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. 2024 Jan 4;2024:9077926. doi: 10.1155/2024/9077926

Role of Angiogenesis and Its Biomarkers in Development of Targeted Tumor Therapies

Anchal Pathak 1, Ajay Kumar Pal 2, Subhadeep Roy 3, Mukesh Nandave 2,, Keerti Jain 1,
PMCID: PMC10783989  PMID: 38213742

Abstract

Angiogenesis plays a significant role in the human body, from wound healing to tumor progression. “Angiogenic switch” indicates a time-restricted event where the imbalance between pro- and antiangiogenic factors results in the transition from prevascular hyperplasia to outgrowing vascularized tumor, which eventually leads to the malignant cancer progression. In the last decade, molecular players, i.e., angiogenic biomarkers and underlying molecular pathways involved in tumorigenesis, have been intensely investigated. Disrupting the initiation and halting the progression of angiogenesis by targeting these biomarkers and molecular pathways has been considered as a potential treatment approach for tumor angiogenesis. This review discusses the currently known biomarkers and available antiangiogenic therapies in cancer, i.e., monoclonal antibodies, aptamers, small molecular inhibitors, miRNAs, siRNAs, angiostatin, endostatin, and melatonin analogues, either approved by the U.S. Food and Drug Administration or currently under clinical and preclinical investigations.

1. Introduction

Angiogenesis is a biological phenomenon, where new blood capillaries in adults are developed from preexisting primary blood vessels by sprouting and branching, responding directly to tissue demands [1].Vascularization is a prerequisite for fulfilling the increased demand for oxygen, nutrient supply to the growing cancer/tumor cells, and waste removal from the cells [2]. Chronic and sustained angiogenesis, a hallmark of cancer, is vital for continued tumor mass development, and is functionally essential for multistage tumorigenesis [3]. Interactions between the stimulatory, mediator, and regulator molecules regulate the proliferative and invasive activity of endothelial cells (ECs), resulting in a new vascular framework. Tumor cells secrete molecules that initiate the angiogenic process, however, the cells cannot express angiogenesis inhibitors to halt the process. The resulting new vessels allow tumor growth beyond the diffusion-limited maximum size. Tumor cells lie close to blood vessels; therefore, the chances of tumor cell dissemination from the tumor into the blood circulation are high, making them metastatic [4]. Thus, the tumor vasculature can be exploited as a therapeutic target in the cancer treatment.

One of the major strategies to kill the cancerous cells is hindering the blood supply to these cells. Hence, the identification of effective angiogenesis biomarkers is an essential step for treating diseases associated with pathological angiogenesis. The deregulation of biomarkers could be related to the initiation and progression of diseases and could be applied for prognosis, diagnosis, and therapeutic purposes. These biomarkers are involved in several molecular pathways associated with angiogenesis in cancer. Various agents, such as specific antibodies, aptamers, small interfering ribonucleic acids (siRNAs), and therapeutic agents, have been developed to target these biomarkers [57].

This review analyses the role of angiogenesis in cancer development and discusses the currently known angiogenic therapeutic biomarkers exploited in antiangiogenic therapy. Further, the available therapeutic strategies targeting the angiogenic biomarkers has also been described. The review also focuses on the recent novel research associated with angiogenesis biomarkers, available therapeutic choices, and future perspectives.

2. Developmental and Pathological Angiogenesis

Angiogenesis is a highly coordinated process involving series of complex events including proliferation and migration of ECs, vascular tube formation and anastomosis of new tubes, protease production and inclusion of smooth muscle cells [8]. Under normal physiological circumstances, novel ECs is generated and subsequently morph into tubes leading to angiogenesis. The de novo blood vessels formation during embryogenesis takes place via the event of vasculogenesis (Figure 1), in which angioblasts–primitive mesodermal cells subset form into primary blood vessel [8, 10].

Figure 1.

Figure 1

Diagrammatic presentation of vasculogenesis and angiogenesis, where hemangioblastic aggregates are formed from undifferentiated mesoderm, which further proceeds to endothelial precursor cells (packed in blood island) and primitive erythrocytes packed in layers of ECs. Also, tip cells sprout out of the proliferating and migrating ECs to form capillary tube [9].

Besides vasculogenesis, balance is disrupted between pro- and antiangiogenic factors, where proangiogenic factors are prominent, this event is termed as “angiogenic switch,” which trigger angiogenesis and initiates tumor progression (Figure 2) [7]. Normally, angiogenesis is uncommon as ECs are nonproliferative and vasculatures are quiescent, except of ovaries and uterus where angiogenesis is required for the reproduction and embryogenesis [11]. Classification of angiogenesis includes physiological angiogenesis, observed in embryonic development, wound repair, endometrial hyperplasia during menstrual cycle, and pathological angiogenesis seen in tumors, diabetes, and chronic hepatitis [12]. Some of the examples of pathological conditions whose underlying cause is abnormal angiogenesis have been mentioned in Table 1.

Figure 2.

Figure 2

“Angiogenic switch” balance hypothesis. The angiogenic balance between angiogenic activators and inhibitors tightly regulates angiogenic switch mechanism. Upregulation of angiogenic inhibitors and angiogenic activators downregulation, spark angiogenesis leading to increased blood vessels formation. Reduction of inhibitor concentration i.e., angiostatin, restin, thrombospondin, and increasing the activator level i.e., vascular endothelial growth factor (VEGF); basic fibroblast growth factor (bFGF); placenta growth factor (PGF); interleukin-8 (IL-8) could induce the growth of novel blood vessels.

Table 1.

Diseases associated with impaired angiogenesis.

Diseases in human Organ/tissue References
Cancer, systemic sclerosis Multiorgan [13, 14]
Diabetes, atherosclerotic plaque Cardiovascular system [15, 16]
Multiple sclerosis Nervous system [17]
Inflammatory bowel diseases GIT [18]
Psoriasis Skin [19]
Endometriosis Reproductive system [20]
Obesity Adipose [21]
Asthma Respiratory system [22]

Angiogenesis, a multistep process, is triggered by several biological signals, which direct the migration and differentiation of ECs [23]. The novel blood vessels formation is initiated via production of VEGF and other angiogenic factors in ECs, which then create wall of an existing small blood capillary, release the factors, and further bind to the surface receptors of ECs. Binding of these factors over ECs activate the series of signalling pathway, which triggers the secretion of enzymes i.e., matrix metalloproteinases (MMPs), followed by the degradation of the extracellular matrix (ECM) of the surrounding tissues and liberating sequestered growth factors from ECM. Further, invasion of the matrix, division and proliferation of ECs takes place. Finally, new ECs strings assemble into hollow tubes creating new network of blood vessels [24]. Recent studies have shown that the inhibition of angiogenesis is reported to be an important strategy to prevent multiple solid tumor, whereas enabling angiogenesis was proven to be critical for the success of tissue repair therapies [1, 24]. Hence, over the last two decades, several approaches have been deployed to target the angiogenic biomarkers.

The vessels growth in adults takes places via two fundamental processes: sprouting and intussusceptive angiogenesis, which occur in all tissues under specific physiological circumstances. Sprouting angiogenesis involves the origination of new capillaries from parental vessels by midvessel lateral budding. It involves (1) basement membrane degradation on the side of the dilated peritumoral post capillary lied close to the angiogenic stimulus; (2) ECs migration in connective tissue due to weakening of interendothelial contacts; (3) solid cord formation of ECs; (4) lumen formation takes place at the migrating front and functional capillary loops are established through anastomose of tubular sprouts, facilitated by synthesis of new basement membrane and pericytes recruitment [25]. Intussusceptive angiogenesis (nonsprouting angiogenesis) occurs when transluminal tissue develops within existing vessels without endothelial proliferation, and subsequently fuse to remodel the vascular plexus. It is a complementary method to sprouting angiogenesis and occurs in the zone of contact between two opposing capillary walls. The formation and fusion of transcapillary tissue pillars are the hallmark of intussusceptive angiogenesis where, longitudinal division of single capillary takes place forming two transluminal septa. ECs junction at opposing capillary walls form leaky bilayer, which allows the penetration of growth factors into the lumen [26]. The leaky contact zone filled with myofibroblasts and pericytes in order to build collagen fibers for vessels lumen development [27].

3. Role of Angiogenesis in the Cancer Pathogenesis

Angiogenesis is generally initiated from capillaries and its regulation exhibits a significant role in tumor progression and metastasis [28]. Malignant cells need consistent access of the circulatory system, hence tumor growth is accompanied by blood vessels ingrowth, either via new blood vessels formation or through co-optation of the preexistent vasculature [29]. As mentioned earlier, pro- and antiangiogenic factors regulate vascular homeostasis [30]. Vasculatures are quiescent and ECs are nonproliferative when these factors are balanced, while dominance of proangiogenic signalling initiates “angiogenic switch,” which activates the tumor growth from dormant state, sparking new blood vessels formation and a rapid growth of malignant cells [31].

Cancer cells, like normal body tissues requires adequate oxygen and metabolites supply and nourishment via vascular capillaries network [32]. Under normal conditions, ECs lining the interior surface do not multiply, restricting the capillaries proliferation. However, hypoxic (low levels of O2) and ischemic signals trigger various transcriptional responses and mediate the ECs precursor convergence, which give rise to capillary plexus and ultimately the development of the novel blood vessels [33]. Hypoxia is one of the physiological feature around tumor microenvironment, which occurs due to high oxygen concentration demands of uncontrolled proliferated cells for their aerobic metabolic activity [34]. Since oxygen demand exceeds the ability to supply through the preexisting blood vessels, tumor cells adapt this hypoxic condition by promoting angiogenic activity i.e., development of novel blood vessels from exiting one [35]. During the onset of tumor, angiogenesis is not stimulated, and its growth remain limited with low oxygen and nutrient supply. In early phase, cell proliferation counterbalances the cell death occurred due to hypoxic condition, and therefore tumor may dwell in dormant state. Angiogenesis is a critical prerequisite for the tumor progression beyond 1–2 mm3. Beyond which, hypoxic microenvironment around the growing tumors activates angiogenic network via upregulation of hypoxia-inducible transcription factor, which triggers various specific transcriptional responses such as cell division, metabolism, and angiogenesis [36]. Furthermore, angiogenic switch is activated by the tumor in the response of augmented angiogenic factors, resulting in the irreversible evolution of an active angiogenic state. Recruitment of new capillaries supplies oxygen and nutrients actively to angiogenic as well as nonangiogenic cells, leading to rapid tumor growth [37].

Upregulation of hypoxia-inducible transcription factor activates “angiogenesis” by activating oncogene. Oncogene activation expresses cytokines proangiogenic factors and suppresses antiangiogenic factors, which lead to the upregulation and uncontrolled angiogenic networking during tumor angiogenesis [38]. Angiogenesis is a coordinated regulation of these proangiogenic and antiangiogenic factors. VEGF, most potent proangiogenic factor and originally determined as vascular permeability factor, induces formation of blood vessels in tumors. Hypoxia instigates VEGF upregulation which is secreted by tumor cells during tumor angiogenesis. VEGF activates VEGF receptor-2 (VEGFR-2) expressed over ECs, which orchestrates the growth of blood vessels and induces EC proliferation [39]. Signalling pathway initiated via VEGFR-2 activation induces various endothelial responses including cell proliferation, vascular permeability, invasion, migration which is coupled with tumor progression and metastasis along with increased vessel density [40].

VEGF induces vascular permeability, which is considered as prerequisite for angiogenesis, via several mechanisms such as fenestrae induction, junctional remodeling, and vesiculo–vascular organelles. In addition to VEGF, MMPs induce angiogenesis via ECM degradation and ECs migration. Other important proangiogenic factors and their respective cognate receptors which promotes different stages of angiogenesis in tumor are bFGF, platelet-derived growth factor (PDGF), chemokines, ephrins, angiopoietins (ANGPTs), and apelin (APLN) [41, 42]. FGF-2 (or bFGF), a proangiogenic mediator, which acts together with VEGF and promote angiogenesis via inducing MMPs secretion and activates collagenase and plasminogen enzymes [43]. PDGF-B induces VEGF upregulation on tumor-associated ECs and pericytes recruitment in newly formed vessels [44]. ANGPTs are the growth factors, mediated through VEGF-independent pathways which promote angiogenesis via regulating blood vessels' remodeling and development [45]. Studies revealed that interplay of the growth factors—VEGF, MMP, and bFGF/FGF-2 promote active angiogenesis and tumor development. Figure 3 represents the schematic diagram showing the role of angiogenic factors in tumor vascularization.

Figure 3.

Figure 3

Mechanism of angiogenesis in cancer. Hypoxia induces the expression of hypoxia inducible factor (HIF), which consequently releases proangiogenic factors, such as VEGF, and upregulates the expression of protease, which leads to basement membrane degradation and pericytes detachment. Furthermore, specialized ECs migrate along the angiogenic factor gradient and differentiate into highly proliferative stalk cells, which initiate the formation of new vessels. PGDF stimulation promotes the attachment of pericytes with reduced proliferation and VEGF sensitivity. VEGF stimulates DLL4 secretion, which binds to Notch-1 receptors, downregulates VEGFR, and suppresses proliferation. Blood supply stimulates further tumor growth.

