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.

To achieve these goals, close collaboration between basic researchers and clinicians in multiple disciplines is absolutely required.

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Am J Pathol 5 — Cancer cells lacking blood circulation expanded 1—2 mm 3 in diameter and afterward halted, but when put in a location where angiogenesis was feasible, they expanded to more than 2 mm 3.

Given that tumors become necrotic or even apoptotic in the absence of a circulatory supply [ 8 ], it has strongly been validated that angiogenesis is a critical component in cancer development. Tumors differ significantly in the patterns and characteristics of the angiogenic vascular system, as well as their sensitivity to anti-angiogenic treatment [ 9 ].

Cancer cells control the angiogenic programming of neoplastic tissues through collaboration with a range of tumor-associated stromal cells as well as their bioactive products, which include cytokines and growth hormones, the extracellular matrix, as well as secreted microvesicles [ 10 ].

Apart from cancer immunotherapy or other pioneering approaches such as chemotherapy and radiotherapy, which have resulted in a significant advance in cancer treatment [ 11 , 12 ], another potential treatment approach is anti-angiogenesis, which aims to impair the vasculature and deprive the tumor of oxygen and nutrition [ 13 ].

This is accomplished mostly by targeting the pro-angiogenic factors-induced signaling pathway, which is prominent in the tumor microenvironment under hypoxic conditions [ 14 ]. VEGF family members are the regulator of angiogenesis both under normal circumstances and in a disease condition.

This family consists of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placenta growth factor PlGF , which binds with divergent affinities and specificities to tyrosine kinase receptors VEGFR 1,-2, and -3 [ 16 , 17 ]. The interfaces between VEGF-A and VEGFR 2 exceed angiogenesis, while VEGF-C and D preferentially make connections with VEGFR-3 [ 18 ].

The improved expression of VEGF inspires tumourigenesis by potentiating the epithelial-mesenchymal transition EMT activation. In addition to VEGF receptor tyrosine kinases, the neuropilins NRPs , potent co-receptors for class 3 semaphorins, are crucial for exerting the impacts of VEGF on cancer cells as a result of their capability to affect the activities of growth factor receptors and integrins [ 19 ].

Meanwhile, multitargeted small-molecule TKI can target multiple receptor sites simultaneously. The main targets included vascular endothelial growth factor receptor VEGFR , platelet-derived growth factor receptor PDGFR , fibroblast growth factor receptor FGFR , c-Kit, and c-Met.

Anti-angiogenic TKIs block the kinase activity of receptors and transduction of downstream signals involved in the proliferation, migration, and survival [ 22 ]. However, monotherapy with an anti-angiogenic drug has shown minimal therapeutic advantages for most cancer patients [ 23 ]. Thereby, it has been suggested and also evidenced that combining anti-angiogenic medicines with other strategies, comprising immune checkpoint inhibitors ICIs , chemotherapy, human epidermal growth factor receptor 2 HER2 -targeted therapies, adoptive cell transfer ACT , cancer vaccines, and also radiotherapy may have a synergistic anti-tumor impact [ 24 ].

This review highlights current knowledge and clinical developments of anti-angiogenesis combination treatment, either alone or in conjunction with other modalities, focusing on last decade in vivo reports. The central role of VEGF in tumor angiogenesis. The VEGF induces angiogenesis in tumor cells following interaction with responding receptor, VEGFR2, on tumor cells and subsequently by activating various signaling axes.

Several successive stages throughout tumor angiogenesis may be emphasized. The vessel wall of mature capillaries comprises an endothelial cell lining, a basement membrane, and a layer of cells termed pericytes that partly surround the endothelium [ 25 ].

Pericytes share the same basement membrane as endothelial cells and sometimes come into touch with them. Tumor-derived angiogenic agents attach to endothelial cell receptors, initiating the angiogenesis process.

VEGF, fibroblast growth factors FGF , tumour necrosis factor α TNFα , transforming growth factor TGF-β , and angiopoietin Ang are the most well-known angiogenic cytokines and growth factors [ 26 , 27 ]. When endothelial cells are encouraged to develop, proteases, heparanase, as well as other digestive enzymes are secreted, which break down the underlying membrane that surrounds the artery [ 28 , 29 ].

Matrix metalloproteinases MMPs , a class of metalloendopeptidase produced by tumor cells and supportive cells, allow for the degradation of the basement membrane as well as the extracellular matrix surrounding pre-existing capillaries, typically postcapillary venules [ 30 , 31 ].

The breakdown of the extracellular matrix also enables the discharge of pro-angiogenic factors out from the matrix. Endothelial cell connections change, cell extensions cross through the gap produced, and the recently created sprout develops towards the source of the stimulation [ 32 ].

Endothelial cells enter the matrix and start migrating and proliferating inside the tumor mass. Freshly created endothelial cells arrange into hollow tubes and produce a new basement membrane for vascular stability at this site [ 33 ]. The blood flow inside the tumor is formed by freshly shaped fused blood vessels.

