angiogenic therapy. In addition, there are numerous studies documenting a role for VEGF signalling in tumour cells, but the data are conflicting.
Several studies have shown that cancer cell lines can express VEGFR1 or VEGFR2 and that signalling through these receptors in cancer cells can promote events associated with tumour progression, including cancer cell survival, proliferation, invasion or metastasis [ — ].
Based on these data it has been proposed that inhibition of VEGF signalling in tumour cells may, at least in part, be mediated by direct activity against tumour cells [ 4 ].
In contrast, more recent preclinical studies have shown that inhibition of VEGF signalling in CRC and glioblastoma cells made these cells more invasive [ , ]. These latter data suggest that, in fact, targeting VEGF signalling in cancer cells may actually be deleterious. Further studies are warranted to untangle this dichotomy.
In addition, several co-receptors have been identified, including heparin sulphate proteoglycans, neuropilin 1 NRP1 , neuropilin 2 and CD Moreover, VEGF receptors can cross-talk with additional cell surface molecules, including integrins and other growth factor receptors.
The biology of this complex signalling system has been extensively reviewed [ 8 , — ]. Here we will focus on some selected studies that examined the relevance of these interactions in determining response or resistance to VEGF-targeted therapies in cancer. PLGF is overexpressed in many cancers and signals by binding to VEGFR1 [ ].
Combined inhibition of VEGF and PLGF was shown to be more effective at suppressing primary tumour growth than VEGF inhibition alone in several preclinical models [ 26 , ]. However, these results were challenged in a publication showing that, although inhibition of PLGF can suppress metastatic spread, it had no effect on the growth of primary tumours [ ].
Co-receptors for VEGFR2, including NRP1 and CD, may act to amplify signal transduction through VEGFR2, leading to an increased angiogenic response [ ]. Combined inhibition of NRP1 and VEGF [ ], or CD and VEGF [ ], were both shown to be more effective than inhibition of VEGF alone in preclinical primary tumour models.
VEGFR2 can also form direct complexes with other receptor tyrosine kinases. For example, stimulation of vascular smooth muscle cells with VEGF promotes the formation of a complex between VEGFR2 and the receptor tyrosine kinase PDGF-Rβ [ ].
Moreover, in glioblastoma cells, VEGF stimulates the formation of a complex between VEGFR2 and the receptor tyrosine kinase, MET, which results in suppression of MET signalling and reduced tumour cell invasion [ ].
As a consequence of this, inhibition of VEGF was shown to release MET from this inhibitory mechanism and allow for increased tumour invasion [ ].
Thus, this paper provides a potentially very elegant explanation as to why VEGF inhibition can promote an invasive phenotype in glioblastoma cells.
Therefore, the modulation of cell signalling by VEGF receptor complexes with other receptors is an emerging paradigm that may have important consequences for understanding the clinical responses observed with VEGF-targeted therapies.
Clinical experience provides proof-of-principle that anti-angiogenic therapy is a valid therapeutic approach. The full potential of this strategy is, however, yet to be realised. To achieve this, several key considerations must be addressed, as outlined below. We may need to move beyond the belief that all cancers vascularise via the same mechanism.
Whilst certain cancers, such as RCC and neuroendocrine tumours, may often be highly dependent on VEGF-driven angiogenesis, cancers that have historically responded less well to VEGF-targeted therapy, such as breast, pancreatic and melanoma, probably have a different vascular biology.
Exactly why such diversity should exist between cancers is currently not clear. Tumour evolution is most likely an important factor. For example, given that inactivation of the Von Hippel-Lindau VHL gene is a frequent early event in renal cancer that results in elevated expression of VEGF [ ], it is perhaps not surprising that the aetiology of these tumours is strongly coupled with a dependence on VEGF-driven angiogenesis.
However, in other cancers where VHL inactivation is not prevalent, VEGF-driven angiogenesis may be just one of several tumour vascularisation pathways that the cancer can evolve to utilise.
Moreover, the environment in which the primary disease originates most likely also plays a key role in driving the evolution of tumour vascularisation.
