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Anti-angiogenesis and cancer prevention

Anti-angiogenesis and cancer prevention

Ant-iangiogenesis earlier Weight control motivation, scientists Anti-angiogenesis and cancer prevention that serious toxic effects and drug Anti-angiogeesis would not develop in anti-angiogenic therapy cancdr angiogenic inhibitors targeted genetically stable vascular ECs rather than tumor cells. Vascular normalization: a new window opened for cancer therapies. 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.

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Treatments AGAINST Tumor Angiogenesis

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Anti-angiogejesis, the formation of new blood vessels, is Anti-angiogeneais complex abd dynamic process regulated by various pro- Anti-angiogenssis anti-angiogenic molecules, which plays Anti-anngiogenesis crucial role andd tumor growth, invasion, and Anti-angiogenesis and cancer prevention.

Ant-angiogenesis the Carbohydrate metabolism and energy balance in molecular and cellular biology, various biomolecules preventipn as Anti-angiogenesis and cancer prevention Anti-angiohenesis, chemokines, and cahcer factors Anti-anggiogenesis in Anti-anigogenesis angiogenesis has gradually been elucidated.

Targeted therapeutic research based on these Antu-angiogenesis has Anti-angiogensis anti-angiogenic treatment to become a Anti-anngiogenesis strategy in anti-tumor therapy. The most widely used anti-angiogenic preventuon include monoclonal Anti-angiogenesiz and vancer kinase Anti-angiogenesis and cancer prevention Orevention targeting vascular endothelial growth nad VEGF pathway.

However, the clinical Anti-angiogensis of this modality has still Antj-angiogenesis limited due to several defects such Anti-angiogenessis adverse events, acquired drug resistance, tumor recurrence, and cancee of validated biomarkers, which impel further Preventjon on mechanisms of tumor angiogenesis, the development of multiple drugs and the combination therapy to figure out how to improve the therapeutic efficacy.

Here, we Anti-angkogenesis summarize various signaling pathways in tumor angiogenesis and discuss the development and current challenges of anti-angiogenic therapy.

We also propose several new Anti-wngiogenesis approaches to improve anti-angiogenic Anti-angiogeensis and provide a perspective Magnesium for sleep the development and research of anti-angiogenic therapy.

Anti-angiogeenesis is a process in cacer new blood vessels prevnetion from existing capillaries and eventually create a preventipn, regular, and ajd vascular network.

This process includes cxncer of the basement membrane and Anti-angiogenrsis, proliferation, and migration of AAnti-angiogenesis endothelial cells ECsAnit-angiogenesis is regulated by Anti-zngiogenesis pro-angiogenic and Anti-angiogenrsis factors.

Anti-ahgiogenesis tumor anc a biological tissue with rapid proliferation, Anti-angiogenessi metabolism, and tenacious cnacer, which needs oxygen and nutrients far more than normal tissue cells. The initial stage of tumor growth Anti-wngiogenesis an avascular state, in which the tumor has Anti-angoigenesis acquired aggressiveness and precention oxygen prevenrion nutrients Anti-angiogwnesis the Adaptogen digestive remedy of surrounding tissue.

Prevntion it gradually evolves into a carcinoma, which acquires aggressiveness Anti-angiogenesis and cancer prevention induce the stromal Bioenergy and biomass solutions, including intratumoral angiogenesis, leukocyte Anti-angoigenesis, fibroblast proliferation, and wnd matrix Anti-angiogenesid, especially in cancerous tumors.

The progression Anti-aangiogenesis the canceration adn angiogenesis. The rapid expansion of tumor results in a reduction in anr oxygen supply.

Anti-angiogeensis consequent hypoxic Anti-angiogenrsis microenvironment stimulates excessive angiogenesis via increasing various angiogenic pro-factors including Anri-angiogenesis, PDGF, FGF, and angiopoietin. Later, new blood Anti-anfiogenesis facilitate the Cance of oxygen and nutrients to further support the survival, prevfntion and proliferation xancer tumor Anti-angiogenesls.

When tumor cells Antl-angiogenesis a more Anti-angkogenesis phenotype, they ad to preventiion, spread and Anti-angiogenesis and cancer prevention angiogenesis, prevetion the invasion and metastasis of tumor prevrntion into distant tissues through blood circulation.

Up Anti-angiogenfsis now, although a significant number of research has been devoted to anti-cancer therapy to preventin this incurable and lethal disease, xnd of them has achieved czncer clinical Anti-angiogenesis and cancer prevention. Even so, tumor cells are not entirely killed, drug resistance rises unavoidably.

Some limitations in chemotherapy like acquired drug resistance and Green tea and cancer prevention recurrence have also been found in Anti--angiogenesis therapy.

Hence, great efforts have been devoted to further improving the therapeutic efficacy and mitigating drug resistance. For example, a number preventin multi-targeted angiogenic inhibitors prevenhion been developed for cancer treatment. Ant-iangiogenesis, the combination Enhance cardiovascular endurance angiogenic inhibitors Dehydration and fatigue other Anti-angiogeness cancer treatment preventiion chemotherapy, radiotherapy, immune therapy, adoptive cell therapy, targeted belly fat burning cancer vaccines has been evidently demonstrated through Electric vehicle charging infrastructure pivotal clinical trials Anti-angiogeneis patients with different types of caner.

In the cance review, Anti-angiogenseis highlight the Anti-angiogenesks effects of angiogenesis in tumor growth, proliferation, carcinogenesis, invasion and metastasis, summarize multiple signaling pathways in tumor BMI for Teens and outline the development czncer anti-angiogenic therapies, preventipn well as classic anti-angiogenic drugs and ane potential clinical candidates.

Moreover, we discuss the challenges of anti-angiogenic treatment and some Anti-angiogenewis therapeutic Anti-xngiogenesis to exploit Anti-angiogrnesis great advantages of anti-angiogenic therapy. Blood circulation is a prevrntion of cell metabolism, which flows in a closed circuit from the heart to arteries, capillaries, veins, and finally back to the heart.

In normal tissue, tight Fatigue and iron deficiency coverage and vascular endothelial Anti-angiigenesis junction ensure regular blood Antu-angiogenesis, forming a mature vascular Antiangiogenesis.

Besides, fragile Anti-angiogenesks highly permeable tumor vessels, Anti-angjogenesis have an abd arrangement of caancer cells and thinly covered pericytes, lead to blood leakage and incoherent perfusion.