Significant interactions between cell-associated surface proteins and the extracellular matrix promote the development of the lumen during canalization. Hybrid oligosaccharides galectin-2, platelet endothelial cell adhesion molecule-1 PECAM-1 or CD31 , and VE-cadherin are among the surface proteins discovered in this interaction [ 34 , 35 ].

Different circumstances, including metabolic and mechanical stressors, hypoxia, and genetic alterations or changed oncogene expression or tumor suppressor genes, may cause an imbalanced shift towards pro-angiogenic factors, while the mechanism behind this is yet unknown.

Numerous pro-angiogenic agents, such as VEGF, platelet-derived growth factor PDGF , and FGF are found in the tumor microenvironment. These compounds are produced by cancer cells or tumor-infiltrating lymphocytes or macrophages and can trigger pro-angiogenic signaling pathways, promoting tumor angiogenesis, development, invasion, and metastasis [ 36 ].

Furthermore, inflammatory cytokines in the tumor microenvironment have a significant role in tumor angiogenesis. However, a few investigations have shown that these factors may promote angiogenesis and tumor development.

These findings suggest that cytokines have a variety of roles in tumorigenesis as well as development. Numerous interleukin 1 IL-1 family members stimulate tumor angiogenesis [ 38 ]. Through the activity of nuclear factor-kappa B NF-κB , p38 mitogen-activated protein kinase MAPK signaling, and Janus kinase JAK , IL-1 signaling stimulates angiogenesis by upregulating VEGF as well as angiogenesis-related molecules [ 39 , 40 ].

IL-6, IL-8, and IL may also increase tumor angiogenesis by modulating angiogenic factor expression [ 41 ]. A hypoxic microenvironment may also encourage tumor development, invasion, metastasis, immune evasion, and angiogenesis. As a result, co-targeting hypoxic, as well as anti-angiogenic factors, may enhance tumor outcomes.

Researchers discovered that co-treatment with hypoxia-inducible factor 1 HIF-1 inhibitors and bevacizumab had a greater anticancer impact than therapy with bevacizumab separately in glioma xenografts [ 42 ]. HIF-1 is an upstream regulator of many angiogenic factors that may directly stimulate angiogenic factor transcription to enhance tumor angiogenesis [ 43 ].

Furthermore, various hypoxia-induced lncRNAs may enhance tumor angiogenesis by influencing angiogenic factor expression [ 44 ]. As angiogenic factors abound in the tumor microenvironment, treating cancer cells with medicines that target several angiogenic agents may result in improved outcomes.

In contrast, tumor-secreted cytokines largely stimulate a proangiogenic and protumorigenic phenotype of the tumor-associated inflammatory infiltrate. Recently, Wang et al.

The contrast effects of immune cells found in TME on tumor progress. While TH2 and M2 macrophages convince tumor angiogenesis, TH1 and M1 macrophage suppress tumor angiogenesis by secreting a diversity of cytokines. Upon successful preclinical studies Table 1 , a myriad of clinical trials have been accomplished or are ongoing to determine the safety, feasibility, and efficacy of anti-angiogenic agents therapy in cancer patients alone or in combination with other therapeutic means Table 2.

The present era of anti-angiogenic treatment for cancer research started in with the publishing of Folkman's creative hypothesis [ 47 ], although it would take 33 years for the FDA to authorize the first drug produced as a blocker of angiogenesis. Bevacizumab, a humanized monoclonal antibody targeted against VEGF, was coupled with standard chemotherapy in a randomly selected phase 3 study of first-line therapy of metastatic colorectal cancer CRC [ 48 ].

When utilized in conjunction with conventional chemotherapy, bevacizumab therapy improved overall survival OS in the first-line treatments of advanced non—small-cell lung cancer NSCLC [ 49 ]. The FDA of the United States has authorized a variety of angiogenesis inhibitors for the treatment of cancer.

Most of them are targeted treatments created to target VEGF, its receptor, or other angiogenesis-related molecules. Bevacizumab, axitinib, everolimus, cabozantinib, lenalidomide, lenvatinib, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, thalidomide, Ziv-aflibercept and vandetanib are most famous accepted angiogenesis inhibitors, which have been approved for human advanced tumors [ 50 ].

As the first VEGF-targeted agent approved by FDA, bevacizumab, is used since February , for the treatment of patients suffering from metastatic m CRC in combination with the standard chemotherapy treatment as first-line treatment [ 51 ].

In June , it was approved with fluorouracil 5-FU -based therapy for second-line mCRC. Also, it has been indicated for NSCLC plus chemotherapy , breast cancer, glioblastoma, ovarian cancer plus chemotherapy , and also cervical cancer [ 51 ]. Another well-known angiogenesis inhibitor, axitinib, has gained approval from FDA for use as a treatment for renal cell carcinoma RCC since January and also has shown promising outcomes in pancreatic cancer plus gemcitabine [ 52 , 53 ].

Moreover, since , it is used for neuroendocrine tumors NET of gastrointestinal GI or lung origin with unresectable, locally advanced, or metastatic disease [ 55 ].

In November , cabozantinib, a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, was approved for thyroid cancer [ 56 ] and also in April was accepted as second-line treatment for RCC [ 57 ].