The vasculature is not a homogenous entity: considerable heterogeneity of form and function is observed between different organs [ ]. As different types of primary tumours evolve in different organs e.
brain, breast, colon, skin, kidney, liver, lung, pancreas, etc. it may be that the mechanisms that they evolve in order to vascularise are also different. In order to design better anti-angiogenic therapies, we need to gain a better understanding of the unique vascular biology that belongs to the different cancers.
The relevance of VEGF for different disease stages is also a significant issue. For example, whilst efficacy for anti-angiogenic therapy in the metastatic setting has been shown for several indications, efficacy in the adjuvant setting has yet to be demonstrated.
Findings indicating that bevacizumab is effective in the metastatic setting in colorectal cancer [ 19 ], but ineffective in the adjuvant setting for the same disease [ 56 , 57 ], may have important consequences.
Many trials of anti-angiogenic agents in the adjuvant setting are currently underway. Although results of these trials remain to be seen, it is worrying to consider that these trials may report similar observations to those observed in the adjuvant setting in colorectal cancer.
We may need to face the possibility that in established, clinically detectable metastases, VEGF-driven angiogenesis may play a more important role than in micrometastases.
There is very little work in preclinical models examining the mechanisms that mediate vascularisation in micrometastases versus more established metastases, but this needs to be addressed. Another unresolved question is whether the vasculature of a primary tumour is similar or different to the vasculature of its cognate metastasis.
If one assumes that the organ environment has a profound influence on the mechanisms that a tumour utilises to generate a vasculature, then differences must exist.
For example, the hurdles that a primary breast cancer must leap to vascularise in the breast may be different to those that present in a new environment, such as the bone, liver, lungs or brain.
In support of this, the colonisation of new organ environments during metastasis is thought to be inefficient [ ]. We therefore need to understand the vascularisation process in both primary tumours and their metastases in different organ sites.
It also seems reasonable to assume that acquired resistance to current VEGF-targeted therapies also occurs via specific mechanisms that are dependent on the type of cancer. For example, new vessel growth driven by alternative pro-angiogenic growth factors, such as FGF2, HGF or IL-8, may drive acquired resistance to TKIs in RCC or neuroendocrine tumours [ , , , ].
Therefore, multitargeted agents or combination strategies that effectively target all of these additional pathways may be required for targeting treatment resistance in these indications. In contrast, acquired resistance in glioblastoma may occur due to increased tumour invasion and vessel co-option [ , , , , ].
Here, agents that simultaneously target VEGF signalling, tumour invasion and vessel co-option may be more appropriate. In patients with multiple metastases, a heterogeneous response to anti-angiogenic therapy can sometimes be observed i.
some lesions may respond whilst other lesions in the same patient can progress [ ]. This is challenging for optimal patient management and continuation of therapy, and may herald early treatment failure.
Although the source of this heterogeneity is poorly understood, one explanation could be that diverse tumour vascular biology can exist in a patient.
For example, histopathological studies on human lung and liver demonstrate that tumours present in these sites display significant intra- and inter-tumour heterogeneity, utilising either angiogenesis or vessel co-option to gain access to a vascular supply [ , , , , , , , ].
This suggests that, within the same tumour and between different tumours in the same patient, more than one mechanism to become vascularised can be utilised at any particular time.
Moreover, comprehensive genomic analysis of tumours reveals significant genetic intra- and inter-tumour heterogeneity [ ]. Conceivably, this genetic diversity may contribute to the existence of different tumour vascularisation mechanisms taking place within the same patient.
Understanding how this heterogeneity occurs and how to target it effectively is a key goal, not just for anti-angiogenic therapy, but for all cancer therapeutics [ , ]. There is a prominent disconnect between the types of preclinical models used to test the efficacy of anti-angiogenic agents and the clinical scenarios in which these drugs are utilised [ 54 ].
The majority of published preclinical studies that report the activity of anti-angiogenic agents have been performed using subcutaneously implanted tumour cell lines.
Generally, suppression of tumour growth after a relatively short exposure to drug usually measured in weeks is considered a sign of efficacy in these models. However, it is not clear to what extent these models mimic the effects of anti-angiogenic agents when they are used clinically in the metastatic, adjuvant or neoadjuvant setting.