Tumor angiogenic vessels display unique features and are well-differentiated from normal blood vessels, thus provide an appealing targeting site for angiogenic therapeutics. The key differences are as follows: (a) genetic stability of ECs of tumor vasculature, thus the chances of developing resistance are low; (b) compared to normal vessels, tumor blood vessels are morphologically leakier, fenestrated, and possess higher vascular permeability, however tumor tissue has impaired lymphatic drainage which leads to the enhanced permeability and retention (EPR) causing more accumulation of nanotherapeutics at the tumor site; (c) proteomics and genomics-based studies indicated the expression of the specific biomarkers (receptors or antigens) at the ECs of tumor vasculature, which are present at insignificant levels in normal blood vessels. These biomarkers are associated with angiogenic processes and can be the proficient targeting sites for tumor therapeutics [4650]

4. Prognostic and Therapeutic Angiogenic Biomarkers

A biomarker is a characteristic indicator of normal biological processes or pharmacological responses to a therapeutic intervention, which is measured objectively and evaluated. Biomarkers in “cancerous cells” can be detected in the patients, which may further define the prognosis and diagnosis of diseases. The predictive biomarkers can also be used to predict the therapeutic response in patient to the therapeutic agents and potential toxicity associated with the drug. Hence, “biomarkers” may further define the optimal therapeutic strategy for cancer patients, thus augmenting the therapeutic response and minimizing the therapy-related toxicity. The antiangiogenic therapy is an effective strategy for cancer treatment and identification of biomarkers for angiogenesis could be the future for development of antiangiogenic drugs. Various strategies have been explored for targeted delivery of these drugs [51, 52]. Generally, angiogenic biomarkers are involved with initiation, progression, and metastasis of cancer and targeting these biomarkers could modulate the angiogenesis in cancerous cells. Since then, various angiogenic biomarkers has been explored, where VEGF has been identified as the most potent biomarker to inhibit the tumor proliferation as it has been overexpressed in the tumor angiogenesis. Humanized monoclonal antibody bevacizumab, and the multi-tyrosine kinase inhibitors (TKIs) such as sunitinib and sorafenib have been developed to target angiogenic biomarker and proven as effective therapeutic strategy for cancer treatment [53]. Besides VEGF, other biomarkers such as FGF, PDGF, and nucleolin has also been explored to design the specific antibody to target cellular pathways related with the cancer angiogenesis.

Angiogenesis induction is considered to be one of the substantial hallmarks of cancer. The morphological distinctions between normal and angiogenic vessels have provided an insight regarding the normalization of cancer vasculature. However, antiangiogenic agents represent very complex mechanisms [54, 55]. Malignant cell genotypes manifest several physiological changes that explains the complications of cancer therapy. The tumor blood vasculatures show anomalous phenotypes i.e., immature morphological hierarchy, heterogeneous microenvironment, and highly permeable lumens, which arises due to the malfunction of ECs and their altered interaction with ECM. Also, the blood vessel compression due to the enhanced interstitial fluid in the cancer microenvironment modulates the mechanosensitivity of ECs with respect to the pressure gradient, which further generates the hypoxic and microenvironment with low pH leading to the cancer progression and production of ascites formation. The hypoxic environment further enhances the expression of angiogenic factors and proangiogenic activity of ECs. Also, these cells are highly susceptible to VEGF with significant upregulation of VEGFRs. Along with this VEGFRs, other angiogenic factors are also overexpressed, which makes the ECs more proliferative. Therefore, the identification of biomarkers could be an effective strategy for cancer treatment. Some of the major biomarkers for angiogenesis under clinical and preclinical studies are mentioned schematically in Figure 4 [56].

Figure 4.

Figure 4

Major biomarkers for angiogenesis in preclinical and clinical studies.

Targeting angiogenic biomarkers could reduce tumor mass and promote tumor regression, providing a rationale for antiangiogenic therapy for tumors. To date, several antiangiogenic treatments have been approved by the Food and Drug Administration (FDA), that target proangiogenic growth factors and their receptors (Table 2). Many pharmaceutical companies have expended massive efforts over angiogenesis therapies involving angiogenesis inhibition in oncology and ophthalmology, as well as angiogenesis stimulation in tissue engineering and wound healing.

Table 2.

FDA approved antiangiogenic agents for cancer therapeutics [41, 57, 58].

Antiangiogenic agent Brand name Company Target biomarker molecule Disease indication
Monoclonal antibodies
Ramucirumab Cyramza® Eli Lily VEGFR-2 Metastatic nonsmall cell lung carcinoma, gastric cancer, colorectal cancer
Bevacizumab Avastin® Genentech/Roche VEGFR Metastatic colorectal cancer, nonsmall cell lungs cancer, cRCC, ovarian cancer, metastatic breast cancer, glioblastoma
Cetuximab Erbitux® Bristol-myers squibb EGFR Second line treatment for colorectal cancer, squamous cell carcinoma of head and neck
Panitumumab Vectibix® Amgen EGFR Colorectal cancer
Necitumumab Portrazza Eli Lily EGFR Squamous nonsmall-cell cancer

TKI
Axitinib Inlyta® Pfizer VEGFR1–3 and PDGFR Metastatic hepatocellular cancer (HCC), thyroid cancer, renal cell carcinoma
Imatinib mesylate Gleevec® Novartis Blocks Abelson cytoplasmic tyrokinase and PDGFR activity Chronic myeloid leukaemia, gastrointestinal stromal tumors, myelodysplastic, myeloproliferative disease
Nintedanib Vargatef® Boehringer ingelheim VEGFR, PDGFR, FGFR Idiopathic pulmonary fibrosis, nonsmall cell lung cancer
Sunitinib malate Sutent® Pfizer VEGFR1–3, PDGFR Pancreatic cancer, RCC, gastrointestinal stroma tumor
Pazopanib Votrient® Novartis VEGFR1–3, PDGFR Metastatic renal cell cancer, advanced soft tissue sarcoma
Vandetanib Caprelsa® Sanofi EGFR, VEGFR2–3, PDGFR Pancreatic cancer, advanced metastatic renal cell cancer
Sorafenib Nexavar® Bayer/Onyx pharmaceuticals VEGFR1–3, PDGFRβ, RET Hepatocellular cancer, iodine resistant advanced thyroid carcinoma
Regorafenib VEGFR1–3, TIE2 Metastatic colorectal cancer, hepatocellular carcinoma, gastrointestinal stroma tumor

Receptor fusion protein
Aflibercept Zaltrap® Regeneron pharmaceuticals VEGF A and B Metastatic colorectal cancer

Aptamers
Pegaptanib sodium (NX1838) Macugen® Eyetech.IN/Pfizer VEGF-165 Macular degeneration

Tumor progression and development are dependent on the process of angiogenesis. Since, secreted cytokines were reported to play a substantial role in angiogenesis by mediating tumors neovascularization, thus indicating their potential role as biomarker candidate for disease detection and treatment response [59]. Numerous angiogenesis markers have been reported till now that have represented simultaneous expression and effective cooperation at different stages of tumor angiogenesis [56]. Some important angiogenesis biomarkers explored for cancer therapy are discussed in the following subsection. Various proangiogenic factors that serve as potential biomarkers in cancer therapy are VEGF, bFGF, IL-8, PDGF, MMPs, endoglin, tissue factor, and hypoxia tissue factor [6071] and among them, the important angiogenesis biomarkers explored for cancer therapy are discussed in the following subsection.

4.1. Vascular Endothelial Growth Factor

VEGF is a key regulator of physiological and pathological angiogenic events, and VEGF-A is the most widely known and major factor in tumor angiogenesis. VEGF/VEGFRs interaction is considered as a chief angiogenic regulator and dominant target for numerous antiangiogenic drugs [72]. The expression of VEGF is induced due to the hypoxic stimulus as a result of loss of tumor suppressor genes i.e., VHL and p53. VEGF are overexpressed in malignant tumors like breast, colorectal, lung, and prostate cancer. VEGF induces ECs proliferation via the ERK (extracellular signal-regulated kinase) and PI3K/Akt (phosphoinositide 3-kinases/protein kinases B) pathways. ECs migration downstream of VEGFR2 is induced through signalling pathway involving Rho GTPases and PI3K activation [73]. VEGF overexpression has been reported in solid tumors, therefore VEGF is considered as a potential marker for cancer [74].VEGF-A, angiogenic multifunctional mediator, binds to extracellular domain of VEGFR2 and transduce the responses of VEGF in ECs including ECs survival and proliferation, migration, permeability, and formation of capillary lumen, thus orchestrating the vasculature of cancer. Recent studies have suggested that VEGF stimulates the overexpression of myeloid cell leukaemia 1 (MCL-1) in cancers and malignancies, which is essential for cancer cell survival and development due to the balance disruption between anti- and proapoptotic proteins [75]. VEGF also interacts with angioregulatory immune cells and modulates T cells as well as myeloid cells in a VEGFR-mediated conduct. These immune cells release pro- or antiangiogenic agents via intercellular signalling and immune cells polarization to demonstrate inhibitory or modulatory characteristics, thus coordinating the cancer angiogenesis progression [76].

VEGF blockers inhibits tumor growth by preventing VEGFRs activation via neutralization of all bioactive forms of VEGF. However, patient may develop resistance to VEGF signalling pathway blockage by opting compensatory and adaptive mechanism through other mediators of angiogenesis such as PDGF or FGF [77, 78]. Therefore, blockage of VEGF signalling pathway via neutralizing antibodies to VEGF was reported to be ineffective as a monotherapy and occurrence of resistance was witnessed. VEGF activates PI3K/Akt/endothelial nitric oxide synthase signalling conduit, which stimulates ECs proliferation and vascular permeability. However, T cell-specific adaptor-c-Src signalling pathway is also involved in increasing the vascular permeability via separation of the endothelial junctions, which in turn is modulated via VEGF [79].

Various studies have proven the advantages of VEGF/VEGFR-based angiogenesis therapy. Recently, combination of VEGF-targeted angiogenic therapy and immune checkpoint inhibitors are under clinical trial, which are being conducted for melanoma, glioblastoma, and renal cancer therapy. Adaptive mechanisms that are responsible for resistance are: (a) upregulation of different proangiogenic factors; (b) alternative angiogenic signalling pathway activation; (c) vascular mimicry, a process in which cancer cells form blood vessels without involvement of ECs; (d) vascular co-option, in which tumor cells avoid angiogenesis via proliferating near existing blood vessels; (e) recruitment of endothelial progenitor cells; and (f) cell mobilization with a proangiogenic phenotype [81]. To improve the efficacy of antiangiogenic drugs, alternative angiogenic pathways need to be targeted along with the VEGF signalling pathway, or a combination of antiangiogenic therapy with chemo- or radiotherapy could be an effective solution to achieve optimal inhibition of cancer angiogenesis [82]. Several angiogenic agents such as aflibercept and ramucirumab targeting VEGF biomarker and VEGFR signalling pathway have been established till now.

Several antiangiogenic drugs based on VEGF/VEGFR signalling inhibition have been developed in the last decade. Multiple agents have been developed, including ribozymes, aptamers, soluble receptors, and small-molecule inhibitors, which aim to improve the efficacy, reduce toxicity, and optimize the clinical use of these therapies in combination with other therapeutic modalities. There is an urgent requirement for the identification of angiogenic therapeutic agents, optimal combination of therapeutic agent, doses and order of usage, and methods to monitor therapeutic results. Hence, research on the antiangiogenic agents targeting VEGF biomarkers holds immense potential for the advancement of cancer therapy.

4.2. Fibroblast Growth Factor (FGF)

FGFs belong to the family of heparin-binding growth factors, and exert their proangiogenic activity via interaction with ECs surface receptors, involving tyrosine kinase receptors, integrins, and heparan-sulphate proteoglycans [83]. FGF signalling regulates blood vascular development by activating ECs proliferation, migration, and sprouting. It modulates ECs metabolism responsible for ECM modulation [84]. FGF expression in tumors via activation of FGF signalling pathway, is utilized by tumor cells to escape VEGF-targeted therapies, inducing antiangiogenic therapeutic resistance. In preclinical studies, dual inhibitors targeting VEGF and FGF pathways simultaneously, have been proven efficacious against cancer.

FGFs are angiogenic biomarkers that are involved in the regulation of cell growth and differentiation, where FGFR-1 is expressed primarily over ECs and its overexpression is associated with cancer. The overexpression of FGF is associated with the various mutations, including gene amplification, altered gene splicing, etc., which could enhance the angiogenic process through stimulation and release of other proangiogenic factors. Studies have suggested that FGF acts in synergistic manner with VEGF to augment the tumor angiogenesis. Hence, the collaborative interaction between FGF and VEGF signalling has shown to be essential for the angiogenic processes; and targeting these pathways simultaneously could supress the angiogenesis more effectively as compared to targeting either pathway alone. In preclinical studies, dual inhibitors targeting the VEGF and FGF pathways have proven efficacious against cancer [85].

4.3. Platelet-Derived Growth Factor (PDGF)

PDGF signalling promotes the secretion of proangiogenic factor, which induces VEGF upregulation and enhances lymphatic angiogenesis along with the ECs proliferation and migration to form tube [86]. In vitro studies of human umbilical veins ECs treated with a PDGFR inhibitor and multi-tyrosine kinase inhibitors (TKI) showed reduced tube forming capacity of ECs [87]. Till now four PDGFs i.e., PDGF-A, PDGF-B, PDGF-C, and PDGF-D have been identified, where PDGF-B was reported to stimulate pericytes recruitment in newly formed blood vessels. Wang et al. examined PDGF-B and its receptor PDGFR expression in clear cell renal cell carcinoma (ccRCC) to evaluate the function of PDGF-B during angiogenesis. PDGF-B represented increased proliferation of vascular smooth muscle cells and migration capability during angiogenesis. Results suggested the proficiency of PDGF-B as promising prognostic marker [88]. Inhibition of PDGF-B signalling could commence vessel walls normalization and could be targeted along with VEGF signalling pathway for effective antiangiogenic therapy [89].