Lenalidomide, a 4-amino-glutamyl analogue of thalidomide, is used to treat multiple myeloma MM [ 58 ] and myelodysplastic syndromes MDS [ 59 ], and also lenvatinib, which acts as a multiple kinase inhibitor against the VEGFR1, VEGFR2, and VEGFR3 kinases, is applied for the treatment of thyroid cancer [ 60 ].

In , lenvatinib was also approved in combination with everolimus for the treatment of advanced RCC [ 61 ]. Since , pazopanib, a potent and selective multi-targeted receptor tyrosine kinase inhibitor, is utilized for metastatic RCC and advanced soft tissue sarcomas therapy [ 62 ].

Besides, since April , the ramucirumab, a direct VEGFR2 antagonist, is indicated as a single-agent treatment for advanced gastric cancer or gastro-esophageal junction GEJ adenocarcinoma after treatment with fluoropyrimidine- or platinum-containing chemotherapy [ 63 ].

Further, ramucirumab in combination with docetaxel has gained approval for treatment of metastatic NSCLC [ 64 ]. Ramucirumab also is used for mCRC since [ 65 ] and HCC since [ 66 ] therapy.

Also, regorafenib, an orally-administered inhibitor of multiple kinases, has been indicated for the treatment of patients with advanced HCC who were previously treated with sorafenib [ 67 ].

Moreover, sorafenib as another type of kinase inhibitor is used since for RCC and HCC therapy, and since for thyroid cancer [ 68 ]. Multi-targeted receptor tyrosine kinase inhibitor sunitinib also is applied for gastrointestinal stromal tumor GIST and RCC therapy [ 69 ].

In addition, since , thalidomide as a type of biological therapy in combination with dexamethasone has been approved for the treatment of newly diagnosed MM patients [ 70 ]. Also, Ziv-aflibercept in combination with 5-fluorouracil, leucovorin, irinotecan FOLFIRI are used to treat patients with metastatic CRC [ 71 ].

Finally, tyrosine kinase inhibitor vandetanib is employed to treat medullary thyroid cancer in adults who are ineligible for surgery [ 72 , 73 ].

Despite their total tumor growth reduction, therapeutic anti-angiogenic agents were linked to enhanced local invasiveness as well as distant metastasis.

These events seem to be significant factors to resistance to anti-angiogenesis treatments. They were originally reported in various preclinical models by Paez-Ribes and coworkers [ 74 ]. Based on the literature, anti-angiogenic treatment may increase tumor invasiveness.

RCC cells, for example, showed increased proliferation and an invasive character after being treated with bevacizumab [ 75 ]. Likewise, glioblastoma cells in mice models were more invasive after VEGF suppression [ 74 ].

Sunitinib treatment also has been found to cause vascular alterations such as decreased adherens junction protein expression, reduced basement membrane, pericyte coverage, and increased leakiness [ 76 , 77 ].

These phenotypic alterations were found in both normal and tumor organ arteries, indicating that they promote tumor cell local intravasation and extravasation, culminating in metastatic colonization [ 78 ]. Angiogenesis blockade therapy may lead to vascular regression and resultant intra-tumoral hypoxia.

Various investigations have been fulfilled to assess an enhancement in hypoxic areas in primary tumors upon angiogenesis blockade therapy [ 76 , 79 ]. Further investigation also exposed an attendant augmentation in HIF-1a expression during treatment.

HIF-1a and hypoxia are recognized drivers of epithelial-mesenchymal transition EMT , a process that induced tumor metastasis. Significant improvement in the expression and activities of EMT-related genes e.

Moreover, loss of the epithelial marker, E-cadherin, and the stimulation of the mesenchymal marker, vimentin, has been evidenced following anti-angiogenic treatment [ 80 ].

Hypoxic milieu also largely promotes VEGF expression by the upstream transcription factor HIF-1a [ 81 ]. HIF-1, in turn, inspires tumors to achieve more angiogenic and invasive competencies, culminating in metastasis [ 82 ]. In fact, hypoxia and EMT bring about increased invasiveness and metastasis of tumors mainly caused by up-regulation of c-Met, Twist, and HIF-1a [ 83 , 84 ].

Conversely, semaphorin 3A Sema3A , a well-known endogenous anti-angiogenic molecule, is substantially down-regulated in tumors, ensuring provoked invasiveness and metastasis [ 85 ].

Ang-Tie signaling system is a vascular-specific receptor tyrosine kinases RTK pathway complicated in modifying the vascular permeability and blood vessel formation and remodeling by potent angiogenic growth factors, Ang-1 and Ang-2 [ 86 ].

Molecular analysis has confirmed that activation of the Ang-Tie pathway as a result of the connection between Ang-1 and Tie2 receptor on the M2 subpopulation of monocytes, hematopoietic stem cells HSCs , and endothelial cells ECs of blood and lymphatic vessels elicits maturation or stabilization of blood vessels [ 80 ].

Besides, Ang-2 suppresses this pathway, eventually sustaining remodeling or generation of vascular sprouts upon exposure to VEGF [ 87 ].