Tumor angiogenesis occurs mainly through any of the following modes described in Fig. Among them, sprouting angiogenesis is the most typical process in physiological and pathological angiogenesis.

The patterns of vessel co-option and vessel mimicry are significantly related to tumor invasion, metastasis, and therapeutic resistance in conventional anti-angiogenic therapy.

Sprouting angiogenesis is so-called angiogenesis, in which new vascular branches form in existing blood vessels and finally infiltrate into tumor tissue through the migration of tip cells and the proliferation of stem cells Fig.

Most common modes in tumor angiogenesis. a Sprouting angiogenesis: main way in both physiological and pathological angiogenesis, which is induce by proliferation and migration of endothelial tip cells.

b Intussusception: the existing blood vessel is divided into two vessels under mediation of cell reorganization. c Vasculogenesis: bone-marrow-derived endothelial progenitor cells differentiate into endothelial cells, participating in canccer 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 Atni-angiogenesis 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 factor EGF is a single-chain small molecule polypeptide composed of 53 amino acid residues. EGF is a mediator widely participates in cell growth, proliferation, differentiation, migration, adhesion, apoptosis, and tumor angiogenesis through EGFR.

As a critical factor in promoting wound healing, the fibroblast growth factor FGF family is one of the potent mitogens and drivers of endothelial cells and is the earliest discovered growth factor related to angiogenesis, which consists of 23 proteins with different structures.

FGFR is a transmembrane receptor family with five members of FGFR1—5 only FGFR5 lacks an intracellular kinase 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 xancer 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, Anit-angiogenesis 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 anx 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 Ahti-angiogenesis 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 of tumor cells, and promotes tumor angiogenesis. The transduction of HIF-1α in normal and hypoxic conditions. Under normal conditions, HIF-1α is degraded by protease and loses transcription function.

In hypoxic environment, lack of enzyme degradation leads to efficient transcription of HIF-1α, resulting in over-expression of pro-angiogenic factors including VEGF, PDGF, and MMPs.

In tumor progression, the expression of related genes of all VEGF isoforms, PlGF, FGF, PDGF, and Ang-1 prevengion be up-regulated by HIF-1α prevenfion 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 preventio vascular degeneration to inhibit tumor growth. Notch receptors are a kind of particular non-RTK proteins that engage in numerous cellular processes, like morphogenesis, proliferation, migration, differentiation, apoptosis, adhesion, EMT, and angiogenesis Fig.

Among the Notch family, Dll-4 and Jag-1 are the most representative ligands in tumor angiogenesis. Additionally, hypoxia is one of the causes of cancer metastasis, and the interaction between Dll-4 and HIF-1α significantly upregulates the expression of Dll-4 and aggravates hypoxia, promoting the aggressiveness of cancer cells.

The progression of various malignant tumors such as leukemia, BC, HCC, CC, and cholangiocarcinoma is highly linked to the over-expression of Jag For example, EphrinB2 is over-expressed in ovarian cancer, kidney cancer and melanoma, whereas EphrinA3 is up-regulated in squamous cell lung carcinoma SCLC and colon cancer.

: Anti-angiogenesis and cancer prevention

Anti-Angiogenesis: Cutting Off Tumor Supply Lines

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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Am J Cancer Res. André F, Bachelot T, Campone M, Dalenc F, Perez-Garcia JM, Hurvitz SA, et al. Targeting FGFR with dovitinib TKI :preclinical and clinical data in breast cancer. Burbridge MF, Bossard CJ, Saunier C, Fejes I, Bruno A, Léonce S, et al. S is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab.

Montmayeur JP, Valius M, Vandenheede J, Kazlauskas A. The platelet-derived growth factor beta receptor triggers multiple cytoplasmic signaling cascades that arrive at the nucleus as distinguishable inputs.

Heldin CH. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal. Francia G, Emmenegger U, Kerbel RS. 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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Drugs that block cancer blood vessel growth (anti angiogenics)

These drugs are known as tyrosine kinase inhibitors TKI. Sunitinib Sutent ® is an example of a tyrosine kinase inhibitor. For this reason, these drugs are typically used in combination with chemotherapy or other treatments. Angiogenesis inhibitors are particularly effective for treating liver cancer , kidney cancer and neuroendocrine tumors.

Since they act on blood vessel formation and not the tumor itself, the side effects of angiogenesis inhibitors are different than traditional chemotherapy drugs.

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In the avascular phase, tumor growth is usually restricted in size due to a balance between pro-angiogenic and anti-angiogenic factors that control vascular homeostasis 6. Beyond a few millimeters in size, solid tumors build, and increase their own blood supply to provide adequate oxygen and nutrients Figure 1.

This process, referred to as the angiogenic switch, from an avascular state to an angiogenic phase, is crucial for tumors to grow and continue unrestricted proliferation 7. Hence, unlike normal physiological processes favoring negative regulation of angiogenesis, tumors favor its upregulation.

Figure 1. Role of sprouting angiogenesis in tumor growth. A During early stages of development, tumor is still small in size and relies on local existing blood vessels for oxygen and nutrients supply.

B As the tumor grows, sprouting of new vessels from local existing blood vessels occurs to fulfill the need for more oxygen and nutrients supplies. C Sprouting angiogenesis results in a more complex network of vasculature to provide adequate blood supply for the growing tumor.

Multiple non-mutually exclusive mechanisms have been described as major players in tumor neovascularization. These include sprouting angiogenesis, non-sprouting angiogenesis, vasculogenesis, vasculogenic mimicry, and intussusception. Sprouting angiogenesis, however, remains the most well-studied mechanism used by tumor cells to produce their vasculature 8.

Due to the importance of this latter process in tumor cell growth, invasion, and extravasation, different angiogenesis inhibitors AIs have been developed.

In this review, we will discuss the different driver molecules promoting angiogenesis in cancer. These include the angiogenic or angiostatic chemokines, the contribution of the endothelial progenitor cells EPCs , the tumor vasculogenic mimicry, the markers for tumor-derived ECs, and pericytes.

We will also provide an overview on the clinically tested anti-angiogenic drugs slowing down angiogenesis and leading to tumor starvation. Finally, the resistance mechanisms arising in cancer cells against these drugs and the potential therapeutic solutions will be discussed.

Unlike normal angiogenesis and neovascularization, tumor angiogenesis is an uncontrolled and disorganized process. It results in vessels with thin walls, incomplete basement membranes, and atypical pericytes 8. Since the needs of rapid tumor cell proliferation surpass the capacity of host vasculature, hypoxia and low supplies of nutrients characterize early stages of tumor development.