PDGFR has been regarded as a significant angiogenic factor, responsible for the expansion of metastatic tumors. It has been demonstrated as a major target for the TKI developed for cancer therapy. Recent studies suggested that interaction of PDGFR pathway with other signalling pathways (P13K/Akt, Ras-MAPK, JAK/STAT, and notch signalling pathway) could accelerate the cancer growth and reduce the sensitivity of cancerous cells. Various strategies have been explored till now to obstruct the PDGF pathway such as (i) usage of neutralizing antibodies or aptamers that may act as ligand traps; (ii) employing antibodies or small molecule inhibitors to disrupt the interaction between the ligand and receptor; or (iii) obstructing the PDGFR kinase function via low-molecular weight inhibitors [90]. Currently, Crenolanib besylate, a PDGFR inhibitor developed by AROG pharmaceuticals has shown to block the PDGFR phosphorylation and proven to be effective RTK inhibitors [91].

4.4. Angiopoietin (ANGPT)

The ANGPTs family comprises the two major ligands where ANGPT-1 promotes the maturation and stabilization of newly formed vessels via Akt/P13K pathway, while ANGPT-2 induces vessel destabilization and sprouting, detachment of pericytes and angiogenesis [92]. ANGPTs bind exclusively to Tie2 receptor tyrosine kinase [93]. ANGPT-2 expression is minimal in physiological conditions but is increased in response to VEGF and hypoxia in tumor-associated vessels [94]. ANGPT-2 upregulation in glioblastoma have been associated with increased resistance to therapy and reduced efficacy in anti-VEGF treatment [95]. Studies suggest that the inhibition of ANGPT-2 along with VEGFR-2 improved survival of glioma bearing mice by blocking macrophage recruitment, impairing tumor growth, and prolonging normalization of vessels. Therefore, ANGPT-2 and VEGFR-2 co-targeting could be effective in tumor therapy [96]. ANGPT1 is one of the ANGPTs, which regulates the integrity of ECs junction via accumulating factors such as vascular endothelial cadherin at the junction, where it permeates the proteins like VEGF and involved in the stabilization of actin cytoskeletons at the ECs junction [92].

Various ANGPT inhibitors are under clinical trials including but not limited to AMG 786 (Trebananib) and REGN 910 (Nesvacumab). Vanucizumab and RG7716 (Faricimab) served as dual inhibitor of ANGPT and VEGF have also demonstrated the enormous potential for cancer treatment. AMG 786, a peptide antibody, is one of the most effective therapeutic agent and nonspecific inhibitor of ANGPT-1 and ANGPT-2, while REGN 910, human monoclonal antibody binds specifically to ANGPT-2 and phase I clinical studies showed that it is efficacious and possess desirable safety profile [92].

4.5. Apelin (APLN)

Apelin receptor (APLNR) expression is restricted to the ECs of developing vascular system during the process of angiogenesis [97]. APLN expression stimulates microvascular proliferation inside tumors' cells and promote tumor development via enhancing angiogenesis, metastasis, and cancer stem cells development [98]. APL could indicate the diagnostic index for the degree of cancer progression, therefore it could serve as a potential biomarker for targeted therapy for cancers and pharmacological blockage via APLNR antagonists [99]. Moreover, APLN targeting could reduce tumor growth, improve blood vessels' function, reduces the invasiveness for tumor cells, and prevent resistance associated with angiogenic therapy [100, 101]. In the recent study, APLN was reported as an activator of the autophagy and showed to promote cell migration in lung carcinoma [102]. In a different study, targeting APLNR with an antagonist exhibited reduced tumor growth in mice [103]. Therefore, targeting APLN/APLNR signalling pathway could be a promising strategy to treat cancer.

The overexpression of APLN biomarker is coupled with the increased microvessel densities and cancer progression in various cancer including nonsmall cell lung cancer and hepatocellular cancer. APLN regulates the microvasculature proliferation and APLN antagonists (F13A and bevacizumab) showed the cancer progression inhibition via reducing this vascular density. Research suggested that APLN pathway has positive outcome on the cancer angiogenesis and disruption of this pathway could be effective for the antiangiogenic therapy in the therapeutic intervention of cancer [104].

4.6. Chemokines

Chemokines, members of the heparin-binding protein family, have emerged as important angiogenesis regulators and promote tumor angiogenesis either via binding through chemokine receptors expressed on ECs or through inflammatory cell recruitment. Chemokines regulate immune responses along with angiogenesis, conferring their dominant role in tissue microenvironment modulation; therefore, chemokines may serve as a potential biomarkers for targeting tumor angiogenesis [105]. Chemokine subfamily classifications based on the amount of cysteine residue deposition at the N-terminal domain of the molecules are CXC, CC, C, and CX3C. The CXC family is further classified based on the presence or absence of the ELR (glu–leu–arg) motif at their N-terminus and is thus indicated as ELR+ and ELR- chemokines, respectively [106]. ELR+ includes CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8, which binds to the receptor CXCR2, that are overexpressed in microvascular ECs and tumor vessels, and enhances angiogenesis [107]. CXCL8 has been reported to induce release of VEGF and MMP-2, which are involved in metastasis-related tissue remodeling, along with the progression and cancer metastasis. Elevated CXCL8 serum level is associated with the severe tumor load and distant metastasis [108]. CL2 interacts with C–C chemokine receptor type 2, expressed in tumor endothelial progenitor cells and enhances endothelial permeability and metastasis. Thus, based on encouraging preclinical studies, cytokines could be explored as effective biomarkers for the establishment of antiangiogenic therapy.

5. Antiangiogenesis-Based Therapy for Cancer Treatment

Antiangiogenic agents block the supply of oxygen and nutrients to cancerous cells. In 1971, Folkman hypothesized regarding the effectiveness of antiangiogenic agents for cancer therapy that these antiangiogenic agents could prevent the formation of new blood vessels and disrupt the existing one by neutralizing the angiogenic protein, inducing EC apoptosis, or inhibiting the endothelial receptors for angiogenic proteins [81]. These inhibitors are capable of targeting angiogenic growth factor receptors, Tei receptor, VEGFR, and PDGFR, or inhibit angiogenic growth factors, PGF and its receptor, VEGF, and bFGF [109]. Therefore, clinical strategies to develop molecules that target angiogenesis molecular pathways have been extensively researched for the treatment of cancers. As mentioned earlier, VEGF could be a potential biomarker, and various clinically available antiangiogenic agents act by targeting the VEGF/VEGFRs pathway, such as monoclonal antibodies (Bevacizumab), small-molecule TKI (Sorafenib), and VEGFR2 inhibitors (Ramucirumab), out of which monoclonal antibodies are being used widely, which act by binding to circulating VEGF (Figure 5). Aptamers, single-stranded DNA or RNA (15–100 nucleotide) ligands that bind specifically to a target molecule with higher affinity and minimal or no immunogenicity, have also been studied for antiangiogenic therapy [110]. Pegaptanib sodium was the first USFDA approved RNA aptamer, developed using systematic evolution of ligands by exponential enrichment methodology directed against a VEGF isoform, is a potent angiogenesis inhibitor [111].

Figure 5.

Figure 5

Antiangiogenic drugs and their targets such as VEGF, PDGF, EGF, and ANGPT2 along with biological substrates and respective inhibitors available in the market.

Gene therapy is also being utilized in antiangiogenesis therapy, which involves the introduction of genetic materials to target cells to reprogram their activity. Gene therapy showed more effective penetration into tumors and less immunogenicity [112]. Antiangiogenic gene therapy aimed at prohibiting the formation of novel vessels and inactivating the preexisting blood vessels [113]. Recently, scientists developed the human soluble FMS-like tyrosine kinase receptor 1 (sFlt-1) encoding recombinant adeno-associated virus-2 (rAAV) vector for sustained antiangiogenic effect, without vector-associated immunity or toxicity [114]. The list of FDA approved angiogenesis inhibitors is mentioned in Table 2.

5.1. Monoclonal Antibodies (mAbs)

Monoclonal antibody-based therapy is an extensively explored strategy for targeting angiogenic biomarkers. Bevacizumab was the first FDA-approved humanized monoclonal antibody for the treatment of metastatic colorectal cancer in combination with chemotherapy that targets VEGF-A, which has been identified as a key factor for inducing tumor angiogenesis [115]. It is derived from murine VEGF, comprised of 93% human and 7% murine protein sequence and results of clinical trial demonstrated progression-free survival when combined with cytotoxic chemotherapies [116]. Currently, it is widely being used for tumor therapy; however monotherapy with bevacizumab may be insufficient for angiogenesis therapy as frequent resistance have been reported therefore generally prescribed in combination with the other chemotherapeutic agents [117, 118].

Ramucirumab, a USFDA approved human mAb has high selectivity for VEGFR-2, act via blocking the interaction between VEGF and its receptor [119]. Cetuximab, first USFDA approved monoclonal antibody that binds to extracellular domain of EGFR with higher affinity than the natural ligand, blocking the tyrosine kinase-dependent signal transduction pathway. Cetuximab exerts antitumor effect due to decreased production of MMPs and VEGF [120]. Aflibercept, another antiangiogenic-agent, is a fusion protein composed of a constant Fc human IgG domain in combination with the second Ig domain of VEGFR-1 and the third Ig domain of VEGFR-2. Aflibercept targets the VEGF pathway in combination with chemotherapy regimens in triple-negative breast cancer [121]. Antibody conjugated delivery systems have been explored by the researchers, which could serve as an efficient tool for cancerous cells' targeting where certain antigens are overexpressed and may attack the blood vessels feeding tumor [122].

5.2. MicroRNAs/Small Interfering RNAs

MicroRNAs and siRNAs have been found to be efficient modulators of genes that express angiogenic factors in an angiogenesis animal model [123]. miR-126 has been reported to have dual functions in pathological angiogenesis, where miR-126-5p overexpression promotes angiogenesis and miR-126-3p silencing inhibits it [124]. In addition, the expression level of oncogenic proteins was reported to be reduced by miR143/145, which binds to the mRNAs of VEGF, KRAS, and EGFR, representing a growth inhibitory effect [125]. The roles of miRNAs in angiogenesis in different tumor therapies are presented in Table 3.

Table 3.

Role of microRNAs against angiogenesis in different tumor therapy.

S. no. microRNA Gene targets References
Breast cancer

1. miR-126 PI3K regulatory subunit 2; VEGF antisense; cluster of differentiation 97; insulin-like growth factor binding protein 2 [126129]

2. miR-21
miR-497
HIF-1 α; VEGFR2 [130132]

3. miR-155 von Hippel-Lindau [133]
miR-199b-5p Activin receptor-like kinase-1-downregulation; attenuated ALK1/Smad/Id1 pathway [134]

4. miR-57
miR-573
VEGF antisense, focal adhesion kinase, ANGPT2, HIF-1 α [135]
miR-204 ANGPT1, transforming growth factor beta receptor 2, phosphoinositide 3-kinases, Src [136, 137]

5. miR-542-3p ANGPT2; CCAAT/enhancer-binding protein β; POU class 2 homeobox 1 [138140]

7. miR-4306 SIX1/Cdc42/VEGF antisense- downregulation; suppressed cell proliferation, migration and invasion and abrogates angiogenesis [141]

Pancreatic cancer

8. miR-21
miR-199
HIF-1α; VEGF [142, 143]

9. miR-34a Sirtuin 1 (SIRT1) [144]

Lung cancer

11. miR-181d-5p Cyclin dependent kinase inhibitor 3-downregulation; suppressed proliferation, and epithelial-mesenchymal transition, and increased cell apoptosis [145]

12. miR-126
let-7b
VEGFA [146]

13. miR-128 Serum VEGFC [147]

14. miR-195 VEGF- downregulation; suppressed the viability and migration and angiogenesis [148]

15. miR-494 Phosphatase and tensin homolog (PTEN) [149]

16. miR-210 VEGFR type 2 [150]

17. miR-29c PVT1-upregulation-promote VEGF pathway [151]

Colorectal cancer

18. miR-126 VEGF, VEGFR2 [152, 153]

19. miR-21 PTEN; tissue inhibitor of metalloproteinases-1 and 3 (TIMP1 and TIMP3) [154]

20. miR-30 Delta-like 4 (DLL4) [155]

21. miR-18a
miR-19
Early growth response 1 [156]

22 miR-194 Tumor suppressor p53 [157, 158]

23. miR-15-16 FGF2, and cyclin B1 (CCNB1) [159, 160]

24. miR-29b FGF2, transcription factor 7-like 2 (TCF7L2), drosophila embryonic protein SNAI1 (SNAIL),
B-cell CLL lymphoma 9-like protein (BCL9L), MMP2, and T-cell lymphoma invasion and metastasis (TIAM1)
[161163]

25. miR-27a
miR-27b
DLL4, SPRY2, VEGFC, SGPP1, SMAD2 [164167]

26. miR-192 β-Cell lymphoma-2, ZEB2, VEGFA [168]

27. miR-145 AKT, N-RAS, IRS1, VEGF, p70S6K1 [169, 170]

28. miR-143 AKT, HIF-1α, VEGF [171]

29. miR-23b 7FZD7, MAP3K1 [172]

30. miR-1249 VEGF A/HMGA2-downregulation; suppressed colorectal cancer cell proliferation, migration, invasion, and angiogenesis, regulate Akt/mTOR pathway and EMT [173]

Ovarian cancer

31. miR-199a
miR-125b
miR-145
HIF-1α, VEGF, p70S6K [174]

32. miR-484
miR-642
miR-217
miR-27a
VEGF, VEGFR2, COX2, SP1 [175, 176]

33. miR-200 family ZEB1, ZEB2, IL8, CXCL1 [177179]

34. miR-204 Inhibits brain-derived neurotrophic factor (BDNF) [180]

35. miR-765 miR-765 downregulates VEGFA/Akt1/SRC-α axis in SKOV3 (ovarian cancer cells) [181]

Gastric cancer

36. miR-20 Downregulate VEGF and inhibits angiogenesis [182]
37. miR-29b [183]
38. miR-93 [184]
39. miR-126 [185]
40. miR-190 [186]
41. miR-195 [187]
42. miR-200 [188]
43. miR-203 [189]
44. miR-497 [190]
45. miR-503 [191]
46. miR-638 [192]