Ang-2 up-regulation has been noticed in multiple types of tumors and is likely involved in resistance versus anti-VEGF therapy [ 88 , 89 ]. For instance, there is clear evidence signifying that enhanced serum Ang-2 levels are in association with an undesired response to bevacizumab therapy in CRC patients [ 90 ].

Studies in lung adenocarcinoma patients revealed that elevated levels of VEGFA and Ang-2 is valued prognostic biomarkers and double targeting of VEGFA and Ang-2 can improve therapeutic outcome [ 91 ]. As well, up-regulation and compensatory mechanisms of other growth factors, in particular basic fibroblast growth factor bFGF , are thought to contribute to the stimulation of the resistance to VEGF targeted therapies.

Improved level of the bFGF has strongly been evidenced in the chronic inflammation area, after tissue injury, as well as human cancers bevacizumab [ 92 ]. Upon bevacizumab treatment in glioblastoma tumor models, Okamoto et al. showed the increased levels of the bFGF and PDGF expression in the endothelial cells, pericytes, and also tumor cells, in turn, caused robust resistance to bevacizumab [ 94 ].

Also, cancer patients with up-regulated bFGF in serum usually show no desired response to sunitinib, indicating the necessity of co-targeting VEGF and bFGF pathways concurrently [ 95 , 96 ].

Increased metastasis and invasiveness in response to anti-angiogenesis therapy vary according to treatment type, dosage, and schedule. Sunitinib and anti-VEGF antibody monotherapy showed varied effects on mice tumor models, according to Singh et al.

reports [ 77 ]. While sunitinib therapy increased tumor cell aggressiveness, anti-VEGF antibody treatment did not [ 77 ]. Chung et al. also corroborated these findings by comparing the effectiveness of several RTK inhibitors and antibody treatments in mouse models [ 97 ].

Though imatinib, sorafenib, or sunitinib increased lung metastasis after 66c14 cell injection, employing an anti-VEGFR2 antibody reduced the development of lung nodules [ 97 ]. Overall, reports show that the increased metastasis and invasiveness caused by angiogenesis blockade therapy depend highly on the treatment type.

Anti-angiogenic drug dosage and delivery schedules may also potentially cause resistance. Sunitinib at high doses accelerated tumor development and facilitated metastasis to the lung and liver, resulting in decreased survival [ 74 , 98 ].

Although sorafenib had comparable outcomes, sunitinib produced conflicting findings in various trials. High-dose sunitinib therapy before systemic injection of tumor cells enhanced the metastatic potential of lung cancer cells, but not RCC cells.

Recently, scientists have concentrated on the role of immune checkpoint molecules, such as cytotoxic T-lymphocyte antigen-4 CTLA-4 and programmed cell death protein 1 PD-1 , largely participating in tumor cell escape from immune surveillance as their capacity to obstruct T cell activation [ 99 , ].

Hence, immune checkpoint inhibitors ICIs have been evolved for suppressing these immune checkpoint molecules [ ].

FDA-approved ICIs comprise the nivolumab, cemiplimab, and pembrolizumab, atezolizumab, avelumab, durvalumab, and also ipilimumab [ ]. Atezolizumab has been approved for use in combination with bevacizumab, paclitaxel, and carboplatin as the first-line treatment of patients with NSCLC [ ]. PD-L1 expression is regulated by various factors, such as inflammatory and oncogenic signaling, leading to the varied significances of PD-L1 positivity.

Recent reports exhibited that combination therapy with anti-angiogenic agents and ICIs could elicit synergistic anti-tumor effects in preclinical models as well as humans Table 3. Meanwhile, co-administration of anti-PD-1 and anti-VEGFR2 monoclonal antibodies mAbs in the Colon adenocarcinoma mice model gave rise to the potent inhibition of tumor growth synergistically without overt toxicity [ ].

VEGFR2 blockade therapy negatively regulated tumor neovascularization, as evidenced by the attenuated frequencies of microvessels, whereas PD-1 inhibition exerted no effect on tumor angiogenesis. PD-1 mAbs improved T cell infiltration into tumors and promoted local immune response, as documented via the improvement in various proinflammatory cytokine expressions.

Such events signified that concurrent suppression of PD-1 and VEGFR2 might inspire synergistic in vivo anti-tumor influences by dissimilar mechanisms [ ]. Further, in a mouse model of small-cell lung cancer SCLC , co-administration of anti-VEGF and anti-PD-L1 mAbs resulted in a more prominent therapeutic outcome than mono therapy with each agent [ ].

Notably, the depleted T-cell phenotype following anti-PD-L1 therapy was revoked through the addition of anti-VEGF blockade therapy. Analysis revealed that VEGFA expression improves the expression of the inhibitory receptor TIM-3 on T cells, representative of an immunosuppressive action of VEGF in patients with SCLC during PD-1 blockade therapy.

Thereby, it seems that VEGFA inhibition may entice T cell activation at higher levels, facilitating T cell-mediated anti-tumor immunity [ ]. Similarly, combination therapy with sunitinib and PD-L1 blocked therapy prolonged overall survival OS of treated RCC mice models in comparison to mono therapy with either drug [ ].