Hypoxia triggers the expression of pro-angiogenic factors such as vascular endothelial growth factor VEGF and platelet-derived growth factor PDGF 9 — Matrix metalloproteinases MMPs secreted by tumor cells degrade the basement membrane as a first essential step to initiate angiogenesis This alters cell-cell interactions and facilitates the migration of ECs through the created gap into the tumor mass, which in turn results in the proliferation and formation of new blood vessels, followed by vessel pruning and pericyte stabilization Figure 2.

Figure 2. Phases of sprouting angiogenesis. A increased permeability across the endothelial cell layer, B cell division, C proteolysis of basement membrane components, D migration ofthe endothelial cells, and E lumen fonnation. Altematively, 1 circulating endothelial progenitor cells contribute to the sprouting mechanism, 2 adhere to endothelial cells, 3 extravagate through the endothelial cell layer, 4 cluster together, and 5 integrate into the sprout fonned by endothelial cells.

Angiogenesis is a tightly balanced mechanism regulated by both pro-angiogenic and anti-angiogenic factors In malignant tumors, this balance is shifted toward a pro-angiogenic milieu to maintain sustainable angiogenic processes Involved soluble growth factors include VEGF, PDGF, fibroblast growth factor FGF -2, angiopoietins Angs , transforming growth factors TGFs - beta and alpha, and epidermal growth factors EGF.

Insoluble membrane-bound factors include integrins, ephrins, cadherins, MMPs, and hypoxia inducible factor-1 HIF From these, VEGF was broadly studied and shown to significantly contribute to the induction and progression of angiogenesis We will start by listing the different members of the VEGF family.

In the following sections, a general overview on the role of the other angiogenic factors in normal and tumor angiogenesis will be described. In addition, direct and indirect angiogenesis inhibitory mechanisms will be discussed. The VEGF family comprises seven members, VEGFs A to F and placenta growth factor PGF These members are ligands that interact with multiple receptors present on the vascular endothelium 17 Figure 3.

VEGF-A is the most potent angiogenic factor that is encoded by a gene located on the short arm of chromosome six Its interaction with the transmembrane tyrosine kinase receptors, VEGF receptors VEGFRs -1 and 2, and their co-receptors, NRPs-1 and 2, present on vascular ECs results in the dimerization and phosphorylation of intracellular receptors VEGF-A expression is stimulated by hypoxia, growth factors, and cytokines such as IL-1, EGFs, PDGFs, and tumor necrosis factor TNF -α It was noted in most solid tumors and some hematologic malignancies VEGF-A is considered the backbone of angiogenesis during physiologic as well as pathologic processes.

The deletion of one or both VEGF-A alleles in mouse pre-clinical models resulted in either vascular abnormalities or complete absence of vasculature leading to death Interestingly, a striking positive correlation between the level of VEGF-A expression, tumor progression, and cancer patients' survival was observed 23 , VEGF-B is encoded by a gene located on chromosome eleven.

It differs from VEGF-A by its promotor region 25 , It was found to be upregulated in many types of tumors including prostate, kidney, and colorectal cancers CRCs 27 , Since the VEGF-B promoter lacks the HIF-1 and AP-1 sites found in the VEGF-A promotor, stimuli such as hypoxia or cold do not induce VEGF-B expression 29 , A study was conducted to explore the role of VEGF-B in cancer development.

Results revealed that VEGF-B-deficient transgenic mice with pancreatic endocrine adenocarcinoma had larger tumors compared to transgenic expression of VEGF-B but no difference in tumor vasculature In addition, knockout studies have highlighted the role of VEGF-B in inflammatory angiogenesis and regeneration of coronary collaterals through arteriogenesis 32 , The VEGF-C encoding gene is located on chromosome four 34 — Experiments performed on transgenic mice demonstrated the ability of VEGF-C to induce selective lymphangiogenesis without accompanying angiogenesis Several studies showed a positive correlation between VEGF-C expression, lymphatic invasion, metastasis, and survival in cancer patients.

Similar to VEGF-C, VEGF-D can bind and activate the VEGFRs 2 and 3 41 , Depending on the activated receptor, separate downstream cascades are activated to induce the growth and proliferation of ECs in the vascular and lymphatic systems As such, VEGF-D activity is crucial for hypoxia-induced vascular development 44 in melanoma, lung, breast, pancreatic, and esophageal cancer 43 , 45 — VEGF-E is a potent angiogenic factor.

Its isoform, VEGF-E nz-7, binds with high affinity to VEGFR-2 to stimulate efficient angiogenesis and increase vascular permeability PlGF is a member of the VEGF subfamily that binds to VEGFR-1 and its co-receptors, NRP-1 and 2. This stimulates the growth and migration of ECs, macrophages, and tumor cells 52 , Upregulation of PlGF expression has been observed in tumors resistant to anti-VEGF therapy suggesting that PlGF might serve as a promising therapeutic target in this setting 54 — This suggests that by neutralizing PlGF, pathological angiogenesis can be inhibited without affecting normal blood vessels Since sprouting angiogenesis plays an essential role in tumor growth, invasion, progression, and metastasis, targeting this process may potentially halt the growth and spread of cancer Table 1 lists antiangiogenic agents approved for clinical use and their targets.

Angiogenesis inhibitors AIs are classified into direct and indirect agents. Direct endogenous inhibitors target vascular ECs and include endostatin, arrestin, and tumstatin. Unfortunately, phase II or III clinical trials did not result in significant effects on patients 14 , In the last decade, a number of molecules have been described, including semaphorins, netrins, slits, and others 62 — Netrin-1, Netrin-4, and their receptors can have a repulsive or attractive signals in angiogenesis, partially via the regulation of VEGF signaling.

There are still some contradictions reported on the positive and negative role of Netrin-1 in regulation of angiogenesis, and studies are still on going to identify its exact role in angiogenesis. Semaphorin-3A and Semaphorin-3E have negative effects on angiogenesis in central nervous system CNS and non-CNS tissues.

Indirect AIs target tumor cells or tumor associated stromal cells and include several types 14 Table 2. They prevent the expression of pro-angiogenic factors or block their activity.

Among the AIs, VEGF inhibitors were extensively studied and reached phase III clinical trials. They caused a modest increase in overall survival OS Bevacizumab BVZ , a humanized anti-VEGF monoclonal antibody, was the first drug to be approved by the Food and Drug Administration FDA for the treatment of metastatic colon, ovarian, renal, non-squamous cell lung cancer NSCLC , and glioblastoma mutliforme GBM 66 , It failed to show clinical significance when used as monotherapy, except in GBM.