47. miR-22 Targets VEGF inducers and regulates VEGF dependent angiogenesis [193]
48. miR-107 [194]
49. miR-519c [195]
50. miR-145 [196]

51. miR-616-3p miR-616-3p upregulates VEGF-A/VEGFR2 and induce tumor angiogenesis [197]

52. miR-126 Directly inhibits VEGF-a expression and thereby inhibit angiogenesis both in vitro and in vivo [198200]

53. miR-29a/c Suppresses VEGF expression in GC cells, inhibiting cell growth, migration and angiogenesis [201]

54. miR-27b
miR-101
miR-128
Downregulate VEGFC and thereby inhibit angiogenesis [202]

55. miR-590 Targets VEGF1/2 and NRP1 expression; inhibit migration, invasion and angiogenesis of GC both in vivo and in vitro [203]

56. miR-574-5p Activates mitogen-activated protein kinases (MAPKs) through suppressing target gene, PTPN3 expression and promotes angiogenesis via enhancing VEGF-A expression [204]

57. miR-210 Highly expressed miRNA in hypoxic conditions and mediates metabolism, angiogenesis, and apoptosis [205]

58. miR-718
miR-382
Targets PTEN and thereby inhibits angiogenesis of gastric cancer [206]

59. miR-135b Suppress FOXO1 protein and enhance angiogenesis in gastric cancer [207]

Glioma

60. miR-26a Overexpression inhibit PTEN and regulate angiogenesis [208]

61. miR-103a-3p
miR-382-5p
miR-103a-3p and miR-382-5p overexpression activates PI3K/Akt signalling pathway and leads to upregulation of MOV10, circ-DICER1, ZIC4, and Hsp90β proteins which promotes cell viability, migration, and tube formation of glioma-exposed ECs [209]

Hepatocellular carcinoma

62. miR-885-5p Overexpression of miR-885-5p silences astrocyte elevated gene 1 (AEG1); inhibit EMT and angiogenesis [210]

Head and neck cancer

63. miR-30e-5p Overexpression of miR-30e-5p silences AEG1 suppresses migration o HUVECs and downregulation of VEGF and HGF, which leads to angiogenesis and metastasis [211]

Gall bladder cancer

64. miR-136 Overexpression of miR-136 downregulates MAP2K4 ad inhibits angiogenesis and proliferation [210]

Renal cell carcinoma

65. miR-21 miR-21 expression targets programed cell death protein 4 (PDCD4)/c-Jun signalling pathway and promotes the migration, invasion and angiogenesis in renal cell cancer cells [212]

KRAS mutations are responsible for the proliferation signalling of RAS/ ERK pathway and indicate poor response to EGFR inhibitors. Double-stranded RNA precursors are processed by a Dicer protein into short fragments, where one strand of the processed duplex is loaded into an argonaute protein (Ago), enabling RNA recognition and its expression modulation via several mechanism [210]. The pathway for siRNA silencing for a particular of gene is diagrammatically represented in Figure 6. Li et al. [211] developed multifunctional nanoparticles to improve VEGF gene silencing efficacy and improve tumor cell antiproliferation effects. The nanoparticles were coated with PEGylated histidine-grafted chitosan-lipoic acid and loaded with siVEGF and etoposide. The nanosystem utilizing siRNA have shown significant suppression of tumor growth and metastasis than monotherapy [211, 213, 214].

Figure 6.

Figure 6

siRNA silencing pathway. Once inside the cytoplasm, siRNA is either directly incorporated into RNA-induced silencing complex (RISC) or undergoes a process mediated by Dicer. Upon RISC loading, the passenger strand dissociates, initiating the RNA interference process by cleaving and degrading the target mRNA.

5.3. Small Molecular Inhibitors

Another strategy for targeting VEGF signalling involves TKI that targets VEGFR, such as Sunitinib, Pazopanib, and Axitinib (Table 2). TKIs target kinases, are being utilized more preferably as secondary and tertiary therapies and are reportedly more effective in combination with chemotherapy [215]. Axitinib was the first TKI compound with established antitumor activity that reduced vascular permeability, tumor volume, and tumor vascularization [212].

These angiogenesis inhibitors downregulate angiogenic activators that promote unregulated neovascularization in tumors. For example, affinitors (everolimus) and torisel (temsirolimus) downregulate angiogenesis by inhibiting the intracellular metabolic pathway of mTOR. Sorafenib is an FDA-approved TKI for hepatocellular carcinoma, metastatic thyroid carcinoma, and advanced RCC [216218]. Withaferin A inhibits protein kinase C, which further inhibits apoptosis induction by caspase-3 activation and exhibits antiangiogenic activity [219]. Regorafenib is a multikinase inhibitor that restricts the kinases involved in tumor angiogenesis and oncogenesis (KIT, RET, RAF1, and BRAF), enhancing the survival of cancer patients [220].

5.4. Angiostatin and Endostatin

Endostatin blocks the binding of VEGF to ECs and inhibits the growth and migration of ECs followed by the suppression of capillary formation. Retinostat®, a Lentiviral Equine infectious anaemia virus vector-based therapy, was investigated for safety and tolerability in a Phase I clinical trial. The recombinant EIAV-based vector contains cDNAs expressing endostatin and angiostatin for long-term antiangiogenic activity in patients with macular degeneration [116, 117]. Angiostatin blocks matrix-enhanced plasminogen activation and inhibits cancer metastasis and invasion; however, angiostatin has a short t1/2, representing the requirement of a specialized delivery system. Zhang et al. [221], hypothesized that the combination of bevacizumab and angiostatin via attacking two different angiogenic pathways could lead to an additive antiangiogenic effect. The combination was tested in thymic mice bearing intracranial human glioma (U87), where the injection of G47δ-mAngio (an oncolytic virus expressing angiotensin) allowed bevacizumab-induced inhibition of invasion markers (MMP2 and MMP9) and angiostatin-mediated inhibition of VEGF expression. The results showed the enhanced antiangiogenic activity of a combination system utilizing viral oncolytic therapy [221].

Despite the development of several antiangiogenic agents, enormous challenges persist with respect to their efficacy, toxicity, drug resistance, and selection of patients who will benefit from antiangiogenic therapy. VEGF-targeted therapies are relatively safe, and several clinical trials have revealed several side effects that can be managed through proper care [222]. Despite the development of several antiangiogenic agents, enormous challenges persist with respect to their efficacy, toxicity, drug resistance, and selection of patients who will benefit from antiangiogenic therapy. VEGF-targeted therapies are relatively safe, and several clinical trials have revealed the side effects, which can be managed through proper care [223].

5.5. Melatonin and Its Analogues

The pharmacological potential of melatonin is found in various biological processes, including circadian rhythm synchronization, immune response stimulation, antioxidant activity, antiestrogen activity, and oncostatic activity. In addition, melatonin exhibits antiangiogenic activity in various cancers through multiple mechanisms, inhibiting cancer growth and metastasis [224]. Melatonin favors angiogenesis in some physiological events, skin lesions, and gastric ulcers while suppressing neovascularization in tissues in hypoxic environments (tumors) and age-associated eye disorders [225]. It also inhibits HIF-1-induced angiogenesis and thereby exerts antitumor action [226].

Melatonin-treated gastric tumor-bearing mice showed significantly reduced expression of both mRNA and protein levels of HIF-1α, RZR-RORγ, and VEGF compared to untreated mice. These changes are attributed to melatonin's antiangiogenic potential in human gastric cancer cells [227]. It exhibits antiangiogenic activity by downregulating VEGFR-2 in ER-negative breast cancers [228]. Furthermore, no significant HIF-1α expression was observed in melatonin-treated tumors than in the vehicle control group. In contrast, melatonin significantly downregulated HIF1-α and VEGF expression in the liver and mouse tumor models [229]. In prostate cancer, melatonin promotes HIF-1α accumulation by suppressing ROS production and the sphingosine kinase-1 pathway, exhibiting antitumor action [230]. Melatonin treatment also resulted in a parallel reduction of VEGF, VEGFR-2, and HIF-1α expression with tumor size and blood capillary density in ovarian tumor-carrying rats [231]. It also impairs vasculogenesis in oral cancer by inhibiting ROS-activated Akt and ERK signalling through the HIF-1α pathway and represses the expression of ROCK-1, HIF-1α, and VEGF genes in oral cancer [232, 233].

Thus, the different mechanisms through which melatonin exhibits antiangiogenic activity are: (a) inhibition of HIF-1α translocation into the nucleus and downregulates the mRNA and proteins such as VEGF, phosphor-STAT3, and the CBP/p300 complex (referred to as angiogenesis-related gene expression); (b) inhibition of VEGF-induced VEGFR2 phosphorylation, thus suppressing the expression and transactivation of VEGFR2; and (c) inhibition of the migration and invasion of ECs in tumor tissues; (d) melatonin receptor (especially MT1) mediated downregulation of VEGF in some cancers [234]; however, receptor involvement in the downregulation of VEGF was independent in tumor tissues and melatonin possesses antiangiogenic effects in tumor tissues, making melatonin, and its analogues a potentially promising drug to inhibit tumor growth and metastasis [235237].

Hence, melatonin and its analogues have gained the attention of new researchers to evaluate their potential as an anticancer drug either as an adjuvant or as a novel formulation in combination with standard anticancer drugs. The synthetic analogues of melatonin, agomelatine and ramelteon can be explored for their anticancer potential against various cancers through their mechanism of inhibiting angiogenesis and the epithelial mesenchymal transition pathway [238].

6. Challenges and Future Direction of Antiangiogenic Therapy

One of the major challenges associated with the antiangiogenic therapy is the heterogeneous nature of cancer. Since angiogenesis is a natural physiological phenomenon that should be maintained for the proper balance for haemostasis, therefore the identification of specific biomarkers is required to avoid damage to healthy organ. Currently, the identification of prognostic biomarkers is the promising strategy for the development of antiangiogenesis therapy. However, modulating the process of angiogenesis via recognized biomarker requires profound insight regarding the molecular mechanisms through which angiogenesis is mediated. Also, resistance mechanisms of antiangiogenic agents can be revealed via the bioprofile information, which can further disclose the additional mechanisms for angiogenesis that can be targeted for cancer therapy. Currently, out of all the available antiangiogenic agents, none has met the expectations regarding the survival of cancer patients. The identification of angiogenic biomarkers and its application in cancer therapy, has been the main objective and vision yet to achieve. Various inhibitors of angiogenic markers including monoclonal antibodies have performed well in specific, but not all, cancers. Hence, extensive research is going on to endorse the better understanding of compensatory pathway within tumor cells and develop the agents with therapeutic potential to inhibit the angiogenesis in cancer.

7. Conclusion

The crucial role of angiogenesis in pathological alterations, especially in cancer progression, proliferation, and metastasis, and how it keeps a regulatory eye on other remaining hallmarks of cancer are extensively detailed in this manuscript. The functioning of prognostic and angiogenic biomarkers like VEGF, FGF, PDGF, ANGPTs, APLN, and chemokines interplay in mediating the progression of angiogenesis are detailed. The antiangiogenic therapy, including monoclonal antibodies, siRNAs, miRNAs, small molecule inhibitors, angiostatin, endostatin, and melatonin analogues, functions in inhibiting angiogenesis through altering angiogenic biomarkers' expression are also described here. However, numerous challenges are on the way for miRNAs and siRNAs to endorse them at the clinical level due to the avoidance of acceptance by human society for treatment and management of disease using foreign genetic materials. Also, the single miRNAs and siRNAs have been incapable of defeating the intensified stages and multiple pathways supporting angiogenesis in various cancer stages. The multicomponent formulations could be possible for sequential blocking of angiogenesis, and transforming the same at the clinical level seems impossible with numerous challenges. Moreover, designing a novel melatonin receptor subtype 1 could be an antiangiogenic candidate for targeting cancer. The anti-HIF-1α phytochemicals can also be explored for inhibiting angiogenesis innervating the tumor tissues. The more network-based studies and artificial intelligence processing are needed to explore these possible agents to target angiogenic pathways for the cancer treatment.

Acknowledgments

The authors, Dr. Keerti Jain and Ms. Anchal, acknowledge the Department of Pharmaceuticals (DoP), Ministry of Chemicals and Fertilizers, Government of India, for providing the facilities to write this manuscript. The authors, Dr. Keerti Jain, Dr. Mukesh Nandave, and Ms. Anchal Pathak, acknowledge the Indian Council of Medical Research (ICMR), New Delhi for financial support in the form of the ICMR Extramural Research Project (Project ID: 2020-4686; Ref. No. 5/13/34/2020/NCD-III). The NIPER-Raebareli communication number of this manuscript is NIPER-R/Communication/517.

Abbreviations

ANGPTs:

Angiopoietins

APLN:

Apelin

APLNR:

Apelin receptor

bFGF:

Basic fibroblast growth factor

ECs:

Endothelial cells

ECM:

Extracellular matrix

ERK:

Extracellular signal-regulated kinase

FGF-2:

Fibroblast growth factor 2

HIF:

Hypoxia inducible factor

IL-8:

Interleukin-8

MMPs:

Matrix metalloproteinases

PDGF:

Platelet-derived growth factor

PDGFR:

Platelet-derived growth factor receptor

PI3K/Akt:

Phosphoinositide 3-kinases/protein kinase B

PTEN:

Phosphatase and tensin homolog

RCC:

Renal cell carcinoma

RISCs:

RNA-induced silencing complex

TKI:

Tyrosine kinase inhibitors

VEGF:

Vascular endothelial growth factor

VEGFA:

VEGF antisense

VEGFR:

Vascular endothelial growth factor receptor.

Contributor Information

Mukesh Nandave, Email: mukeshnandave@gmail.com.