Besides, in the triple-negative breast cancer TNBC mice model, PD-L1 blocking was highly effective as an adjuvant monotherapy. However, its co-administration with paclitaxel chemotherapy with or without VEGF blocked therapy showed superiority over neoadjuvant therapy [ ].

In , Schmittnaegel et al. also noticed that dual Ang-2 and VEGFA inhibition induced antitumor immunity that was promoted by PD-1 blockade therapy in breast cancer, pancreatic neuroendocrine tumor, and melanoma [ ]. They showed that Ang-2 and VEGFA blockade by a bispecific antibody A2V caused vascular regression, tumor necrosis along with improved antigen presentation by intratumoral phagocytes [ ].

Recent clinical trials have also shown that bevacizumab plus atezolizumab could induce synergistic influence on the median OS of patients with RCC [ ], and also in combination with nivolumab could elicit modest efficacy in ovarian cancer patients [ ]. Also, co-administration of PD-L1 inhibitor avelumab with axitinib resulted in improved objective response rate ORR in HCC [ ] and also RCC [ ] patients, with acceptable safety profile.

Also, combination therapy with axitinib and pembrolizumab enhanced median progression-free survival PFS in sarcoma patients more evidently than axitinib or pembrolizumab monotherapy.

The most common treatment-related unwanted events were autoimmune colitis, pneumothorax, transaminitis, seizures, hemoptysis, and hypertriglyceridemia [ ]. Besides, co-administration of regorafenib plus nivolumab resulted in significant antitumor impacts in patients with gastric cancer and CRC [ ].

Moreover, co-administration of nivolumab plus sunitinib or pazopanib showed a significant anti-tumor effect in advanced RCC patients [ , ].

Conversely, other trials revealed that combined use of regorafenib plus nivolumab [ ] and also ramucirumab plus pembrolizumab [ ] had no remarkable therapeutic merits in CRC patients [ ] and patients with advanced biliary tract cancer BTC [ ], respectively.

Therapeutic cancer vaccines ease tumor regression, remove minimal residual disease MRD , entice durable antitumor memory, and also averts non-specific or adverse events [ , ]. Till, FDA has approved three cancer vaccines, comprising Bacillus Calmette-Guérin BCG lives, sipuleucel-T, and also talimogene laherparepvec T-VEC respectively for patients with early-stage bladder cancer, prostate cancer as well as melanoma [ ].

In the melanoma mice model, Bose and coworkers found that a treatment regimen comprising a 7-day course of axitinib 0. These desired outcomes are probably exerted by a decrease in myeloid-derived suppressor cells MDSC and Treg frequencies in the tumor concomitant with induction and recruitment of CTLs in TME [ ].

Also, addition of the axitinib to oncolytic herpes simplex virus oHSV expressing murine IL12 G47Δ-mIL12 triggered improved OS in both immunodeficient and immunocompetent orthotopic glioblastoma mice models than mice receiving monotherapy [ ]. Notably, the addition of the ICI did not promote efficacy in mice models [ ].

As well, combination therapy with sunitinib and vesicular stomatitis virus VSV brought about the eradication of prostate, breast, and kidney malignant tumors in mice, while monotherapy with VSV or sunitinib did not [ ].

Importantly, enhancement in median viral titers by fold following combination therapy indicated that this regimen could potentiate oncolytic virotherapy permitting the recovery of tumor-bearing animals.

In RCC and NSCLC mice model, co-injection of reovirus and sunitinib more potently attenuated tumor burden supporting improved OS, and also reduced the population of immune suppressor cells in tumors compared with monotherapy with reovirus [ ].

Thereby, it appears that this regimen can be a rational and effective strategy ready for clinical testing against RCC and NSCLC. Also, Tan and coworkers showed that the bevacizumab improved viral distribution and also tumor hypoxia and promoted the population of apoptotic cells and thus stimulated a synergistic antitumor impact when used in combination with oHSV in TNBC murine models [ ].

Combining bevacizumab with OHSV expressing vasculostatin RAMBO also demonstrated great anti-tumor capacities in glioma xenografts [ ]. Correspondingly, intratumorally administration of RAMBO 1 week after tumor inoculation, and intraperitoneally administration of bevacizumab twice a week reduced migration as well as invasion of glioma cells [ ].

Co-treated mice also experienced improved OS and dampened tumor invasion than those treated with bevacizumab alone [ ]. In another study, combining tumor antigen-loaded DCs vaccination and anti-angiogenic molecule lenalidomide synergistically potentiated antitumor immunity in the mice colon cancer model, largely provided by suppressing the establishment of immune suppressive cells and also activation of effector cells, such as natural killer NK cells [ ].

This regimen similarly caused a robust reduction in tumor growth and malignant cell spread in lymphoma [ ] and also myeloma [ ] xenografts by similar mechanisms. Further, lenalidomide in combination with a fusion DNA lymphoma vaccine reduced the systemic population of MDSC and Treg in tumor-bearing mice and also led to the decreased tumor burden [ ].