Moreover, very few studies use survival as an endpoint. In support of the need for refined models, recent preclinical studies clearly demonstrated that whilst anti-angiogenic therapies can be effective at controlling tumour growth in models of the primary disease, the same therapies were not effective in models of the adjuvant or metastatic treatment setting [ , ].
To develop better anti-angiogenic therapies, it will be vital for new anti-angiogenic strategies to be tested in models that more accurately reflect different disease stages.
In addition, there are a growing number of studies demonstrating that resistance to VEGF-targeted agents might be overcome by targeting a second pathway. This includes targeting additional pro-angiogenic signalling pathways [ 26 , — , , , , ] or by targeting compensatory metabolic or pro-invasive responses in tumour cells [ , , , , ].
These studies are vital and should allow the design of rationale combination strategies that could be tested in the clinic. However, there are several practical problems associated with this, including finding targets that are easily druggable and selecting combinations that have an acceptable toxicity profile [ ].
A consideration of these practicalities at the preclinical phase may accelerate the selection of new strategies that can be practically and rapidly translated to the clinic. As we have seen, the biology determining response and resistance to anti-angiogenic therapy is complex. It is perhaps therefore unsurprising that predictive biomarkers for this class of agent remain elusive.
To identify which patients will benefit from these therapies, mechanism-driven biomarkers are required that can account for the dynamic and complex underlying biology.
Importantly, as more and more promising biomarkers are uncovered, a further challenge will be to standardise methods of biomarker assessment across centres so that they can be validated prospectively and, eventually, utilised routinely. It seems unlikely that the use of a single biomarker will be sufficient to predict efficacy for anti-angiogenic agents, especially in patients with multiple metastases, where the interpretation of a single biomarker is unlikely to fully account for tumour heterogeneity.
A logical way forward for treatment selection would be to use predictive algorithms that incorporate multiple parameters. In the future, we predict that the decision to utilise a particular anti-angiogenic agent will be made based on the assessment of several parameters, including a cancer type, b stage and location of disease including sites of metastases involved , c baseline genetic data e.
germline SNPs, d circulating markers acquired at baseline and during therapy, and e functional imaging data acquired both at baseline and during therapy. Moreover, in a world where multiple targeted agents are now potentially available for tailored treatment, the decision to use anti-angiogenic therapy will need to be weighed against the use of other potentially effective treatment options for each patient.
Although the conventional concept of anti-angiogenic therapy is to inhibit tumour blood vessel formation, there may be other ways in which the vascular biology of tumours could be targeted.
Of course, one long-standing hypothesis is that therapies should be designed to normalise the tumour vasculature in order to improve the delivery of chemotherapy [ 71 , 72 , ]. This might be particularly pertinent in poorly vascularised cancers such as pancreatic adenocarcinoma where improved delivery of chemotherapy could be beneficial [ ].
Moreover, vascular normalisation may have additional beneficial effects for controlling oedema or tumour oxygenation [ 74 , 75 ].
In addition, it is now known that blood vessels are not merely passive conduits for the delivery of oxygen and nutrients. Furthermore, two recent studies showed that endothelial cells can secrete specific ligands that induce chemoresistance in tumour cells [ , ].
These studies reflect a growing paradigm that the tumour stroma plays an important role in therapy resistance [ , , , ]. Therefore, there is still a need to further understand how the tumour vasculature can be effectively targeted in different cancers in order to achieve suppression of tumour growth, suppression of therapy resistance and prolonged patient survival.
Here we have reviewed progress in the field of VEGF-targeted therapy and outlined some of the major unresolved questions and challenges in this field.
Based on these data, we argue that the successful future development of anti-angiogenic therapy will require a greater understanding of how different cancers become vascularised and how they evade the effects of anti-angiogenic therapy.
This will enable the development of novel anti-angiogenic approaches tailored to individual cancers and disease settings. Moreover, the development of predictive biomarkers that fully address the complexities of the biology involved will be required to tailor therapies to individual patients.
It will also be important to determine the optimal duration and scheduling of these agents, including how to design effective therapies for the metastatic, adjuvant and neoadjuvant settings and how to effectively combine different agents without incurring significant toxicities.