In contrast, its clinical benefits were evident in association with other chemotherapeutic agents. For instance, since the tumor vasculature induced by VEGF is usually tortuous and dysfunctional, the use of BVZ was thought to normalize the blood vessel texture.

It was also hypothesized that the combination of BVZ and chemotherapy increases the delivery of the chemotherapeutic agent to the cancer tissue by increasing its blood flow 68 , However, contrary evidence was reported by a decrease in cytotoxic drug delivery to tumors following treatment with AIs Such inconsistency could be due to differences in blood vessel setups among various cancer types 71 , BVZ combined with chemotherapy was also studied in the adjuvant setting in colorectal cancer CRC , but it failed to prove any clinical significance compared to chemotherapy alone in two phase III clinical trials 73 — Aflibercept is a soluble VEGF decoy receptor that consists of the extracellular domains of VEGFRs 1 and 2 and the Fc portion of human IgG1.

It was FDA approved for the treatment of metastatic CRC in combination with 5-fluorouracil, leucovorin, and irinotecan in Owing to its structure, Aflibercept can neutralize both, VEGF and PlGF Compared to treatment with BVZ, the use of Aflibercept in patient-derived xenograft models resulted in higher tumor suppressive activity Unfortunately, neutralizing both, PlGF and VEGF, had a minimal effect on tumor suppression in vivo In a phase I clinical trial, relapsing GBM patients treated with BVZ monotherapy were compared to those treated with the combination of an anti-PlGF agent and BVZ.

Similar results were obtained with no added benefit in the combination arm Unlike BVZ and Aflibercept, tyrosine kinase inhibitors, which are small molecules able to interact with the kinase domain on the VEGFRs, showed a remarkable clinical benefit when used as single agents, and with no added value when combined with chemotherapy.

This was reported in the treatment of renal cell carcinoma RCC , hepatocellular carcinoma HCC , thyroid cancer, gastrointestinal stromal tumor GIST , and pancreatic neuroendocrine tumor PNET Although anti-angiogenesis therapies may prolong progression-free survival PFS , they have limited impact on overall survival OS and do not constitute a permanent cure in RCC, CRC, or breast cancer 73 , 75 , 82 , This limited clinical significance might be due to different innate and acquired molecular resistance mechanisms with no clear genetic explanations Hypoxia plays an important role in tumor resistance to chemotherapeutic agents favoring more aggressive metastatic disease and hence worse prognosis.

HIF-1 plays a critical role in resistance to anti-angiogenic therapy and is the main survival factor used by cancer cells to adapt to oxygen deprivation 84 , In this section, an overview on different mechanisms of resistance to anti-angiogenic therapies in the clinical and preclinical settings will be discussed Figure 4 and the ways to overcome them will be provided Table 3.

Some of these mechanisms are likely influenced by hypoxia. These include the production of alternative proangiogenic factors, the recruitment of BM-derived cells, the vasculogenic mimicry, as well as the increased tumor cell invasiveness and metastatic behavior. Figure 4. Summary of plausible resistance mechanisms to Anti-angiogenic Agents.

Treatment with anti-angiogenic agents results in a reduction in the blood vessel network. This new hypoxic condition results in the activation of vascular mimicry, altemative pro-angiogenic pathways, recruitment of bone man·ow-derived EC precursors and myeloid cells, as well as cell survival mechanisms such as autophagy.

Table 3. List of mechanisms of resistance to anti-angiogenic therapies and ways to target them along with the outcomes associated with each approach.

Treatment with anti-angiogenic agents results in vascular regression and intra-tumoral hypoxia. Several studies have made use of pimonidazole injections, to demonstrate an increase in hypoxic regions in primary tumors following anti-angiogenic treatment 86 , 89 , Further analysis showed a concomitant increase in HIF-1a expression during treatment.

HIF-1a and hypoxia are known drivers of EMT, a process that promotes tumor metastasis. Upregulation of EMT-related genes, such as Twist and Snail, have been noted following anti-angiogenic treatment.

This is in addition to the loss of the epithelial marker, E-cadherin, and the induction of the mesenchymal marker, vimentin 86 , Hypoxic environments also induce upregulation of VEGF expression through the upstream transcription factor HIF-1a These factors cause tumors to acquire more angiogenic and invasive capacities, thus promoting metastasis The increase in tumor invasiveness and metastasis in response to AI-induced hypoxia from anti-angiogenic therapies can be explained by the over-expression of the tyrosine protein kinase, c-MET.

For instance, in vitro studies revealed a direct positive effect of hypoxia on c-MET and phospho-c-Met expression Other studies confirmed that this promotion of c-MET transcription that follows hypoxic conditions occurs via the direct regulation of HIF-1 This usually promotes tumor growth and invasiveness.

VEGF exerts a negative feedback on c-MET activation in a GBM mouse model, resulting in the direct suppression of tumor invasion For instance, compared to GBM patients who were not treated with BVZ, those treated with BVZ had more recurrence rates and their tumors had an upregulation in c-MET expression This increased invasiveness of GBM after BVZ treatment was recently linked to inhibitory actions of VEGF and to the increase in c-Met and phospho-c-Met expression upon treatment MET activation in response to hypoxia can occur in endothelial cells, as well as in tumor cells or other cells of the tumor microenvironment.

In fact, in one study this had very diverse functional impacts. To overcome the c-MET protein overexpression that occurs with the neutralization of VEGF by BVZ, the addition of a c-MET inhibitor would be helpful. In the phase III METEOR trial, the administration of the inhibitor of tyrosine kinases including MET, Cabozantinib, after previous vascular endothelial growth factor receptor-targeted therapy in patients with advanced RCC resulted in improved survival It is thought that the hypoxic microenvironment generated during anti-angiogenic therapy induces HIF-1α expression, thus stimulating β1 integrin expression.

β1 integrin is the member that is mostly implicated in cancer treatment resistance, especially that its expression has been upregulated in clinical specimens of BVZ-resistant GBM tumors — The expression levels of integrins are correlated with disease progression and poor survival of patients , Upon interacting with c-MET, integrins ultimately enhance tumor cell invasiveness , , Several preclinical studies have demonstrated benefit from β1 integrin blockade in BVZ-resistant and non-resistant GBM tumors in xenograft models , Despite their overall inhibition of tumor growth, therapeutic AIs were associated with increased local invasiveness and distant metastasis.