Keerti Jain, Email: keertijain02@gmail.com.

Data Availability

The authors confirm that all the data supporting the findings of this study are presented within the article. If any further information is required, then it may be provided upon reasonable request.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors' Contributions

AP and AKP performed the major writing work and designed the graphical illustration mechanism. KJ, SR, and MN conceived the idea, performed final proofreading, and approved the final manuscript. All authors have contributed to the manuscript and approved the submitted version.

References

  • 1.Lee J.-H., Parthiban P., Jin G.-Z., Knowles J. C., Kim H.-W. Materials roles for promoting angiogenesis in tissue regeneration. Progress in Materials Science . 2021;117 doi: 10.1016/j.pmatsci.2020.100732.100732 [DOI] [Google Scholar]
  • 2.Taylor A. M., Bordoni B. Histology, Blood Vascular System . StatPearls Publishing; 2020. [PubMed] [Google Scholar]
  • 3.Chwalek K., Bray L. J., Werner C. Tissue-engineered 3D tumor angiogenesis models: potential technologies for anti-cancer drug discovery. Advanced Drug Delivery Reviews . 2014;79-80:30–39. doi: 10.1016/j.addr.2014.05.006. [DOI] [PubMed] [Google Scholar]
  • 4.Brannon-Peppas L., Blanchette J. O. Nanoparticle and targeted systems for cancer therapy. Advanced Drug Delivery Reviews . 2012;64:206–212. doi: 10.1016/j.addr.2012.09.033. [DOI] [PubMed] [Google Scholar]
  • 5.Mashreghi M., Azarpara H., Bazaz M. R., et al. Angiogenesis biomarkers and their targeting ligands as potential targets for tumor angiogenesis. Journal of Cellular Physiology . 2018;233(4):2949–2965. doi: 10.1002/jcp.26049. [DOI] [PubMed] [Google Scholar]
  • 6.Ahmad J., Rizwanullah M., Suthar T., et al. Receptor-targeted surface-engineered nanomaterials for breast cancer imaging and theranostic applications. Critical Reviews™ in Therapeutic Drug Carrier Systems . 2022;39(6):1–44. doi: 10.1615/CritRevTherDrugCarrierSyst.2022040686. [DOI] [PubMed] [Google Scholar]
  • 7.Suthar T., Jain V. K., Popli H., Jain K. Nanocarriers for Drug-Targeting Brain Tumors . Elsevier; 2022. Nanoemulsions as effective carriers for targeting brain tumors; pp. 347–363. [DOI] [Google Scholar]
  • 8.Saravanan S., Vimalraj S., Pavani K., Nikarika R., Sumantran V. N. Intussusceptive angiogenesis as a key therapeutic target for cancer therapy. Life Sciences . 2020;252 doi: 10.1016/j.lfs.2020.117670.117670 [DOI] [PubMed] [Google Scholar]
  • 9.DeSesso J. M. Vascular ontogeny within selected thoracoabdominal organs and the limbs. Reproductive Toxicology . 2017;70:3–20. doi: 10.1016/j.reprotox.2016.10.007. [DOI] [PubMed] [Google Scholar]
  • 10.Naito H., Iba T., Takakura N. Mechanisms of new blood-vessel formation and proliferative heterogeneity of endothelial cells. International Immunology . 2020;32(5):295–305. doi: 10.1093/intimm/dxaa008. [DOI] [PubMed] [Google Scholar]
  • 11.Falkenberg K. D., Rohlenova K., Luo Y., Carmeliet P. The metabolic engine of endothelial cells. Nature Metabolism . 2019;1(10):937–946. doi: 10.1038/s42255-019-0117-9. [DOI] [PubMed] [Google Scholar]
  • 12.Tan S., Zang G., Wang Y., et al. Differences of angiogenesis factors in tumor and diabetes mellitus. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy . 2021;14:3375–3388. doi: 10.2147/DMSO.S315362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Ribatti D., Annese T., Tamma R. Controversial role of mast cells in breast cancer tumor progression and angiogenesis. Clinical Breast Cancer . 2021;21(6):486–491. doi: 10.1016/j.clbc.2021.08.010. [DOI] [PubMed] [Google Scholar]
  • 14.Henrot P., Moisan F., Laurent P., et al. Decreased CCN3 in systemic sclerosis endothelial cells contributes to impaired angiogenesis. Journal of Investigative Dermatology . 2020;140(7):1427–1434.e5. doi: 10.1016/j.jid.2019.11.026. [DOI] [PubMed] [Google Scholar]
  • 15.Cheng Z., Kishore R. Potential role of hydrogen sulfide in diabetes-impaired angiogenesis and ischemic tissue repair. Redox Biology . 2020;37 doi: 10.1016/j.redox.2020.101704.101704 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Camaré C., Pucelle M., Nègre-Salvayre A., Salvayre R. Angiogenesis in the atherosclerotic plaque. Redox Biology . 2017;12:18–34. doi: 10.1016/j.redox.2017.01.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Van den Broek B., Wuyts C., Irobi J. Extracellular vesicle-associated small heat shock proteins as therapeutic agents in neurodegenerative diseases and beyond. Advanced Drug Delivery Reviews . 2021;179 doi: 10.1016/j.addr.2021.114009.114009 [DOI] [PubMed] [Google Scholar]
  • 18.Alkim C., Alkim H., Koksal A. R., Boga S., Sen I. Angiogenesis in inflammatory bowel disease. International Journal of Inflammation . 2015;2015:10. doi: 10.1155/2015/970890.970890 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Niu X., Han Q., Liu Y., et al. Psoriasis-associated angiogenesis is mediated by EDIL3. Microvascular Research . 2020;132 doi: 10.1016/j.mvr.2020.104056.104056 [DOI] [PubMed] [Google Scholar]
  • 20.Khazaei M. R., Rashidi Z., Chobsaz F., Niromand E., Khazaei M. Inhibitory effect of resveratrol on the growth and angiogenesis of human endometrial tissue in an in vitro three-dimensional model of endometriosis. Reproductive Biology . 2020;20(4):484–490. doi: 10.1016/j.repbio.2020.07.012. [DOI] [PubMed] [Google Scholar]
  • 21.Nijhawans P., Behl T., Bhardwaj S. Angiogenesis in obesity. Biomedicine & Pharmacotherapy . 2020;126 doi: 10.1016/j.biopha.2020.110103.110103 [DOI] [PubMed] [Google Scholar]
  • 22.Meyer N., Christoph J., Makrinioti H., et al. Inhibition of angiogenesis by IL-32: possible role in asthma. Journal of Allergy and Clinical Immunology . 2012;129(4):964–973.e7. doi: 10.1016/j.jaci.2011.12.1002. [DOI] [PubMed] [Google Scholar]
  • 23.Baru O., Nutu A., Braicu C., et al. Angiogenesis in regenerative dentistry: are we far enough for therapy? International Journal of Molecular Sciences . 2021;22(2) doi: 10.3390/ijms22020929.929 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Al-Ostoot F. H., Salah S., Khamees H. A., Khanum S. A. Tumor angiogenesis: current challenges and therapeutic opportunities. Cancer Treatment and Research Communications . 2021;28 doi: 10.1016/j.ctarc.2021.100422.100422 [DOI] [PubMed] [Google Scholar]
  • 25.Ribatti D., Crivellato E. “Sprouting angiogenesis”, a reappraisal. Developmental Biology . 2012;372(2):157–165. doi: 10.1016/j.ydbio.2012.09.018. [DOI] [PubMed] [Google Scholar]
  • 26.Karthik S., Djukic T., Kim J.-D., et al. Synergistic interaction of sprouting and intussusceptive angiogenesis during zebrafish caudal vein plexus development. Scientific Reports . 2018;8(1) doi: 10.1038/s41598-018-27791-6.9840 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Fallah A., Sadeghinia A., Kahroba H., et al. Therapeutic targeting of angiogenesis molecular pathways in angiogenesis-dependent diseases. Biomedicine & Pharmacotherapy . 2019;110:775–785. doi: 10.1016/j.biopha.2018.12.022. [DOI] [PubMed] [Google Scholar]
  • 28.Bielenberg D. R., Zetter B. R. The contribution of angiogenesis to the process of metastasis. The Cancer Journal . 2015;21(4):267–273. doi: 10.1097/PPO.0000000000000138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Pezzella F., Ribatti D. Vascular co-option and vasculogenic mimicry mediate resistance to antiangiogenic strategies. Cancer Reports . 2022;5(12) doi: 10.1002/cnr2.1318.e1318 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Cheng L., Liu W., Zhong C., et al. Remodeling the homeostasis of pro- and anti-angiogenic factors by Shenmai injection to normalize tumor vasculature for enhanced cancer chemotherapy. Journal of Ethnopharmacology . 2021;270 doi: 10.1016/j.jep.2020.113770.113770 [DOI] [PubMed] [Google Scholar]
  • 31.Yadav L., Puri N., Rastogi V., Satpute P., Sharma V. Tumour angiogenesis and angiogenic inhibitors: a review. Journal of Clinical and Diagnostic Research . 2015;9(6):XE01–XE05. doi: 10.7860/JCDR/2015/12016.6135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Rimini M., Casadei-Gardini A. Angiogenesis in biliary tract cancer: targeting and therapeutic potential. Expert Opinion on Investigational Drugs . 2021;30(4):411–418. doi: 10.1080/13543784.2021.1881479. [DOI] [PubMed] [Google Scholar]
  • 33.Eelen G., de Zeeuw P., Treps L., Harjes U., Wong B. W., Carmeliet P. Endothelial cell metabolism. Physiological Reviews . 2018;98(1):3–58. doi: 10.1152/physrev.00001.2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Bader S. B., Dewhirst M. W., Hammond E. M. Cyclic hypoxia: an update on its characteristics, methods to measure it and biological implications in cancer. Cancers . 2021;13(1) doi: 10.3390/cancers13010023.23 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Seo B. R., DelNero P., Fischbach C. In vitro models of tumor vessels and matrix: engineering approaches to investigate transport limitations and drug delivery in cancer. Advanced Drug Delivery Reviews . 2014;69-70:205–216. doi: 10.1016/j.addr.2013.11.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Madu C. O., Wang S., Madu C. O., Lu Y. Angiogenesis in breast cancer progression, diagnosis, and treatment. Journal of Cancer . 2020;11(15):4474–4494. doi: 10.7150/jca.44313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Klein D. The tumor vascular endothelium as decision maker in cancer therapy. Frontiers in Oncology . 2018;8 doi: 10.3389/fonc.2018.00367.367 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Xia Y., Lu R.-N., Li J. Angiogenic factors in chronic lymphocytic leukemia. Leukemia Research . 2012;36(10):1211–1217. doi: 10.1016/j.leukres.2012.05.021. [DOI] [PubMed] [Google Scholar]
  • 39.Novotný J., Zikán M. Tumor angiogenesis. Klinická Farmakologie a Farmacie . 2010;24(3):124–126. [Google Scholar]
  • 40.Lamalice L., Le Boeuf F., Huot J. Endothelial cell migration during angiogenesis. Circulation Research . 2007;100(6):782–794. doi: 10.1161/01.RES.0000259593.07661.1e. [DOI] [PubMed] [Google Scholar]
  • 41.Lugano R., Ramachandran M., Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cellular and Molecular Life Sciences . 2020;77(9):1745–1770. doi: 10.1007/s00018-019-03351-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Apte R. S., Chen D. S., Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell . 2019;176(6):1248–1264. doi: 10.1016/j.cell.2019.01.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Turner N., Grose R. Fibroblast growth factor signalling: from development to cancer. Nature Reviews Cancer . 2010;10(2):116–129. doi: 10.1038/nrc2780. [DOI] [PubMed] [Google Scholar]
  • 44.Guo P., Hu B., Gu W., et al. Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. The American Journal of Pathology . 2003;162(4):1083–1093. doi: 10.1016/S0002-9440(10)63905-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Oliner J., Min H., Leal J., et al. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell . 2004;6(5):507–516. doi: 10.1016/j.ccr.2004.09.030. [DOI] [PubMed] [Google Scholar]
  • 46.Seyyednia E., Oroojalian F., Baradaran B., Mojarrad J. S., Mokhtarzadeh A., Valizadeh H. Nanoparticles modified with vasculature-homing peptides for targeted cancer therapy and angiogenesis imaging. Journal of Controlled Release . 2021;338:367–393. doi: 10.1016/j.jconrel.2021.08.044. [DOI] [PubMed] [Google Scholar]
  • 47.Jain K., Mehra N. K., Jain N. K. Potentials and emerging trends in nanopharmacology. Current Opinion in Pharmacology . 2014;15:97–106. doi: 10.1016/j.coph.2014.01.006. [DOI] [PubMed] [Google Scholar]
  • 48.Jain A., Jain K., Kesharwani P., Jain N. K. Low density lipoproteins mediated nanoplatforms for cancer targeting. Journal of Nanoparticle Research . 2013;15(9) doi: 10.1007/s11051-013-1888-7.1888 [DOI] [Google Scholar]
  • 49.Sharma P., Jain K., Jain N. K., Mehra N. K. Ex vivo and in vivo performance of anti-cancer drug loaded carbon nanotubes. Journal of Drug Delivery Science and Technology . 2017;41:134–143. doi: 10.1016/j.jddst.2017.07.011. [DOI] [Google Scholar]
  • 50.Jain K., Ahmad J. Nanotheranostics for Treatment and Diagnosis of Infectious Diseases . Elsevier; 2022. [DOI] [Google Scholar]
  • 51.Bajwa N., Mehra N. K., Jain K., Jain N. K. Targeted anticancer drug delivery through anthracycline antibiotic bearing functionalized quantum dots. Artificial Cells, Nanomedicine, and Biotechnology . 2016;44(7):1774–1782. doi: 10.3109/21691401.2015.1102740. [DOI] [PubMed] [Google Scholar]