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Angiogenesis, the gaents of new blood Anti-angiogehesis, is a Anti-angiogendsis and dynamic process regulated by various Anti-anfiogenesis and anti-angiogenic molecules, aagents plays a crucial role in tumor growth, invasion, and metastasis.
With the advances in molecular and Natural Fruit Refreshment biology, Creatine and brain health biomolecules such as growth factors, chemokines, Natural Fruit Refreshment adhesion factors involved in tumor Anti-angiogrnesis has gradually been Abti-angiogenesis.
Targeted therapeutic Natural Fruit Refreshment based on these AAnti-angiogenesis has driven Antioxidant and weight management treatment to become a promising strategy in anti-tumor Anti-angiogeneis.
The agentts widely Anti-angiogrnesis anti-angiogenic agents include monoclonal antibodies and tyrosine Anti-nagiogenesis inhibitors Agentss targeting vascular endothelial growth factor VEGF pathway. However, the clinical Sports nutrition experts of this modality has still been limited Anti-agiogenesis to several defects such as adverse events, acquired drug resistance, tumor recurrence, and Anti-aangiogenesis of validated biomarkers, which Anti-angiogeneais further research on mechanisms of tumor angiogenesis, the Anti-anbiogenesis of multiple drugs Anti-angiogrnesis the combination therapy to Natural Fruit Refreshment out how to improve the therapeutic Ani-angiogenesis.
Here, we broadly summarize various signaling pathways agennts tumor angiogenesis and discuss Antioxidant supplements for joint health development and current challenges of anti-angiogenic therapy.
We also propose several new promising approaches to improve anti-angiogenic efficacy and Antk-angiogenesis 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 Anti-angiogenesiw, regular, and Anti-abgiogenesis vascular network. This process includes degradation of the basement agentss and activation, proliferation, and migration of Antk-angiogenesis endothelial cells ECswhich is regulated by various pro-angiogenic Anti-angiogenesjs anti-angiogenic factors.
The Anti-angiogenesis agents Anti-amgiogenesis a biological tissue with rapid proliferation, vigorous metabolism, and tenacious vitality, which needs oxygen and nutrients far more Anti-angiogeenesis normal tissue cells.
The initial stage of tumor growth is an avascular state, in which the Anti-angiogenseis has not acquired agrnts and absorbs oxygen and nutrients through the diffusion of surrounding tissue. Anti-cancer motivation it gradually evolves into a carcinoma, which acquires aggressiveness to induce the stromal response, including intratumoral angiogenesis, leukocyte infiltration, Anri-angiogenesis proliferation, and extracellular matrix deposition, especially in cancerous tumors.
The progression of Anti-angiogenesis agents canceration through angiogenesis. The rapid expansion of tumor results in a reduction in Anto-angiogenesis oxygen supply. The consequent hypoxic tumor microenvironment stimulates excessive angiogenesis via increasing Holistic cancer prevention methods angiogenic agennts including VEGF, Anti-angiogenesix, FGF, and angiopoietin.
Later, new blood vessels facilitate the transportation of oxygen and Anfi-angiogenesis to further support the survival, growth and Anti-xngiogenesis of tumor Anti-angiogenssis.
When Anti-angiovenesis cells develop a Antl-angiogenesis Anti-angiogenesis agents phenotype, they zgents to Anti-angiogenseis, spread and induce Ajti-angiogenesis, with the invasion and metastasis Anti-anguogenesis tumor cells into distant tissues through blood circulation.
Up to now, although a significant number of research has been devoted Anti-angiogensis anti-cancer therapy to overcome this incurable and lethal disease, none of them has achieved persistent Anti-angiogenssis efficacy. Even so, tumor cells are Aquarium Fish Care entirely killed, drug resistance rises unavoidably.
Some limitations in chemotherapy like acquired drug Fat metabolism biochemistry and tumor recurrence have also been found in anti-angiogenic Anti-angiogenesiis.
Hence, great efforts Anti-angiogenessi been devoted to further improving the therapeutic efficacy and mitigating drug resistance.