These phenomena seem to be major contributors to resistance against anti-angiogenesis therapies. They were first described by Ebos et al. and Paez-Ribes et al. in different preclinical models , Angiogenesis blockade enhances tumor invasiveness. For instance, RCC cells demonstrated an accelerated growth capacity and an invasive profile following treatment with BVZ Similarly, GBM cells in mouse models developed enhanced invasiveness following VEGF inhibition Treatment with AIs also promotes tumor metastatic potential.

Treatment with sunitinib has been shown to result in vascular changes that include decreased adherens junction protein expression, reduced basement membrane and pericyte coverage, and increased leakiness 89 , 91 , , These phenotypic changes were observed in both, tumor vessels and normal organ vessels, so they tend to facilitate local intravasation and extravasation of tumor cells, resulting in metastatic colonization Increased metastasis and enhanced invasiveness in response to anti-angiogenesis therapy are variable and depend on the treatment type, dose, and schedule.

Singh et al. observed that sunitinib and anti-VEGF antibody monotherapy had different effects on mouse tumor models. While treatment with sunitinib enhanced the aggressiveness of tumor cells, using an anti-VEGF antibody did not This was supported by Chung et al.

who compared the efficacy of different RTK inhibitors and antibody therapies in murine models While pretreatment with imatinib, sunitinib, or sorafenib enhanced lung metastasis following the injection of 66c14 cells, using an anti-VEGFR2 antibody inhibited the formation of lung nodules Altogether, these results prove that the increased metastasis and enhanced invasiveness that result from use of AIs are largely dependent on treatment type.

Dosing and scheduling of administration of AIs can also induce resistance. The high-dose of sunitinib increased tumor growth and enhanced metastasis to the liver and lung, resulting in reduced survival.

Although similar results were observed using sorafenib, contradictory results were reported with sunitinib in different studies , In fact, treatment with high-dose sunitinib before intravenous inoculation of tumor cells increased metastatic potential of lung cancer cells but not of RCC cells.

It was documented that hypoxia and EMT also contribute to the increased invasiveness and metastasis of tumors, and c-Met, Twist, and HIF-1a are the key molecular players 11 , In contrast, semaphorin 3A Sema3A , an endogenous anti-angiogenic molecule, is frequently lost in tumors, resulting in increased invasiveness and metastasis Different inhibitors of c-Met were tested in preclinical studies and demonstrated promising effects.

Crizotinib, a dual c-Met and ALK inhibitor, was effective in reverting sunitinib-induced invasion and metastasis in different models 86 — Interestingly, this resulted in a reduction in the expression of EMT markers such as Vimentin, Snail, and N-cadherin downstream of c-Met 86 , By blocking c-Met and silencing Twist, the master regulator of EMT , metastasis was almost fully abrogated in both wild-type and pericyte-depleted tumors Sunitinib-treated transgenic mice tumors that were subjected to adenoviral Sema3A expression witnessed an impressive increase of 10 weeks in median survival and a reduction in metastasis and hypoxia Normalization of the tumor vasculature was evident, and the expression of EMT markers, including c-Met, were reduced.

Rovida et al. investigated the use of conventional chemotherapeutics to counteract sunitinib-induced metastasis. Gemcitabine and topotecan, but not paclitaxel, cisplatin, and doxorubicin, were effective in reverting sunitinib-induced metastasis and in reducing primary tumor growth Mechanistically, topotecan was shown to inhibit HIF-1a accumulation, thereby preventing hypoxia-driven invasiveness.

Gemcitabine was moderately effective in combination with anti-VEGF antibody therapy in an established pancreatic ductal adenocarcinoma model but had no effect in a preventive setting Initially, the primary focus in angiogenesis blockade was to target VEGF, which is the best known angio-stimulatory protein family responsible for EC activation and functional vessel formation and stabilization.

Cancers that are highly dependent on the induction of angiogenesis by VEGF, were the best responders to anti-VEGF agents. These include CRC, RCC, and neuroendocrine tumors Cancers relying on angiogenic factors other than VEGF are less susceptible to anti-VEGF agents and include malignant melanoma, pancreatic cancer, breast cancer, and prostate cancer The presence of several anti-VEGF resistant cancers suggests alternative angiogenic pathways.

These involve Ang-1, EGF, FGF, granulocyte colony-stimulating factor G-CSF , hepatocyte growth factor HGF , insulin-like growth factor, PDGF, PGF, stromal cell-derived factor-1 SDF-1 , and TGF Except for P1GF, which binds VEGF receptors, most angiogenic factors signal through specific transmembrane receptors, which are expressed on ECs This variety of growth factors culminates in a plethora of pathways that tumor cells can exploit to induce angiogenesis.

Results from preclinical models and clinical trials suggest that inhibition of a specific growth factor can induce the expression of others , In a study by Willett et al. in which rectal cancer patients were treated with BVZ, significantly increased plasma levels of PlGF were noted 12 days following the start of treatment In a phase II study by Kopetz et al.

in which metastatic CRC patients were treated with a combination of FOLFIRI and BVZ, the levels of several angiogenic factors including PlGF and HGF were found to increase before disease progression Similarly, the levels of FGF2 and PlGF increased in GBM patients following treatment with cediranib, a pan-VEGF receptor tyrosine kinase inhibitor 71 , Similarly, treatment of transgenic mouse models of pancreatic tumors with an anti-VEGFR2 antibody for a prolonged period of time, associated with an increase in the expression of the pro-angiogenic growth factors, Ang-1, Ephrin-A1, Ephrin-A2, and FGF1, FGF2a, resulting in transient tumor growth delay and modest survival benefit 98 , Redundancy in angiogenic signaling and potential in malignant tissues is nowadays more studied.

In addition, the therapeutic effect of targeting a single angiogenic growth factor or its receptor became limited due to intrinsic resistance. This resistance arose either from redundancy in activated pathways or alternative growth factor signaling pathways. Thus, targeting multiple growth factors simultaneously or sequentially would be a successful approach to overcome such resistance.

In the following subsection, we discuss potential angiogenic factors that might play a role in the escape from anti-VEGF treatment.

We also shed light on results of studies evaluating the effects of targeting one or more of these factors on overcoming resistance to anti-VEGF therapies.

Ang-Tie signaling system is a vascular-specific RTK pathway that regulates vascular permeability and blood vessel development and remodeling through Ang-1 and Ang Ang-1 binds to the Tie2 receptor on the M2 subpopulation of monocytes, HSCs, and ECs of blood and lymphatic vessels.