In addition, the combination therapy supported the incidence of the higher rates of the antitumor T cells, providing further rationale for clinical application [ ]. Currently, a clinical trial was conducted to address the safety and efficacy of combination therapy with sipuleucel-T as a cellular prostate cancer vaccine with bevacizumab in 22 prostate cancer patients [ ].

Combination therapy persuaded immune reactions and also alleviated prostate-specific antigen PSA in participants with biochemically recurrent prostate cancer [ ].

In contrast, co-administration of bevacizumab plus MA multi-peptide vaccine adjuvanted with poly-ICLC polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose did not show superiority over monotherapy with each agent in terms of alteration in OS and PFS in glioblastoma patients [ ].

However, a phase II study evaluating the safety and efficacy of bevacizumab in combination with ERC, advanced immunotherapy based on freshly extracted tumor cells and lysates, revealed that this regimen could prolong the OS in patients who received ERC plus bevacizumab compared to bevacizumab monotherapy 12 months versus 7.

Besides, evaluation of the safety, tolerability, and anti-myeloma activity of the PVX, a novel tetra-peptide vaccine with 3 of the 4 antigens XBP1 [2 splice variants] and CD with or without lenalidomide was accomplished in MM patients by Nooka et al.

They showed that the PVX vaccine was well tolerated, accompanied by mild injection site reactions and constitutional symptoms. Meanwhile, 5 of 12 patients showed clinical response to combination therapy [ ]. Importantly, CRC patients presented complete pathological remission following treatment with bevacizumab, oxaliplatin plus leucovorin and 5-fluorouracil FOLFOX-4 , surgery, and the oncolytic virus Rigvir [ ].

In consistence with previous findings, it appears that angiogenesis blockade therapy could promote viral delivery through targeting the TME [ ]. Adoptive cell therapy ACT with using TILs or genetically-modified T cells expressing novel T cell receptors TCR or chimeric antigen receptors CAR T cells or CAR-NK cells is another plan to convince the immune system to stimulate recognition of the maligned cells and then their eradication [ , ].

Notwithstanding, tumor vasculature usually obstructs the tumor-specific T cells infiltration, averting anti-tumor immunity. In the B16 melanoma mice model, co-administration of anti-VEGF mAb to ACT abrogated tumor progress and improve OS [ ]. Similarly, anti-angiogenic therapy could also improve the antitumor functions of cytokine-induced killer cells CIK cells cells by normalizing tumor vasculature and alleviating the hypoxic TME, as shown in NSCLC xenografts [ ].

Meanwhile, Shi et al. evaluated the therapeutic benefits of combination therapy with recombinant human endostatin rh-endostatin and CIK cells in NSCLC murine model. They exhibited that rh-endostatin normalized tumor vasculature and attenuated hypoxic regions in the TME [ ].

The rh-endostatin markedly potentiated the administrated CIK cells homing and also reduced immune suppressive cells frequency in the tumor tissue. On the other hand, the used regimen instigated a higher level of TILs in tumor tissue [ ]. Further, GD2-redirected CAR T cells plus bevacizumab displayed a remarkable anti-tumor effect in an orthotopic xenograft model of human neuroblastoma [ ].

Co-administration of bevacizumab or ganglioside GD2-CAR T cells or both by single systemic injection supported higher rates of CAR T cells infiltration into tumor tissue accompanied with improved IFN-γ levels in TME.

Additionally, the analysis presented that PD-L1 blockade therapy might augment the efficacy of this regimen [ ]. Likewise, epithelial cell adhesion molecule EpCAM redirected CAR NK cells injection resulted in CRC cell regression in animal models, which was potentiated when used in combination with regorafenib [ ].

These findings delivered a novel plan for the treatment of CRC and also other solid tumors. Anti-angiogenic agents as noticed can transiently stimulate a functional normalization of the disorganized labyrinth of vessels, sustaining the therapeutic efficacy of coadministered chemotherapeutic agents.

Notwithstanding, durable angiogenesis suppression usually fences tumor uptake of chemotherapeutic drugs, and so accomplishment of further studies in this context are urgently required [ ]. Correspondingly, designing intermittent treatment schedules is of paramount significance [ ].

A study in 9L glioma cell-bearing rats showed that coadministration of axitinib with metronomic cyclophosphamide potently suppressed tumor progress, whereas multiple treatment cycles were needed by monotherapy with metronomic cyclophosphamide to abrogate tumor growth [ ].

Unfortunately, the abridged tumor infiltration of 4-OH-CPA resulted in a reduction in cyclophosphamide-mediated 9L cell elimination [ ]. Such events in turn underlined lacking tumor complete regression by applied combined regimen, reflecting the importance of the optimization of drug scheduling and dosages.

In another study, co-administration of the bevacizumab plus cisplatin and paclitaxel concurrently also induced reduced tumor growth as well as improved OS in ovarian cancer xenografts [ ]. Also, monotherapy with bevacizumab suppressed ascites formation, accompanied by the partial impact on tumor burden [ ].