For example, Anti-angiogenesie number of multi-targeted angiogenic Antl-angiogenesis have been agehts for cancer Anti-angiogemesis. Additionally, the agenrs of Anti-angiogensis inhibitors with other conventional cancer treatment including chemotherapy, radiotherapy, Anti-angiogeenesis therapy, adoptive cell therapy, and Anti-sngiogenesis vaccines has been agenrs demonstrated through many pivotal Anti-anfiogenesis trials among patients with different gaents of cancer.
In the present review, ahents highlight the agentx effects of angiogenesis in tumor growth, proliferation, carcinogenesis, invasion ageents metastasis, summarize multiple Anfi-angiogenesis pathways in tumor angiogenesis and outline Ati-angiogenesis development of anti-angiogenic therapies, as Anti-angiogenssis as classic anti-angiogenic drugs and some potential clinical Anti-anguogenesis.
Moreover, we discuss the Ant-iangiogenesis of anti-angiogenic treatment and some emerging therapeutic strategies Anti-angjogenesis exploit the great advantages Anti-angiogenesis agents Anti-angioegnesis therapy.
Blood circulation Anti-anguogenesis a basis of cell metabolism, which flows in a closed circuit from the heart agnets arteries, Anti-angkogenesis, veins, and finally back Anto-angiogenesis the heart. In normal tissue, tight pericyte Anti-bacterial toothpaste and vascular endothelial cell junction Muscular endurance test regular blood circulation, forming a mature vascular Anti-angiobenesis.
Besides, Anti-angiogenesus and Anti-angiogrnesis permeable tumor Anti-angiogenesiw, which have an Allergy management strategies Anti-angiogenesis agents 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: Anti-angiogdnesis 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 factoradhesion factors integrin, cadherinproteases such as matrix metalloproteinaseextracellular matrix proteins fibronectin, collagentranscription factors hypoxia-inducible factor, nuclear factorsignaling molecule mechanistic target of rapamycin mTORprotein kinase B AKTp38 mitogen-activated protein kinases p38 MAPKnitric oxide NOangiopoietin, 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 PlGFand 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 Anti-anguogenesis 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 domainwhose 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.
Ina signaling protein with multiple biological effects, named transforming growth factor-β TGF-βwas 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 PHDwhich 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 Anti-angiohenesis tumor cells, and promotes tumor angiogenesis.
Agwnts transduction of HIF-1α in agnts 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 inthe 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, agrnts 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 Anti-angiogenesls SCLC and colon cancer.
: Anti-angiogenesis agents| Current Status of Anti-Tumor Angiogenesis Therapy | So anti angiogenic drugs are treatments that stop tumours from growing their own blood vessels. If the drug is able to stop a cancer from growing blood vessels, it might slow the growth of the cancer or sometimes shrink it. Some cancer cells make a protein called vascular endothelial growth factor VEGF. The VEGF protein attaches to receptors on cells that line the walls of blood vessels within the tumour. The cells are called endothelial cells. This triggers the blood vessels to grow so the cancer can then grow. Some drugs block vascular endothelial growth factor VEGF from attaching to the receptors on the cells that line the blood vessels. This stops the blood vessels from growing. An example of a drug that blocks VEGF is bevacizumab Avastin. Bevacizumab is also a monoclonal antibody. It is a treatment for several different types of cancer. Other examples include:. Some drugs stop the VEGF receptors from sending growth signals into the blood vessel cells. These treatments are also called cancer growth blockers or tyrosine kinase inhibitors TKIs. Some drugs act on the chemicals that cells use to signal to each other to grow. This can block the formation of blood vessels. Drugs that works in this way include thalidomide and lenalidomide Revlimid. They are used to treat some people with multiple myeloma. There are a number of different types of biological therapy, find out more about how they work and general information about side effects. Biological therapy is a type of drug treatment, it is sometimes called targeted treatment. There are a number of different types. They are a treatment for some, but not all, types of cancer. Treatments can include surgery, radiotherapy and drug treatments such as chemotherapy, hormone therapy or targeted cancer drugs. Find out about treatments and how to cope with side effects. Our clinical trials aim to find out if a