  • 52.Jain K. Biopolymer-Based Composites . Elsevier; 2017. Dendrimers: smart nanoengineered polymers for bioinspired applications in drug delivery; pp. 169–220. [DOI] [Google Scholar]
  • 53.Young R. J., Reed M. W. R. Anti-angiogenic therapy: concept to clinic. Microcirculation . 2012;19(2):115–125. doi: 10.1111/j.1549-8719.2011.00147.x. [DOI] [PubMed] [Google Scholar]
  • 54.De Gruttola V. G., Clax P., DeMets D. L., et al. Considerations in the evaluation of surrogate endpoints in clinical trials: summary of a national institutes of health workshop. Controlled Clinical Trials . 2001;22(5):485–502. doi: 10.1016/S0197-2456(01)00153-2. [DOI] [PubMed] [Google Scholar]
  • 55.Gauro R., Nandave M., Jain V. K., Jain K. Advances in dendrimer-mediated targeted drug delivery to the brain. Journal of Nanoparticle Research . 2021;23(3) doi: 10.1007/s11051-021-05175-8. [DOI] [Google Scholar]
  • 56.Sessa C., Guibal A., Del Conte G., Rüegg C. Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations? Nature Clinical Practice Oncology . 2008;5(7):378–391. doi: 10.1038/ncponc1150. [DOI] [PubMed] [Google Scholar]
  • 57.Binley K., Widdowson P. S., Kelleher M., et al. Safety and biodistribution of an equine infectious anemia virus-based gene therapy, RetinoStat®, for age-related macular degeneration. Human Gene Therapy . 2012;23(9):980–991. doi: 10.1089/hum.2012.008. [DOI] [PubMed] [Google Scholar]
  • 58.Ellis S. The LentiVector® gene therapy platform for ocular disease: a clinical update. Acta Ophthalmologica . 2013;91(s252) doi: 10.1111/j.1755-3768.2013.4232.x. [DOI] [Google Scholar]
  • 59.Merritt W. M., Sood A. K. Markers of angiogenesis in ovarian cancer. Disease Markers . 2007;23:13. doi: 10.1155/2007/257602.257602 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Melincovici C. S., Boşca A. B., Şuşman S., et al. Vascular endothelial growth factor (VEGF)—key factor in normal and pathological angiogenesis. Romanian Journal of Morphology & Embryology . 2018;59(2):455–467. [PubMed] [Google Scholar]
  • 61.Bashiri J., Gaeini A. A., Hadi H. Endurance training affects muscular angiogenesis and serum VEGF concentration in diabetic rats. Koomesh . 2015;17:123–132. [Google Scholar]
  • 62.Ruf W., Yokota N., Schaffner F. Tissue factor in cancer progression and angiogenesis. Thrombosis Research . 2010;125:S36–S38. doi: 10.1016/S0049-3848(10)70010-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Masumoto S., Ono A., Ito A., Kawabe Y., Kamihira M. Hypoxia-responsive expression of vascular endothelial growth factor for induction of angiogenesis in artificial three-dimensional tissues. Journal of Bioscience and Bioengineering . 2021;132(4):399–407. doi: 10.1016/j.jbiosc.2021.06.010. [DOI] [PubMed] [Google Scholar]
  • 64.Yılmaz Şaştım Ç., Gürsoy M., Könönen E., et al. Salivary and serum markers of angiogenesis in periodontitis in relation to smoking. Clinical Oral Investigations . 2021;25(3):1117–1126. doi: 10.1007/s00784-020-03411-4. [DOI] [PubMed] [Google Scholar]
  • 65.Lehrer S., Diamond E. J., Mamkine B., Stone N. N., Stock R. G. Serum interleukin-8 is elevated in men with prostate cancer and bone metastases. Technology in Cancer Research & Treatment . 2004;3(5) doi: 10.1177/153303460400300501.411 [DOI] [PubMed] [Google Scholar]
  • 66.Fousek K., Horn L. A., Palena C. Interleukin-8: a chemokine at the intersection of cancer plasticity, angiogenesis, and immune suppression. Pharmacology & Therapeutics . 2021;219 doi: 10.1016/j.pharmthera.2020.107692.107692 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Lu J.-F., Hu Z.-Q., Yang M.-X., et al. Downregulation of PDGF-D inhibits proliferation and invasion in breast cancer MDA-MB-231 cells. Clinical Breast Cancer . 2022;22(2):e173–e183. doi: 10.1016/j.clbc.2021.06.002. [DOI] [PubMed] [Google Scholar]
  • 68.Bicer A., Guclu B., Ozkan A., et al. Expressions of angiogenesis associated matrix metalloproteinases and extracellular matrix proteins in cerebral vascular malformations. Journal of Clinical Neuroscience . 2010;17(2):232–236. doi: 10.1016/j.jocn.2009.06.008. [DOI] [PubMed] [Google Scholar]
  • 69.Kudo Y., Iizuka S., Yoshida M., et al. Matrix metalloproteinase-13 (MMP-13) directly and indirectly promotes tumor angiogenesis. Journal of Biological Chemistry . 2012;287(46):38716–38728. doi: 10.1074/jbc.M112.373159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Santhekadur P. K., Gredler R., Chen D., et al. Late SV40 factor (LSF) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP-9) Journal of Biological Chemistry . 2012;287(5):3425–3432. doi: 10.1074/jbc.M111.298976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Chen C.-Y., Lin Y.-J., Wang C. C. N., Lan Y.-H., Lan S.-J., Sheu M.-J. Epigallocatechin-3-gallate inhibits tumor angiogenesis: involvement of endoglin/Smad1 signaling in human umbilical vein endothelium cells. Biomedicine & Pharmacotherapy . 2019;120 doi: 10.1016/j.biopha.2019.109491.109491 [DOI] [PubMed] [Google Scholar]
  • 72.Zhang C., Wang N., Tan H.-Y., Guo W., Li S., Feng Y. Targeting VEGF/VEGFRs pathway in the antiangiogenic treatment of human cancers by traditional chinese medicine. Integrative Cancer Therapies . 2018;17(3):582–601. doi: 10.1177/1534735418775828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Guerra A., Belinha J., Jorge R. N. A preliminary study of endothelial cell migration during angiogenesis using a meshless method approach. International Journal for Numerical Methods in Biomedical Engineering . 2020;36(11) doi: 10.1002/cnm.3393.e3393 [DOI] [PubMed] [Google Scholar]
  • 74.Tsai M. M., Wang C. S., Tsai C. Y., Chi H. C., Tseng Y. H., Lin K. H. Potential prognostic, diagnostic and therapeutic markers for human gastric cancer. World Journal of Gastroenterology . 2014;20(38):13791–13803. doi: 10.3748/wjg.v20.i38.13791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Ghalehbandi S., Yuzugulen J., Pranjol M. Z. I., Pourgholami M. H. The role of VEGF in cancer-induced angiogenesis and research progress of drugs targeting VEGF. European Journal of Pharmacology . 2023;949 doi: 10.1016/j.ejphar.2023.175586.175586 [DOI] [PubMed] [Google Scholar]
  • 76.Zhang Y., Brekken R. A. Direct and indirect regulation of the tumor immune microenvironment by VEGF. Journal of Leukocyte Biology . 2022;111(6):1269–1286. doi: 10.1002/JLB.5RU0222-082R. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Kopetz S., Hoff P. M., Morris J. S., et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. Journal of Clinical Oncology . 2010;28(3):453–459. doi: 10.1200/JCO.2009.24.8252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Lieu C. H., Tran H. T., Jiang Z., et al. The association of alternate VEGF ligands with resistance to anti-VEGF therapy in metastatic colorectal cancer. Journal of Clinical Oncology . 2011;29(15_suppl):3533–3533. doi: 10.1200/jco.2011.29.15_suppl.3533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Li X., Padhan N., Sjöström E. O., et al. VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread. Nature Communications . 2016;7 doi: 10.1038/ncomms11017.11017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Lieu C. H., Tran H., Jiang Z. Q., et al. The association of alternate VEGF ligands with resistance to anti-VEGF therapy in metastatic colorectal cancer. PLOS ONE . 2013;8(10) doi: 10.1371/journal.pone.0077117.e77117 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Lopes-Coelho F., Martins F., Pereira S. A., Serpa J. Anti-angiogenic therapy: current challenges and future perspectives. International Journal of Molecular Sciences . 2021;22(7) doi: 10.3390/ijms22073765.3765 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Liu G., Chen T., Ding Z., Wang Y., Wei Y., Wei X. Inhibition of FGF-FGFR and VEGF-VEGFR signalling in cancer treatment. Cell Proliferation . 2021;54(4) doi: 10.1111/cpr.13009.e13009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Presta M., Dell’Era P., Mitola S., Moroni E., Ronca R., Rusnati M. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine & Growth Factor Reviews . 2005;16(2):159–178. doi: 10.1016/j.cytogfr.2005.01.004. [DOI] [PubMed] [Google Scholar]
  • 84.Yu P., Wilhelm K., Dubrac A., Tung J. K., Alves T. C., Fang J. S. FGF-dependent metabolic control of vascular development. Journal of Vascular Surgery . 2017;66(3) doi: 10.1016/j.jvs.2017.07.055.959 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Zhao Y., Adjei A. A. Targeting angiogenesis in cancer therapy: moving beyond vascular endothelial growth factor. The Oncologist . 2015;20(6):660–673. doi: 10.1634/theoncologist.2014-0465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Heil F., Babitzki G., Julien-Laferriere A., et al. Vanucizumab mode of action: serial biomarkers in plasma, tumor, and skin-wound-healing biopsies. Translational Oncology . 2021;14(2) doi: 10.1016/j.tranon.2020.100984.100984 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Massaro F., Molica M., Breccia M. Ponatinib: a review of efficacy and safety. Current Cancer Drug Targets . 2018;18(9):847–856. doi: 10.2174/1568009617666171002142659. [DOI] [PubMed] [Google Scholar]
  • 88.Wang W., Qi L., Tan M., et al. Effect of platelet-derived growth factor-B on renal cell carcinoma growth and progression. Urologic Oncology: Seminars and Original Investigations . 2015;33(4):168.e17–168.e27. doi: 10.1016/j.urolonc.2014.12.015. [DOI] [PubMed] [Google Scholar]
  • 89.Falcon B. L., Pietras K., Chou J., et al. Increased vascular delivery and efficacy of chemotherapy after inhibition of platelet-derived growth factor-B. The American Journal of Pathology . 2011;178(6):2920–2930. doi: 10.1016/j.ajpath.2011.02.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Pandey P., Khan F., Upadhyay T. K., Seungjoon M., Park M. N., Kim B. New insights about the PDGF/PDGFR signaling pathway as a promising target to develop cancer therapeutic strategies. Biomedicine & Pharmacotherapy . 2023;161 doi: 10.1016/j.biopha.2023.114491.114491 [DOI] [PubMed] [Google Scholar]
  • 91.Kampa-Schittenhelm K. M., Frey J., Haeusser L. A., et al. Crenolanib is a type I tyrosine kinase inhibitor that inhibits mutant KIT D816 isoforms prevalent in systemic mastocytosis and core binding factor leukemia. Oncotarget . 2017;8(47):82897–82909. doi: 10.18632/oncotarget.19970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Eklund L., Saharinen P. Angiopoietin signaling in the vasculature. Experimental Cell Research . 2013;319(9):1271–1280. doi: 10.1016/j.yexcr.2013.03.011. [DOI] [PubMed] [Google Scholar]
  • 93.Jones N., Iljin K., Dumont D. J., Alitalo K. Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nature Reviews Molecular Cell Biology . 2001;2(4):257–267. doi: 10.1038/35067005. [DOI] [PubMed] [Google Scholar]
  • 94.Reiss Y., Knedla A., Tal A. O., et al. Switching of vascular phenotypes within a murine breast cancer model induced by angiopoietin-2. The Journal of Pathology . 2009;217(4):571–580. doi: 10.1002/path.2484. [DOI] [PubMed] [Google Scholar]
  • 95.Chae S. S., Kamoun W. S., Farrar C. T., et al. Angiopoietin-2 interferes with anti-VEGFR2-induced vessel normalization and survival benefit in mice bearing gliomas. Clinical Cancer Research . 2010;16(14):3618–3627. doi: 10.1158/1078-0432.CCR-09-3073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Kloepper J., Riedemann L., Amoozgar Z., et al. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proceedings of the National Academy of Sciences . 2016;113(16):4476–4481. doi: 10.1073/pnas.1525360113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Cox C. M., D’Agostino S. L., Miller M. K., Heimark R. L., Krieg P. A. Apelin, the ligand for the endothelial G-protein-coupled receptor, APJ, is a potent angiogenic factor required for normal vascular development of the frog embryo. Developmental Biology . 2006;296(1):177–189. doi: 10.1016/j.ydbio.2006.04.452. [DOI] [PubMed] [Google Scholar]
  • 98.Kälin R. E., Kretz M. P., Meyer A. M., Kispert A., Heppner F. L., Brändli A. W. Paracrine and autocrine mechanisms of apelin signaling govern embryonic and tumor angiogenesis. Developmental Biology . 2007;305(2):599–614. doi: 10.1016/j.ydbio.2007.03.004. [DOI] [PubMed] [Google Scholar]
  • 99.Yang Y., Lv S.-Y., Ye W., Zhang L. Apelin/APJ system and cancer. Clinica Chimica Acta . 2016;457:112–116. doi: 10.1016/j.cca.2016.04.001. [DOI] [PubMed] [Google Scholar]