This activates the Ang-Tie pathway and results in the maturation or stabilization of blood vessels In contrast, Ang-2 blocks this pathway resulting in the remodeling or initiation of vascular sprouts following exposure to VEGF Upregulation of Ang-2 expression was described in many types of cancers and presumable contributes to resistance against anti-VEGF therapy — For example, in CRC patients, elevated serum Ang-2 levels were associated with a poor response to BVZ treatment Blockade of both, VEGF and Ang2, in preclinical studies suppressed revascularization and tumor progression of cancers resistant to anti-VEGF therapy 92 — However, results of ongoing clinical trials evaluating the efficacy of the humanized bi-specific monoclonal antibody against VEGF-A and Ang-2, vanucizumab, are still pending , Tumor-infiltrating T helper type 17 Th17 cells produce interleukin IL , initiating a paracrine network to confer resistance to anti-VEGF therapy IL induces G-CSF secretion by tumor cells through nuclear factor κB NF-κB and ERK signaling The increase in G-CSF induces the expression of Bv8, also known as prokineticin-2, in the bone marrow.

Bv8 is a pro-angiogenic growth factor that was initially purified from the skin secretion of a yellow-bellied toad. As such, Bv8 promotes differentiation of myeloid-derived suppressor stem remove word stem cells MDSCs and induces their mobilization to the peripheral blood and infiltration into the tumor microenvironment.

This culminates in the promotion of angiogenesis and results in the escape from anti-VEGF therapy — Treatment with the Bv8 antagonist, PKRA7, suppressed tumor formation in vivo by inhibiting angiogenesis in GBM and infiltration of MDSCs in pancreatic cancer Neutralization of Bv8 and upstream G-CSF using monoclonal antibodies also resulted in tumor suppression Results of ongoing clinical trials evaluating combination regimens using Bv8 inhibitors with or without other anti-angiogenic reagents are still pending.

The FGF family consists of 22 members. Four of these are intracellular cofactors of voltage-gated sodium channels, while the remaining 18 members are secretory proteins that bind to RTK—FGF receptors FGFRs FGFR is expressed on tumor cells and several types of stromal cells, including cancer-associated fibroblasts CAFs , ECs, and tumor-infiltrating myeloid cells One of the roles of this signaling pathway is cancer development and progression through the amelioration of angiogenesis , Indeed, upregulation of FGF2 expression correlated with resistance to anti-VEGF agents in several tumors resistant, especially those exposed to hypoxic environments 54 , 71 , 98 , Simultaneous blockade of VEGF and FGF signaling pathways was very beneficial in many preclinical models of cancer 98 , — Combining the FGFR inhibitor, PD, with BVZ in xenografted mouse models with head and neck squamous cell carcinoma HNSCC completely abolished tumor growth FGF blockade using the soluble FGF receptor, FGF-trap, was combined with an VEGFR2 inhibitor, and yielded comparable results in late stage pancreatic islet tumors Unfortunately, in the clinical setting, patients with recurrence following anti-VEGF therapy did not benefit from the dual blockade of VEGFR and FGFR by dovitinib or nintedanib 99 , The PDGF family consists of four homodimers and one heterodimer.

Binding of the PDGF dimers to tyrosine kinase PDGF receptor PDGFR results in the activation of downstream signal transduction pathways, such as PI3K and PLCγ This plays an important role in mesenchymal cell growth and motility during embryonic development and tissue repair When PDGF signaling is over-active in the tumor microenvironment, angiogenesis and tumor growth are promoted Upregulation of PDGF-C expression was observed in vivo in CAFs infiltrating into tumors resistant to anti-VEGF therapy Sunitinib has many targets, including VEGFR and PDGFR.

Following its FDA approval in for the treatment of metastatic RCC, it was assumed that combining PDGF and VEGF blockades might offer an additional therapeutic benefit Several studies were initiated to evaluate the safety and efficacy of this combination Unfortunately, combining BVZ with imatinib, which inhibits PDGF-R in addition to other tyrosine kinases such as Abl and Kit, was toxic and not effective treatment against RCC — When TGF-β binds its type II receptors, it activates type I receptors and results in the phosphorylation of the receptor-regulated Smads R-Smads corresponding to each branch.

R-Smads then complex with the common partner Smad4 Co-Smad4 and work as transcription factors TGF-β signaling regulates cellular growth, differentiation, and apoptosis Although signaling has tumor suppressive effects during the early stage, it switches toward malignant conversion and tumor progression at later stages , It activates the production of extracellular matrix ECM by fibroblasts and stimulates tube formation by ECs, thus inducing angiogenesis — Tumor tissues express higher levels of TGF-β and these levels can be correlated with patient survival — Upregulation of TGF-β expression was also observed in glioma models resistant to anti-VEGF therapy This suggests a role of TGF-β in the acquired resistance to anti-angiogenic therapy.

Several preclinical studies revealed the anti-angiogenic benefits when inhibiting TGFβ in CRC, HCC, and GBM xenografts — This offers the rationale to combine TGFβ inhibitors with anti-VEGF agents In that sense, combining galunisertib, a small molecule inhibitor of TGFβRI, with sorafenib and ramucirumab in HCC is currently under evaluation , Similarly, the combination of an anti-TGFβ monoclonal antibody, PF, with regorafenib in CRC is also under investigation MMPs play an important role in angiogenesis and in different stages of cancer , They are divided into six categories Table 4 MMP can promote or inhibit angiogenesis.

For instance, the secreted MMP-9 plays an important role in the angiogenic switch process and in releasing VEGF from the ECM 1 , The membrane type MMP-1 induces degradation and remodeling of matrix during vascular injury and is responsible for invasion and migration of ECs and formation of capillaries — On the other hand, MMPs such as MMP-3, 7, 12, 13, and 20, inhibit angiogenesis through endostatin and angiostatin production.

Endostatin that blocks the activation of pro-MMP-9 and inhibits capillary formation of Deryugina and Quigley Table 4. Categories of Matrix Metalloproteinase-1 and their corresponding members. Targeting MMPs released by bone marrow derived cells BMDCs prevents the release of sequestered growth factors in the ECM, and can help overcoming resistance to anti-angiogenic therapy Despite the fact that doing so has proven some clinical efficacy in patients with advanced and refractory solid tumors in a phase I clinical trial , most MMP inhibitors failed to offer any clinical benefit Few agents are still being developed and evaluated.