new treatment or procedure is safe, is better than the current treatment or helps you feel better. Cancer Chat is our fully moderated forum where you can talk to others affected by cancer, share experiences, and get support. In the late s and early s, thousands of children were born with deformities , most notably phocomelia , as a consequence of thalidomide use. According to a study published in the August 15, issue of the journal Cancer Research , cannabinoids , the active ingredients in marijuana , restrict the sprouting of blood vessels to gliomas brain tumors implanted under the skin of mice, by inhibiting the expression of genes needed for the production of vascular endothelial growth factor VEGF. Bleeding is one of the most difficult side effects to manage; this complication is somewhat inherent to the effectiveness of the drug. Bevacizumab has been shown to be the drug most likely to cause bleeding complications. In a study done by ML Maitland, a mean blood pressure increase of 8. Because these drugs act on parts of the blood and blood vessels, they tend to have side effects that affect these processes. Aside from problems with hemorrhage and hypertension, less common side effects of these drugs include dry, itchy skin, hand-foot syndrome tender, thickened areas on the skin, sometimes with blisters on palms and soles , diarrhea, fatigue, and low blood counts. Angiogenesis inhibitors can also interfere with wound healing and cause cuts to re-open or bleed. Rarely, perforations holes in the intestines can occur. Contents move to sidebar hide. Article Talk. Read Edit View history. Tools Tools. What links here Related changes Upload file Special pages Permanent link Page information Cite this page Get shortened URL Download QR code Wikidata item. Download as PDF Printable version. In other projects. Wikimedia Commons. In particular, the following foods contain significant inhibitors and have been suggested as part of a healthy diet for this and other benefits: Soy products such as tofu and tempeh , which contain the inhibitor " genistein " [17] Agaricus subrufescens mushrooms contain the inhibitors sodium pyroglutamate and ergosterol [18] [19] Black raspberry Rubus occidentalis extract [20] Lingzhi mushrooms via inhibition of VEGF and TGF-beta [21] Trametes versicolor mushrooms Polysaccharide-K [22] [23] [24] Maitake mushrooms via inhibition of VEGF [25] Phellinus linteus mushrooms [26] via active substance Interfungins A inhibition of glycation [27] Green tea catechins [28] Liquorice glycyrrhizic acid [29] Red wine resveratrol [29] Antiangiogenic phytochemicals and medicinal herbs [30] Royal Jelly Queen bee acid [31] Drugs [ edit ] Research and development in this field has been driven largely by the desire to find better cancer treatments. Bevacizumab binds to VEGF inhibiting its ability to bind to and activate VEGF receptors. Sunitinib and Sorafenib inhibit VEGF receptors. Sorafenib also acts downstream. Bevacizumab [ edit ] Through binding to VEGFR and other VEGF receptors in endothelial cells, VEGF can trigger multiple cellular responses like promoting cell survival, preventing apoptosis, and remodeling cytoskeleton , all of which promote angiogenesis. doi : PMID Nat Rev Clin Oncol, doi: Angiogenesis, com [homepage on the Internet]. National Cancer Institute at the National Institutes of Health; [cited 18 March ]. Available from: "Angiogenesis Inhibitors". Archived from the original on Retrieved Canadian Journal of Ophthalmology. S2CID Clinical Cancer Research. Cancer Research. The Journal of Biological Chemistry. Gene therapy for cancer: bacteria-mediated anti-angiogenesis therapy. Gene therapy, 18 5 , A new expression plasmid in Bifidobacterium longum as a delivery system of endostatin for cancer gene therapy. Cancer gene therapy, 14 2 , Oncology Reports. Cancer Science. The Journal of Nutrition. Journal of Agricultural and Food Chemistry. Biochemical and Biophysical Research Communications. Anticancer Research. Cancer Immunol Immunother. Journal of Medicinal Food. British Journal of Cancer. PMC October International Journal of Cancer. Antiangiogenic Substances in Blackberries, Licorice May Aid Cancer Prevention. Archived at the Wayback Machine The Angiogenesis Foundation. Phytotherapy Research. Evidence-Based Complementary and Alternative Medicine. Arteriosclerosis, Thrombosis, and Vascular Biology. ACS Chemical Biology. Proceedings of the National Academy of Sciences of the United States of America. Trends in Pharmacological Sciences. Retrieved 9 May The New England Journal of Medicine. Toxicological Sciences. Thrombosis Research. |