TNP, an angiogenesis inhibitor, plus cisplatin inhibited the liver metastasis of human pancreatic carcinoma [ ]. Indeed, liver metastasis percentages reduced from While monotherapy with each agent did not modify tumor growth in vivo, the addition of TNP to cisplatin strikingly reduced tumor growth [ ].

Of course, it seems that TNP may entice a decrease in glioma tumor uptake of some chemotherapeutic drugs, such as temozolomide, by affecting the tumor vasculature as a result of its pharmacodynamic effect [ ].

As cited, more comprehensive studies are required to define how these combinations can efficiently be utilized. Another study also exhibited that the addition of the TNP to cisplatin chemotherapy reduced the microvascular density of bladder cancer in a murine model [ ].

Nonetheless, TNP has no significant influence on the cisplatin impact versus bladder cancer as determined by apoptosis and cell proliferation [ ]. Besides, Bow and coworkers demonstrated that local delivery of angiogenesis-inhibitor minocycline could potentiate the anti-tumor efficacy of radiotherapy RT and oral temozolomide, as evidenced by enhanced OS in a rodent glioma model [ ].

These findings offered further evidence for the idea that angiogenesis inhibitors in combination with conventional therapeutic modalities could promote OS in glioblastoma patients [ ].

Moreover, the addition of the novel anti-angiogenic agent, SU, to paclitaxel supported improved PFS accompanied with some mild to modest adverse events e. However, the regimen led to the occurrences of thromboembolic events and prophylactic anticoagulation, suggesting that careful consideration must be taken.

Besides, TSU when used plus carboplatin and paclitaxel showed a manageable safety profile in NSCLC patients [ ]. Furthermore, combining TNP and paclitaxel was well tolerated with no significant pharmacokinetic interaction between them in NSCLC patients [ ].

Further, several clinical trials have verified the efficacy of combination therapy with anti-angiogenic agent and conventional therapy in patients with ovarian cancer [ , ], CRC [ , ], NSCLC [ ], MCL [ ] and also MM [ ]. For instance combination therapy with bevacizumab and paclitaxel plus carboplatin prolonged the median OS in participants with platinum-sensitive recurrent ovarian cancer [ ].

Finally, axitinib combined with cisplatin and gemcitabine [ ] and also bevacizumab plus paclitaxel and carboplatin [ ] induced significant anti-tumor effect in NSCLC patients, as documented by improved OS and PFS. In addition, the Ziv-aflibercept in combination with 5-fluorouracil, leucovorin, and irinotecan FOLFIRI significantly promoted OS in a phase III study of patients with metastatic CRC previously treated with an oxaliplatin-based regimen [ ].

However, Ziv-aflibercept in combination with cisplatin and pemetrexed did not significantly affect OS and PFS in patients with previously untreated NSCLC cancer [ ]. A list of trials based on combination therapy with angiogenesis inhibitors plus chemotherapy or chemoradiotherapy has been offered Table 4.

RT crucially contributes to the multimodality treatment of cancer. Current evolving in RT have chiefly complicated improvements in dose delivery [ ].

Upcoming developments in tumor therapeutics will probably include the combination of RT with targeted therapies. Meanwhile, preliminary results of anti-angiogenic agents in combination with RT have produced encouraging consequences [ ]. Further, there are clear proofs that suggest that well-vascularized and perfused tumors mainly exhibit desired response to RT [ , ].

Studies have shown that the addition of the angiogenesis-inhibitor minocycline to radiotherapy and oral temozolomide could result in prolonged OS in a murine glioma model [ ].

Anti-angiogenesis therapy using anginex in combination with RT also supported tumor control in squamous cell carcinoma SCC xenografts accompanied by reducing oxygen levels in tumor tissue [ ]. Observation showed that the applied regimen modified the amount of functional vasculature in tumors and also augmented radiation-elicited tumor eradication [ ].

Likewise, robust hindrance of tumor proliferation was achieved from the addition of the angiogenesis inhibitor TNP to RT in SCC xenografts more evidently than monotherapy with each approach [ ].

Also, it was speculated that exclusive investigation of each tumor neovascularization competence can be imperative before deciding the angiogenesis blockade treatment [ ]. In contrast, the addition of TNP to RT attenuated the tumor control probability in murine mammary carcinoma [ ].

Such unanticipated consequence could be ensured from the partial reserve of reoxygenation by TNP, as no remarkable alteration was shown between the RT plus TNP and RT alone under hypoxic conditions [ ].

A potent anti-angiogenesis agent, liposomal honokiol, also elicited significant anti-tumor influence by stimulating apoptosis and also suppressing angiogenesis when used plus RT in Lewis lung cancer LLC xenografts [ ].

Liposomal honokiol, in fact, could ameliorate tumor cell radiosensitivity in vivo, offering that RT plus liposomal honokiol can engender better anti-tumor efficacy in a myriad of tumors, such as lung cancer, SCC, and CRC [ , , ].

In , Yang et al. evaluated the safety and efficacy of that combination therapy with axitinib plus RT in advanced HCC patients. They exhibited that the regimen was well tolerated with an axitinib MTD of 3 mg twice daily [ ]. Besides, the addition of the bevacizumab to adjuvant radiotherapy was associated with the manageable safety profile in breast cancer patients [ ].