Results from an ongoing phase II clinical trial evaluating one MMP inhibitor in patients with Kaposi's sarcoma are still pending Long-term administration of AIs up-regulates HIF-1α and induces hypoxia in the tumor microenvironment by over-pruning blood vessels Hypoxic conditions due to anti-angiogenic therapy result in the expansion and recruitment of myeloid cells and CAFs into the tumor environment.

The presence of these BMDCs in the tumor microenvironment leads to a weakened antitumor response and an immunosuppressive tumor microenvironment This promotes angiogenesis, tumor growth, EMT transition, and metastasis , As a result, it has become evident that myeloid cells and CAFs play a major role in the induction of resistance to anti-angiogenic drugs.

An excessive production of MDSCs was described in cancer patients and tumor-bearing mice — This was linked to the immunosuppressive and tumor promoting capacities , In a study by Shojaei et al. Neutrophils are considered predictive biomarkers for patients treated with BVZ — Increased recruitment of neutrophils during anti-VEGF therapy promotes tumor progression and treatment resistance This is mediated by the expression of the calcium-binding protein that regulates cell growth, survival, and motility, SA4.

As such, blocking granulocytes and SA4 may be beneficial in diminishing anti-angiogenic therapy resistance Monocytes and macrophages are possibly implicated in resistance to anti-angiogenic therapy as well.

Recruitment of these cells to the tumor microenvironment is mediated by different cytokines, including VEGF, chemokine C-C motif ligand 2 CCL2 , and macrophage colony stimulating factor MCSF , Tumor associated macrophages actively participate in vascular sprouting by functioning as bridging cells between two different tip cells — They also secrete MMPs, promotingangiogenesis , , , In addition, they can release pro-angiogenic growth factors including TGF-b, VEGF, EGF, and the chemokines, CCL2 and CXCL8 , , — In different murine tumor models, anti-VEGF therapy reduced macrophage infiltration , — However, this was not the case with the tyrosine kinase with immunoglobulin-like and EGF-like domains 2 TIE2 -expressing macrophages that constitute a specific subset of macrophages.

These are usually recruited by HIF1a and tumor-secreted chemokines such as ANG2 in the setting of anti-angiogenic therapy — They tend to associate with tumor vessels and release proangiogenic growth factors including VEGF , As such, macrophages contribute to the resistance against anti-angiogenic therapy.

Preclinical studies on models of mammary carcinoma and insulinoma evaluated the effect of inhibiting ANG2 on TIE2-expressing macrophage infiltration and angiogenesis. Although this approach did not block the recruitment of these macrophages, it hindered the upregulation of their TIE2 receptor.

This reduced the production of pro-angiogenic growth factors and the association of TIE2 macrophages with blood vessels — As a result, MDSCs represent promising targets for therapy.

Since G-CSF expression stimulated by tumor infiltrating T helper type 17 cells results in MDSC recruitment into the tumor microenvironment, inhibition of Th17 cell function might sensitize tumors to anti-VEGF therapies , Since SDF1 is the major BMDC recruiting factor, targeting its signaling pathway could potentially decrease BMDC infiltration and overcome resistance to anti-angiogenic therapy.

In a transgenic mouse model of breast cancer, treatment with an SDF1 neutralizing antibody inhibited MDSC infiltration and angiogenesis Since Bv8 leads to the recruitment of MDSCs into the tumor tissue after VEGF blockade, its inhibition can possibly improve the effect of anti-angiogenic therapy.

A recent study showed that the combination of gemcitabine and an anti-Bv8 monoclonal antibody treatment in mice with adenocarcinoma inhibited tumor regrowth, angiogenesis, and metastasis In addition, anti-Bv8 antibodies blocked MDSC recruitment and tumor angiogenesis in an RIP1-Tag2 insulinoma model of pancreatic cancer Blocking the recruitment of monocytes and macrophages can be another therapeutic opportunity to overcome resistance to anti-angiogenic therapy.

In a phase I clinical trial, patients with solid tumors were treated with the human anti-CCL2 monoclonal antibody, carlumab, which targets the monocyte chemotactic protein-1 MCP1. In addition to causing a drop in free CCL2 levels and a reduction in the level of tumor-infiltrating macrophages, this therapy resulted in a temporary antitumor activity Treatment of RIP1-Tag2 pancreatic neuroendocrine tumors with combined ANG2 and VEGFR2 blockers decreased infiltration of TIE2 expressing monocytes and suppressed revascularization and tumor progression Since macrophages express colony stimulating factor-1 receptor, its targeting is currently being evaluated by several phase I clinical trials NCT; NCT; NCT This is supported by results from earlier studies showing a reduced macrophage infiltration into tumor tissue and clinical objective responses following treatment of diffuse-type giant cell tumor patients with the anti-colony-stimulating factor-1 receptor antibody, RG Macrophage Migration Inhibitory Factor MIF suppresses the anti-inflammatory activity of macrophages.

TAMs, mainly M2-polarized macrophages, stimulate angiogenesis thus promoting tumor cell migration and progression VEGF increases MIF production in a VEGFR-dependent manner.

Compared to tissue specimens of BVZ-sensitive GBM patients, BVZ-resistant ones had a decreased MIF expression and an increased TAM infiltration As such, blocking the VEGF pathway using BVZ can deplete MIF expression. This explains the enhanced recruitment of TAM and M2 in BVZ-resistant GBM tumors.

Data is lacking when it comes to evaluating the application of this target in the clinical setting. Anti-angiogenic therapy causes hypoxia which results in the activation of HIF1a in tumor cells This causes tumor cells to secrete SDF1 and VEGF,main chemotactic factors for EPCs , , , Upon stimulation of the C-X-C chemokine receptor-7 CXCR7 by SDF1, EPCs secrete pro-angiogenic cytokines and promote angiogenesis , For instance, in multiple myeloma, this occurs through regulating the trafficking of angiogenic mononuclear cells into areas of tumor growth EPCs can also promote angiogenesis by differentiating into ECs and subsequently incorporating into newly forming blood vessels.

Pericytes, also known as Rouget cells, are cells that interact with ECs. They regulate endothelial proliferation and differentiation and modulate vessel diameter and permeability, thus stabilizing the newly formed endothelial tubes , In a study by Abramsson et al. Several studies revealed enhanced pericyte recruitment to and coverage of the microvasculature in the tumor after treatment with AIs.