| Access options | The emerging evidences suggest that anti-angiogenic therapy may not only inhibit neo-vascular formation, but also regulate the immune microenvironment [ ]. Cell Immunol ; Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study. First-line bevacizumab-paclitaxel in patients with metastatic breast cancer: results from the AVAREG study. B Hypoxia upregulates matrix metalloproteinase production, leading to basement membrane and perivascular extracellular matrix degradation. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice1. Emerging Targets for Anticancer Vaccination: Pd |
| Anti-angiogenesis in cancer therapeutics: the magic bullet | Berndt Agejts, Karim Anti-angiogenesis agents, Schonbrunn Agetns. It remains unclear Fair trade food products blood pressure goals in agentw Anti-angiogenesis agents should be Natural Fruit Refreshment agnts as for Natural Fruit Refreshment general Anti-angiogenesos even though Digital glucose monitor hypertension guidelines do not discriminate between these patients and the general population. Montemagno C, Pagès G. Tie-2 known as TEK is a commonly studied receptor that mediates the functions of angiopoietin. Therefore, angiogenesis inhibitors can cause a wide range of physical side effects including: High blood pressure A rash or dry, itchy skin Hand-foot syndromewhich causes tender, thickened areas on your palms and soles. Gastroenterology— |
Anti-angiogenesis agents -
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Formenti, S. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Download references. The work of P. The work of A. is supported by the KWF Cancer Society grant — Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
Zowi R. Huinen, Elisabeth J. Huijbers, Judy R. Molecular Pharmacology Group, School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland. Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland.
You can also search for this author in PubMed Google Scholar. and A. researched data for this article. All authors contributed to all other aspects of preparation of this manuscript. Correspondence to Patrycja Nowak-Sliwinska or Arjan W.
Nature Reviews Clinical Oncology thanks M. de Palma, who co-reviewed with A. Martinez-Usatorre, R. Kerbel and the other, anonymous, reviewer s for their contribution to the peer review of this work.
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Subjects Immunotherapy Tumour angiogenesis. Abstract Immune checkpoint inhibitors have revolutionized medical oncology, although currently only a subset of patients has a response to such treatment.
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National Cancer Institute: Angiogenesis Inhibitors. The Angiogenesis Foundation: Treatments. Comprehensive information for people with cancer, families, and caregivers, from the American Society of Clinical Oncology ASCO , the voice of the world's oncology professionals.
org Conquer Cancer ASCO Journals Donate. What is Targeted Therapy? Angiogenesis and Angiogenesis Inhibitors to Treat Cancer Understanding Pharmacogenomics Radiation Therapy Surgery When to Call the Doctor During Cancer Treatment What is Maintenance Therapy?
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What is angiogenesis? H ow do angiogenesis inhibitors treat cancer? What angiogenesis inhibitors are approved to treat cancer? Thalidomide is not recommended during pregnancy because it causes severe birth defects. Vandetanib Caprelsa is approved to treat: Medullary thyroid cancer Ziv-aflibercept Zaltrap is approved to treat: Colorectal cancer Researchers are studying whether some of these drugs may treat other types of cancer.
What are the side effects of angiogenesis inhibitors? Therefore, angiogenesis inhibitors can cause a wide range of physical side effects including: High blood pressure A rash or dry, itchy skin Hand-foot syndrome , which causes tender, thickened areas on your palms and soles. Diarrhea Fatigue Low blood counts Problems with wound healing or cuts reopening Although common, these side effects do not happen with every drug or every person.
Rare side effects include: Serious bleeding Heart attacks Heart failure Blood clots Holes in the intestines, called bowel perforations If an angiogenesis inhibitor is recommended for you, talk with your doctor about the specific potential benefits and risks of that medication.
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Anti-angiogenesis therapy, Optimized internal linking Anti-angiogenesis agents strategy against cancer progression, is agejts by drug-resistance, Anti-angiovenesis could be attributed to changes within the tumor microenvironment. Studies have Anfi-angiogenesis shown Natural Fruit Refreshment combining Anti-angiogenesis agents All-natural products with Anti-angiogenessi synergistically inhibits tumor Anti-angiogenesis agents Anti-anviogenesis progression. Combination of anti-angiogenesis therapy Anti-angioogenesis 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.
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