  • 100.Uribesalgo I., Hoffmann D., Zhang Y., et al. Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy. EMBO Molecular Medicine . 2019;11(8) doi: 10.15252/emmm.201809266.e9266 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101.Feng M., Yao G., Yu H., Qing Y., Wang K. Tumor apelin, not serum apelin, is associated with the clinical features and prognosis of gastric cancer. BMC Cancer . 2016;16 doi: 10.1186/s12885-016-2815-y.794 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Lv D., Luo X., Chen Z., et al. Apelin/APJ signaling activates autophagy to promote human lung adenocarcinoma cell migration. Life Sciences . 2021;281 doi: 10.1016/j.lfs.2021.119763.119763 [DOI] [PubMed] [Google Scholar]
  • 103.Harford-Wright E., Andre-Gregoire G., Jacobs K. A., et al. Pharmacological targeting of apelin impairs glioblastoma growth. Brain . 2017;140(11):2939–2954. doi: 10.1093/brain/awx253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104.Wu L., Chen L., Li L. Apelin/APJ system: a novel promising therapy target for pathological angiogenesis. Clinica Chimica Acta . 2017;466:78–84. doi: 10.1016/j.cca.2016.12.023. [DOI] [PubMed] [Google Scholar]
  • 105.Dimberg A. The Chemokine System in Experimental and Clinical Hematology . Vol. 341. Berlin, Heidelberg: Springer; 2010. Chemokines in angiogenesis; pp. 59–80. (Current Topics in Microbiology and Immunology). [DOI] [PubMed] [Google Scholar]
  • 106.Bosisio D., Salvi V., Gagliostro V., Sozzani S. Angiogenesis, Lymphangiogenesis and Clinical Implications . Vol. 95. Karger Publishers; 2013. Angiogenic and antiangiogenic chemokines; pp. 89–104. (Chemical Immunology and Allergy). [DOI] [PubMed] [Google Scholar]
  • 107.Strieter R. M., Belperio J. A., Phillips R. J., Keane M. P. CXC chemokines in angiogenesis of cancer. Seminars in Cancer Biology . 2004;14(3):195–200. doi: 10.1016/j.semcancer.2003.10.006. [DOI] [PubMed] [Google Scholar]
  • 108.Liu Q., Li A., Tian Y., et al. The CXCL8-CXCR1/2 pathways in cancer. Cytokine & Growth Factor Reviews . 2016;31:61–71. doi: 10.1016/j.cytogfr.2016.08.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109.Wu H. C., Huang C. T., Chang D. K. Anti-angiogenic therapeutic drugs for treatment of human cancer. Journal of Cancer Molecule . 2008;4:37–45. [Google Scholar]
  • 110.Alizadeh N., Memar M. Y., Moaddab S. R., Kafil H. S. Aptamer-assisted novel technologies for detecting bacterial pathogens, Biomed. Biomedicine & Pharmacotherapy . 2017;93:737–745. doi: 10.1016/j.biopha.2017.07.011. [DOI] [PubMed] [Google Scholar]
  • 111.Lee J.-H., Canny M. D., De Erkenez A., et al. A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF165. Proceedings of the National Academy of Sciences . 2005;102(52):18902–18907. doi: 10.1073/pnas.0509069102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112.Sanz L., Blanco B., Álvarez-Vallina L. Antibodies and gene therapy: teaching old ‘magic bullets’ new tricks. Trends in Immunology . 2004;25(2):85–91. doi: 10.1016/j.it.2003.12.001. [DOI] [PubMed] [Google Scholar]
  • 113.Guijarro-Munoz I., Compte M., Alvarez-Vallina L., Sanz L. Antibody gene therapy: getting closer to clinical application? Current Gene Therapy . 2013;13(4):282–290. doi: 10.2174/15665232113139990025. [DOI] [PubMed] [Google Scholar]
  • 114.Mahendra G., Kumar S., Isayeva T., et al. Antiangiogenic cancer gene therapy by adeno-associated virus 2-mediated stable expression of the soluble FMS-like tyrosine kinase-1 receptor. Cancer Gene Therapy . 2005;12(1):26–34. doi: 10.1038/sj.cgt.7700754. [DOI] [PubMed] [Google Scholar]
  • 115.Garcia J., Hurwitz H. I., Sandler A. B., et al. Bevacizumab (Avastin®) in cancer treatment: a review of 15 years of clinical experience and future outlook. Cancer Treatment Reviews . 2020;86 doi: 10.1016/j.ctrv.2020.102017.102017 [DOI] [PubMed] [Google Scholar]
  • 116.Mulder K., Scarfe A., Chua N., Spratlin J. The role of bevacizumab in colorectal cancer: understanding its benefits and limitations. Expert Opinion on Biological Therapy . 2011;11(3):405–413. doi: 10.1517/14712598.2011.557657. [DOI] [PubMed] [Google Scholar]
  • 117.Wang L., Xu G.-L., Gao K., et al. Development of a robust reporter-based assay for the bioactivity determination of anti-VEGF therapeutic antibodies. Journal of Pharmaceutical and Biomedical Analysis . 2016;125:212–218. doi: 10.1016/j.jpba.2016.03.042. [DOI] [PubMed] [Google Scholar]
  • 118.Chellappan D. K., Leng K. H., Jia L. J., et al. The role of bevacizumab on tumour angiogenesis and in the management of gynaecological cancers: a review. Biomedicine & Pharmacotherapy . 2018;102:1127–1144. doi: 10.1016/j.biopha.2018.03.061. [DOI] [PubMed] [Google Scholar]
  • 119.Oguntade A. S., Al-Amodi F., Alrumayh A., Alobaida M., Bwalya M. Anti-angiogenesis in cancer therapeutics: the magic bullet. Journal of the Egyptian National Cancer Institute . 2021;33 doi: 10.1186/s43046-021-00072-6.15 [DOI] [PubMed] [Google Scholar]
  • 120.Muraro E., Fanetti G., Lupato V., et al. Cetuximab in locally advanced head and neck squamous cell carcinoma: biological mechanisms involved in efficacy, toxicity and resistance. Critical Reviews in Oncology/Hematology . 2021;164 doi: 10.1016/j.critrevonc.2021.103424.103424 [DOI] [PubMed] [Google Scholar]
  • 121.Wu F. T. H., Paez-Ribes M., Xu P., et al. Aflibercept and Ang1 supplementation improve neoadjuvant or adjuvant chemotherapy in a preclinical model of resectable breast cancer. Scientific Reports . 2016;6 doi: 10.1038/srep36694.36694 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 122.Jain K., Kesharwani P., Gupta U., Jain N. K. Dendrimer toxicity: let’s meet the challenge. International Journal of Pharmaceutics . 2010;394(1-2):122–142. doi: 10.1016/j.ijpharm.2010.04.027. [DOI] [PubMed] [Google Scholar]
  • 123.Rupaimoole R., Slack F. J. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nature Reviews Drug Discovery . 2017;16:203–222. doi: 10.1038/nrd.2016.246. [DOI] [PubMed] [Google Scholar]
  • 124.Nammian P., Razban V., Tabei S. M. B., Asadi-Yousefabad S.-L. MicroRNA-126: dual role in angiogenesis dependent diseases. Current Pharmaceutical Design . 2020;26(38):4883–4893. doi: 10.2174/1381612826666200504120737. [DOI] [PubMed] [Google Scholar]
  • 125.van Beijnum J. R., Giovannetti E., Poel D., Nowak-Sliwinska P., Griffioen A. W. miRNAs: micro-managers of anticancer combination therapies. Angiogenesis . 2017;20(2):269–285. doi: 10.1007/s10456-017-9545-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 126.Zhao D., Tu Y., Wan L., et al. In vivo monitoring of angiogenesis inhibition via down-regulation of Mir-21 in a VEGFR2-Luc murine breast cancer model using bioluminescent imaging. PLOS ONE . 2013;8(8) doi: 10.1371/journal.pone.0071472.e71472 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 127.Png K. J., Halberg N., Yoshida M., Tavazoie S. F. A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature . 2012;481(7380):190–194. doi: 10.1038/nature10661. [DOI] [PubMed] [Google Scholar]
  • 128.Wu Z., Cai X., Huang C., Xu J., and A. Liu. miR-497 suppresses angiogenesis in breast carcinoma by targeting HIF-1α. Oncology Reports . 2016;35(3):1696–1702. doi: 10.3892/or.2015.4529. [DOI] [PubMed] [Google Scholar]
  • 129.Tu Y., Liu L., Zhao D., et al. Overexpression of miRNA-497 inhibits tumor angiogenesis by targeting VEGFR2. Scientific Reports . 2015;5 doi: 10.1038/srep13827.13827 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 130.Kong W., He L., Coppola M., et al. MicroRNA-155 regulates cell survival, growth, and chemosensitivity by targeting FOXO3a in breast cancer. Journal of Biological Chemistry . 2010;285(23):17869–17879. doi: 10.1074/jbc.M110.101055. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 131.Lin X., Qiu W., Xiao Y., et al. MiR-199b-5p suppresses tumor angiogenesis mediated by vascular endothelial cells in breast cancer by targeting ALK1. Frontiers in Genetics . 2020;10 doi: 10.3389/fgene.2019.01397.1397 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 132.Kong W., He L., Richards E. J., et al. Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer. Oncogene . 2014;33(6):679–689. doi: 10.1038/onc.2012.636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 133.Flores-Pérez A., Marchat L. A., Rodríguez-Cuevas S., et al. Dual targeting of ANGPT1 and TGFBR2 genes by miR-204 controls angiogenesis in breast cancer. Scientific Reports . 2016;6(1) doi: 10.1038/srep34504.34504 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 134.Kirschmann D. A., Seftor E. A., Hardy K. M., Seftor R. E. B., Hendrix M. J. C. Molecular pathways: vasculogenic mimicry in tumor cells: diagnostic and therapeutic implications. Clinical Cancer Research . 2012;18(10):2726–2732. doi: 10.1158/1078-0432.CCR-11-3237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 135.Mathsyaraja H., Thies K., Taffany D. A., et al. CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth. Oncogene . 2015;34(28):3651–3661. doi: 10.1038/onc.2014.294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 136.Tarighi R., Farajzadeh K., Hematkhah H. Prolong network lifetime and improve efficiency in WSN–UAV systems using new clustering parameters and CSMA modification. International Journal of Communication Systems . 2020;33(7) doi: 10.1002/dac.4324.e4324 [DOI] [Google Scholar]
  • 137.He T., Qi F., Jia L., et al. Tumor cell-secreted angiogenin induces angiogenic activity of endothelial cells by suppressing miR-542-3p. Cancer Letters . 2015;368(1):115–125. doi: 10.1016/j.canlet.2015.07.036. [DOI] [PubMed] [Google Scholar]
  • 138.Zhao Z., Li L., Du P., et al. Transcriptional downregulation of miR-4306 serves as a new therapeutic target for triple negative breast cancer. Theranostics . 2019;9(5):1401–1416. doi: 10.7150/thno.30701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 139.Kadera B. E., Li L., Toste P. A., et al. MicroRNA-21 in pancreatic ductal adenocarcinoma tumor-associated fibroblasts promotes metastasis. PLOS ONE . 2013;8(8) doi: 10.1371/journal.pone.0071978.e71978 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 140.Chan Y. C., Roy S., Huang Y., Khanna S., Sen C. K. The microRNA miR-199a-5p down-regulation switches on wound angiogenesis by derepressing the v-ets erythroblastosis virus E26 oncogene homolog 1-matrix metalloproteinase-1 pathway. Journal of Biological Chemistry . 2012;287(49):41032–41043. doi: 10.1074/jbc.M112.413294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 141.Zhao T., Li J., Chen A. F. MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1. American Journal of Physiology-Endocrinology and Metabolism . 2010;299(1):E110–E116. doi: 10.1152/ajpendo.00192.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 142.Hsu Y.-L., Hung J.-Y., Chang W.-A., et al. Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene . 2017;36(34):4929–4942. doi: 10.1038/onc.2017.105. [DOI] [PubMed] [Google Scholar]
  • 143.Gao L.-M., Zheng Y., Wang P., et al. Tumor-suppressive effects of microRNA-181d-5p on non-small-cell lung cancer through the CDKN3-mediated Akt signaling pathway in vivo and in vitro. American Journal of Physiology-Lung Cellular and Molecular Physiology . 2019;316(5):L918–L933. doi: 10.1152/ajplung.00334.2018. [DOI] [PubMed] [Google Scholar]
  • 144.Liu B., Peng X.-C., Zheng X.-L., Wang J., Qin Y.-W. MiR-126 restoration down-regulate VEGF and inhibit the growth of lung cancer cell lines in vitro and in vivo. Lung Cancer . 2009;66(2):169–175. doi: 10.1016/j.lungcan.2009.01.010. [DOI] [PubMed] [Google Scholar]
  • 145.Tejero R., Navarro A., Campayo M., et al. miR-141 and miR-200c as markers of overall survival in early stage non-small cell lung cancer adenocarcinoma. PLOS ONE . 2014;9(7) doi: 10.1371/journal.pone.0101899.e101899 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 146.Liu H., Chen Y., Li Y., et al. miR-195 suppresses metastasis and angiogenesis of squamous cell lung cancer by inhibiting the expression of VEGF. Molecular Medicine Reports . 2019;20:2625–2632. doi: 10.3892/mmr.2019.10496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 147.Mao G., Liu Y., Fang X., et al. Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer. Angiogenesis . 2015;18(3):373–382. doi: 10.1007/s10456-015-9474-5. [DOI] [PubMed] [Google Scholar]
  • 148.Pesta M., Kulda V., Radek K., et al. Prognostic significance of TIMP-1 in non-small cell lung cancer. Anticancer Research . 2011;31:4031–4038. [PubMed] [Google Scholar]