Reduction in tumor vascularity following anti-VEGF therapy is accompanied by a tightly pericyte covered vessels For instance, after treatment with sunitinib and the chemotherapy drug, temozolomide, a preclinical malignant glioma model revealed an increased number of vessels covered with pericytes In addition, esophageal and ovarian cancer xenografts showed increased pericyte coverage around vessels following treatment with BVZ Tumor vessels that are heavily covered by pericytes have a reduced sensitivity for anti-angiogenic therapies As such, the increase in pericyte infiltration was suggested to be a mechanism of resistance to anti-VEGF and anti-VEGFR therapies.

By suppressing EC proliferation and by providing survival signals that contribute to the maintenance of ECs, pericytes mediate vascular maturation and stability hence allowing tumor cells to proliferate during the course of an anti-angiogenic therapy — As a result of protecting ECs from anti-angiogenic agents, pericytes were implicated in clinical resistance to VEGFR inhibitors While there is a broad consensus on the fact that pericyte-covered vessels are less sensitive to AI, several recent studies have highlighted that tumor vessels typically lack pericyte coverage due to their immaturity and rapid growth phase while normal quiescent vessels are well covered — This could identify a selective therapeutic window to target abnormal tumor blood vessels, rather than suggesting to target pericyte coverage.

In keeping with that, accumulating evidence supports the idea that—in addition to pruning non-covered vessels- cancer therapies should aim at promoting the establishment of a normal vasculature in tumors in order to favor wide distribution of standard chemotherapeutics and innovative drugs into the tumor mass and improve radiotherapy efficacy.

By therapeutically improving, rather than reducing, the stability and function of tumor blood vessels, these may be exploited for delivery of therapeutics including endogenous anti-cancer immune cells. This would also improve perfusion, reduce hypoxia, and thereby reduce metastasis.

Tumor vessel normalization for cancer therapy has been achieved by the application of molecules directly targeting endothelial cells, such as semaphorins , Although ANG1 is a growth factor that provides ECs with survival signals, its introduction in CRC tumor cells displays an anti-angiogenic therapy in one study Although this approach was accompanied by a major increase in tumor microvessel pericyte coverage, it resulted in smaller tumors with less vasculature, suggesting a decreased sensitivity for angiogenesis In a more recent study, tumor-bearing mice were treated with antibodies against ANG2A, and a similar observation was noted Combining the chemotherapeutic agent, topotecan, with pazopanib significantly inhibited tumor growth, despite an increase in the number of vessels that were infiltrated by pericytes Similar results were observed in a preclinical malignant glioma model following treatment with the combination of temozolomide and sunitinib Targeting blood vessel maturation by inhibiting pericyte coverage of the tumor vasculature was suggested as a promising strategy, to break the resistance to anti-angiogenic therapies and improve their efficacy.

ECs secrete PDGF-B that mediates migration and proliferation of pericytes expressing PDGFR-b Since SDF1, and the heparin-binding EGF-like growth factor also play a major role in pericyte behavior , blocking the PDGF pathway alone might not be sufficient to prevent pericyte coverage of vasculature.

Although several studies showed that targeting pericytes and ECs leads to impaired tumor growth and improved efficacy to anti-angiogenic agents, data negating the potentiation of treatment outcome with dual blockade exists For instance, in a study by Nisancioglu et al.

As a result, anti-pericyte agents should always be combined with other therapies, including chemotherapeutic agents. For instance, in a preclinical study by Pietras et al.

Compared to monotherapies, combination therapies significantly improved anti-tumor responses. Of note, the combination of all three approaches resulted in complete responses. Also, treatment of neuroblastoma mouse xenograft models with a combination of metronomic topotecan and pazopanib resulted in a sustained anti-angiogenic effect.

but induced resistance mediated by elevated glycolysis CAFs are activated by growth factors released from tumor and inflammatory cells, including TGFb, PDGF, and FGF , , CAFs also secrete several pro-angiogenic growth factors, including EGF, HGF, and FGF. For instance, VEGF-producing CAFs maintain tumor angiogenesis in VEGF-deficient tumor cells When CAFs were isolated from a mixture of EL4 tumors resistant to anti-VEGF agents and TIB6 tumors sensitive to anti-VEGF agents, they were able to promote tumor cell proliferation and growth even when VEGF was blocked.

Angiogenesis inhibitors can be given alone or in combination with other types of treatment. Researchers are studying whether some of these drugs may treat other types of cancer.

Talk with your health care team about clinical trials for angiogenesis inhibitors. Many of the body's normal functions depend on angiogenesis. Therefore, angiogenesis inhibitors can cause a wide range of physical side effects including:. Hand-foot syndrome , which causes tender, thickened areas on your palms and soles.

Sometimes, it causes blisters. Although common, these side effects do not happen with every drug or every person. And, there are medicines can help manage these side effects when they do occur.

Be sure to let your health care team know about side effects you experience. If an angiogenesis inhibitor is recommended for you, talk with your doctor about the specific potential benefits and risks of that medication. Also, ask about ways side effects can be managed and what side effects to watch for.

Angiogenesis inhibitors for cancer can be prescribed by a doctor to take orally by mouth or intravenously by vein; IV. If you are prescribed an oral angiogenesis inhibitor to take at home, ask if you need to fill the prescription at a pharmacy that handles complex medications, such as a specialty pharmacy.

Check with the pharmacy and your insurance company about your insurance coverage and co-pay of the oral medication. Also, be sure to ask about how to safely store and handle your prescription at home.

If you are prescribed an IV treatment, that will be given at the hospital or other cancer treatment facility. Talk with your treatment center and insurance company about how your specific prescription is covered and how any co-pays will be billed.

If you need financial assistance, talk with your health care team, including the pharmacist or a social worker , about co-pay assistance options. National Cancer Institute: Angiogenesis Inhibitors. The Angiogenesis Foundation: Treatments.

MINI REVIEW article Anti-angiogenesis and cancer prevention Natural muscle preservation reason, these drugs are typically Anti-angoigenesis in combination with chemotherapy or other cacner. A pro-angiogenic Anti-angiogfnesis can create, around the tumor mass, an extensive preventoin of well-structured blood vessels that facilitate Anti-angiogenesis and cancer prevention Antl-angiogenesis and thus the effectiveness of a cancer drug. Mice lacking the vascular endothelial growth factor-B gene Vegfb have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Moreno Garcia V et al Combining antiangiogenics to overcome resistance: rationale and clinical experience. 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-angiogenesis and cancer prevention

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