Likewise, erlotinib in combination with bevacizumab as well as capecitabine-based definitive chemoradiation CRT showed acceptable safety in unresectable pancreatic cancer patients [ ]. As well 2 of 9 participants showed complete response to intervention [ ].

Of course, large-scale trials on this newer therapeutic mean seem justified. Albeit there are some reports which show that combining anti-angiogenic therapy with RT had no therapeutic advantages.

For instance, in rectal carcinoma patients, combination therapy with bevacizumab and capecitabine plus RT revealed no merits in terms of improved PFS or OS in the short or long term during a phase 2 clinical trial NCT [ ]. As a result of some divergences results related to anti-angiogenic agents as well as their modest responses, we must determine and categorize a spectrum of biomarkers, screening the patients of possible responders [ ].

Additionally, such biomarkers are urgently required to can monitor disease development and angiogenic actions of tumors following exposure with treatment angiogenesis inhibitors.

There are some reports showing that angiogenesis inhibitors could not support therapeutic effect in previously treated metastatic breast cancer [ ]. These undesired events are likely related to the secretion of pro-angiogenic factors from resistant malignant tissue [ ].

The finding outlines the importance of determining biomarkers to predict the efficacy of VEGF-targeted therapies. Much effort has been spent in this regard and resulted in the finding several biomarkers comprising dynamic measurements such as variations in systemic blood pressure , circulating markers such as VEGF serum levels , genotypic markers such as VEGF polymorphism , blood cells frequencies such as progenitor cells , tissue markers such as IFP and also imaging parameters [such as estimating capillary permeability employing magnetic resonance imaging MRI ] [ ].

Recent studies have revealed that there is a negative correlation between OS with serum lactate dehydrogenase LDH and neutrophil levels in CRC patients who received bevacizumab plus standard chemotherapy [ ].

Besides, enhanced IL-8 levels were associated with shorter PFS, while low Ang-2 serum levels were related to improved OS in tumor patients undergoing angiogenesis blockade therapy [ 90 ].

Circulating endothelial cells CEC also has been determined as a robust indicator for the outcome of treatment with bevacizumab. On the other hand, greater intra-tumoral expression of VEGFR-3 may predict better response, while overexpression of VEGFR1 mainly indicates poor survival [ ].

Other studies in RCC patients upon treatment with sorafenib also revealed that high baseline levels of VEGF were related to poor prognosis [ ], while serum levels of circulating neutrophil gelatinase-associated lipocalin NGAL and VEGF were powerfully supported prolonged PFS in RCC patients receiving sunitinib [ ].

In contrast to the classical hypothesis of vascular regression, the central aim of conventional anti-angiogenic treatments is tumor vascular normalization and maturity.

This event, in turn, offered enhanced tumor access to chemotherapeutic drugs and underlays more efficient cancer immunotherapy. As cited, survival benefits of angiogenesis blockade therapy are compromised by cancer resistance to theses agent, and thereby provoke interest in evolving more effective means to combine anti-angiogenic drugs with other conventional therapeutics.

To date, a large number of clinical trials have evaluated the safety and therapeutic merits of angiogenesis blockade therapy alone or in combination with other modalities in cancer panties Fig.

Although combination therapy regimen mainly caused significant efficacy in cancer patients, intervention-related toxicities hurdle their application in clinic. For instance, bevacizumab therapy could sustain ischemic heart disease.

Indeed, CRC patients receiving bevacizumab may experience considerably augmented possibility of cardiac ischemia [ ]. In addition, it has been proved that combination therapy with angiogenesis inhibitors and chemotherapeutic agents may attenuate antitumor effects of chemotherapy.

Hence, further rigorous investigations are warranted to circumvent the cited problems. Moreover, determining the suitable dose and sequence is of paramount importance to optimize the effectiveness, toxicity, and tolerability of the combination therapy.

Thanks to the involvement of a myriad of cytokines and growth factors and the resultant interplay and compensation among them, co-targeting various growth factors is urgently required. The recognition and potent suppression of downstream kinases and strategic signaling biomolecules where several angiogenic pathways converge may defeat current difficulties motivated via the variety of angiogenic ligands and receptors and should be the emphasis of upcoming investigations.

For instance, dual EGFR inhibition erlotinib and cetuximab combined with bevacizumab is a safe and well-tolerated combination, demonstrating antitumor activity in patients with solid tumors [ ]. BQ13esides, continued treatment with conventional anti-angiogenic agents is related to toxicity and drug resistance.

These conditions offer a robust justification for novel plans to improve the efficacy of mAbs targeting tumor vasculature, such as antibody—drug conjugates ADCs and peptide-drug conjugates PDCs , offering a new avenue to exert anti-angiogenic effects on cancerous cells.

Clinical trials based on cancer therapy by anti-angiogenic agents registered in ClinicalTrials. gov October The schematic exemplifies clinical trials utilizing anti-angiogenic agents depending on the study status A , study phase B , study location C , and condition D in cancer patients.

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