  • 149.Mao Z., Xu B., He L., Zhang G. PVT1 promotes angiogenesis by regulating miR-29c/vascular endothelial growth factor (VEGF) signaling pathway in non-small-cell lung cancer (NSCLC) Medical Science Monitor . 2019;25:5418–5425. doi: 10.12659/MSM.917601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 150.Zhang Y., Wang X., Xu B., et al. Epigenetic silencing of miR-126 contributes to tumor invasion and angiogenesis in colorectal cancer. Oncology Reports . 2013;30(4):1976–1984. doi: 10.3892/or.2013.2633. [DOI] [PubMed] [Google Scholar]
  • 151.Hansen T. F., Andersen C. L., Nielsen B. S., et al. Elevated microRNA-126 is associated with high vascular endothelial growth factor receptor 2 expression levels and high microvessel density in colorectal cancer. Oncology Letters . 2011;2(6):1101–1106. doi: 10.3892/ol.2011.372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 152.Nagao Y., Hisaoka M., Matsuyama A., et al. Association of microRNA-21 expression with its targets, PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma. Modern Pathology . 2012;25(1):112–121. doi: 10.1038/modpathol.2011.142. [DOI] [PubMed] [Google Scholar]
  • 153.Hansen T. F., Christensen R. D. P., Andersen R. F., Sørensen F. B., Johnsson A., Jakobsen A. MicroRNA-126 and epidermal growth factor-like domain 7–an angiogenic couple of importance in metastatic colorectal cancer. Results from the Nordic ACT trial. British Journal of Cancer . 2013;109(5):1243–1251. doi: 10.1038/bjc.2013.448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 154.Bridge G., Monteiro R., Henderson S., et al. The microRNA-30 family targets DLL4 to modulate endothelial cell behavior during angiogenesis. Blood . 2012;120(25):5063–5072. doi: 10.1182/blood-2012-04-423004. [DOI] [PubMed] [Google Scholar]
  • 155.Amodeo V., Bazan V., Fanale D., et al. Effects of anti-miR-182 on TSP-1 expression in human colon cancer cells: there is a sense in antisense? Expert Opinion on Therapeutic Targets . 2013;17(11):1249–1261. doi: 10.1517/14728222.2013.832206. [DOI] [PubMed] [Google Scholar]
  • 156.Sundaram P., Hultine S., Smith L. M., et al. p53-responsive miR-194 inhibits thrombospondin-1 and promotes angiogenesis in colon cancers. Cancer Research . 2011;71(24):7490–7501. doi: 10.1158/0008-5472.CAN-11-1124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 157.Braun C. J., Zhang X., Savelyeva I., et al. p53-responsive MicroRNAs 192 and 215 are capable of inducing cell cycle arrest. Cancer Research . 2008;68(24):10094–10104. doi: 10.1158/0008-5472.CAN-08-1569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 158.Dai L., Wang W., Zhang S., et al. Vector-based miR-15a/16-1 plasmid inhibits colon cancer growth in vivo. Cell Biology International . 2012;36(8):765–770. doi: 10.1042/cbi20110404. [DOI] [PubMed] [Google Scholar]
  • 159.Fang Y., Liang X., Jiang W., et al. Cyclin B1 suppresses colorectal cancer invasion and metastasis by regulating E-cadherin. PLOS ONE . 2015;10(5) doi: 10.1371/journal.pone.0126875.e0126875 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 160.Wang B., Li W., Liu H., et al. miR-29b suppresses tumor growth and metastasis in colorectal cancer via downregulating Tiam1 expression and inhibiting epithelial–mesenchymal transition. Cell Death & Disease . 2014;5(7):e1335–e1335. doi: 10.1038/cddis.2014.304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 161.Subramanian M., Rao S. R., Thacker P., Chatterjee S., Karunagaran D. MiR-29b downregulates canonical Wnt signaling by targeting BCL9L and other coactivators of β-catenin in human colorectal cancer cells. Journal of Cellular Biochemistry . 2014;115:1974–1984. doi: 10.1002/jcb.24869. [DOI] [PubMed] [Google Scholar]
  • 162.Colangelo T., Fucci A., Votino C., et al. MicroRNA-130b promotes tumor development and is associated with poor prognosis in colorectal cancer. Neoplasia . 2013;15(9):1086–1099. doi: 10.1593/neo.13998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 163.Urbich C., Kaluza D., Frömel T., et al. MicroRNA-27a/b controls endothelial cell repulsion and angiogenesis by targeting semaphorin 6A. Blood . 2012;119(6):1607–1616. doi: 10.1182/blood-2011-08-373886. [DOI] [PubMed] [Google Scholar]
  • 164.Veliceasa D., Biyashev D., Qin G., et al. Therapeutic manipulation of angiogenesis with miR-27b. Vascular Cell . 2015;7(1):1–16. doi: 10.1186/s13221-015-0031-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 165.Bao Y., Chen Z., Guo Y., et al. Tumor suppressor MicroRNA-27a in colorectal carcinogenesis and progression by targeting SGPP1 and Smad2. PLOS ONE . 2014;9(8) doi: 10.1371/journal.pone.0105991.e105991 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 166.Geng L., Chaudhuri A., Talmon G., et al. MicroRNA-192 suppresses liver metastasis of colon cancer. Oncogene . 2014;33(46):5332–5340. doi: 10.1038/onc.2013.478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 167.Yin Y., Yan Z.-P., Lu N.-N., et al. Downregulation of miR-145 associated with cancer progression and VEGF transcriptional activation by targeting N-RAS and IRS1. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms . 2013;1829(2):239–247. doi: 10.1016/j.bbagrm.2012.11.006. [DOI] [PubMed] [Google Scholar]
  • 168.Xu Q., Liu L.-Z., Qian X., et al. MiR-145 directly targets p70S6K1 in cancer cells to inhibit tumor growth and angiogenesis. Nucleic Acids Research . 2012;40(2):761–774. doi: 10.1093/nar/gkr730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 169.Qian X., Yu J., Yin Y., et al. MicroRNA-143 inhibits tumor growth and angiogenesis and sensitizes chemosensitivity to oxaliplatin in colorectal cancers. Cell Cycle . 2013;12(9):1385–1394. doi: 10.4161/cc.24477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 170.Zhang H., Hao Y., Yang J., et al. Genome-wide functional screening of miR-23b as a pleiotropic modulator suppressing cancer metastasis. Nature Communications . 2011;2(1) doi: 10.1038/ncomms1555.554 [DOI] [PubMed] [Google Scholar]
  • 171.Chen X., Zeng K., Xu M., et al. P53-induced miR-1249 inhibits tumor growth, metastasis, and angiogenesis by targeting VEGFA and HMGA2. Cell Death & Disease . 2019;10 doi: 10.1038/s41419-018-1188-3.131 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 172.He J., Jing Y., Li W., et al. Roles and mechanism of miR-199a and miR-125b in tumor angiogenesis. PLOS ONE . 2013;8(2) doi: 10.1371/journal.pone.0056647.e56647 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 173.Vecchione A., Belletti B., Lovat F., et al. A microRNA signature defines chemoresistance in ovarian cancer through modulation of angiogenesis. Proceedings of the National Academy of Sciences . 2013;110(24):9845–9850. doi: 10.1073/pnas.1305472110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 174.Lai Y., Zhang X., Zhang Z., et al. The microRNA-27a: ZBTB10-specificity protein pathway is involved in follicle stimulating hormone-induced VEGF, Cox2 and survivin expression in ovarian epithelial cancer cells. International Journal of Oncology . 2013;42(2):776–784. doi: 10.3892/ijo.2012.1743. [DOI] [PubMed] [Google Scholar]
  • 175.Korpal M., Kang Y. The emerging role of miR-200 family of MicroRNAs in epithelial–mesenchymal transition and cancer metastasis. RNA Biology . 2008;5(3):115–119. doi: 10.4161/rna.5.3.6558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 176.Pecot C. V., Rupaimoole R., Yang D., et al. Tumour angiogenesis regulation by the miR-200 family. Nature Communications . 2013;4 doi: 10.1038/ncomms3427.2427 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 177.Imam J. S., Plyler J. R., Bansal H., et al. Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Rac1 signaling and actin reorganization. PLOS ONE . 2012;7(12) doi: 10.1371/journal.pone.0052397.e52397 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 178.Salinas-Vera Y. M., Gallardo-Rincón D., García-Vázquez R., et al. Corrigendum: hypoxamiRs profiling identify miR-765 as a regulator of the early stages of vasculogenic mimicry in SKOV3 ovarian cancer cells. Frontiers in Oncology . 2020;10 doi: 10.3389/fonc.2020.00889.889 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 179.Lei Z., Li B., Yang Z., et al. Regulation of HIF-1α and VEGF by miR-20b tunes tumor cells to adapt to the alteration of oxygen concentration. PLOS ONE . 2009;4(10) doi: 10.1371/journal.pone.0007629.e7629 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 180.Chou J., Lin J. H., Brenot A., Kim J.-W., Provot S., Werb Z. GATA3 suppresses metastasis and modulates the tumour microenvironment by regulating microRNA-29b expression. Nature Cell Biology . 2013;15(2):201–213. doi: 10.1038/ncb2672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 181.Long J., Wang Y., Wang W., Chang B. H. J., Danesh F. R. Identification of MicroRNA-93 as a novel regulator of vascular endothelial growth factor in hyperglycemic conditions. Journal of Biological Chemistry . 2010;285(30):23457–23465. doi: 10.1074/jbc.M110.136168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 182.Hao Y., Yang J., Yin S., et al. The synergistic regulation of VEGF-mediated angiogenesis through miR-190 and target genes. RNA . 2014;20(8):1328–1336. doi: 10.1261/rna.044651.114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 183.Wang R., Zhao N., Li S., et al. MicroRNA-195 suppresses angiogenesis and metastasis of hepatocellular carcinoma by inhibiting the expression of VEGF, VAV2, and CDC42. Hepatology . 2013;58(2):642–653. doi: 10.1002/hep.26373. [DOI] [PubMed] [Google Scholar]
  • 184.Zhang H.-F., Xu L.-Y., Li E.-M. A family of pleiotropically acting MicroRNAs in cancer progression, miR-200: potential cancer therapeutic targets. Current Pharmaceutical Design . 2014;20(11):1896–1903. doi: 10.2174/13816128113199990519. [DOI] [PubMed] [Google Scholar]
  • 185.Zhu X., Er K., Mao C., et al. miR-203 suppresses tumor growth and angiogenesis by targeting VEGFA in cervical cancer. Cellular Physiology and Biochemistry . 2013;32(1):64–73. doi: 10.1159/000350125. [DOI] [PubMed] [Google Scholar]
  • 186.Yan J.-J., Zhang Y.-N., Liao J.-Z., et al. MiR-497 suppresses angiogenesis and metastasis of hepatocellular carcinoma by inhibiting VEGFA and AEG-1. Oncotarget . 2015;6(30):29527–29542. doi: 10.18632/oncotarget.5012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 187.Zhou B., Ma R., Si W., et al. MicroRNA-503 targets FGF2 and VEGFA and inhibits tumor angiogenesis and growth. Cancer Letters . 2013;333(2):159–169. doi: 10.1016/j.canlet.2013.01.028. [DOI] [PubMed] [Google Scholar]
  • 188.Cheng J., Chen Y., Zhao P., et al. Downregulation of miRNA-638 promotes angiogenesis and growth of hepatocellular carcinoma by targeting VEGF. Oncotarget . 2016;7(21):30702–30711. doi: 10.18632/oncotarget.8930. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 189.Yamakuchi M., Yagi S., Ito T., Lowenstein C. J., Emanueli C. MicroRNA-22 regulates hypoxia signaling in colon cancer cells. PLOS ONE . 2011;6(5) doi: 10.1371/journal.pone.0020291.e20291 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 190.Yamakuchi M., Lotterman C. D., Bao C., et al. P53-induced microRNA-107 inhibits HIF-1 and tumor angiogenesis. Proceedings of the National Academy of Sciences . 2010;107(14):6334–6339. doi: 10.1073/pnas.0911082107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 191.Cha S.-T., Chen P.-S., Johansson G., et al. Editor’s note: MicroRNA-519c suppresses hypoxia-inducible factor-1α expression and tumor angiogenesis. Cancer Research . 2019;79(14) doi: 10.1158/0008-5472.CAN-19-1710.3790 [DOI] [PubMed] [Google Scholar]
  • 192.Zhang H., Pu J., Qi T., et al. MicroRNA-145 inhibits the growth, invasion, metastasis and angiogenesis of neuroblastoma cells through targeting hypoxia-inducible factor 2 alpha. Oncogene . 2014;33(3):387–397. doi: 10.1038/onc.2012.574. [DOI] [PubMed] [Google Scholar]
  • 193.Wu Z.-H., Lin C., Liu C.-C., et al. MiR-616-3p promotes angiogenesis and EMT in gastric cancer via the PTEN/AKT/mTOR pathway. Biochemical and Biophysical Research Communications . 2018;501(4):1068–1073. doi: 10.1016/j.bbrc.2018.05.109. [DOI] [PubMed] [Google Scholar]
  • 194.Chen H., Li L., Wang S., et al. Reduced miR-126 expression facilitates angiogenesis of gastric cancer through its regulation on VEGF-A. Oncotarget . 2014;5(23):11873–11885. doi: 10.18632/oncotarget.2662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 195.Cuzziol C. I., Castanhole-Nunes M. M. U., Pavarino É. C., Goloni-Bertollo E. M. MicroRNAs as regulators of VEGFA and NFE2L2 in cancer. Gene . 2020;759 doi: 10.1016/j.gene.2020.144994.144994 [DOI] [PubMed] [Google Scholar]
  • 196.Yang Q., Zhang R.-W., Sui P.-C., He H.-T., Ding L. Dysregulation of non-coding RNAs in gastric cancer. World Journal of Gastroenterology . 2015;21(39) doi: 10.3748/wjg.v21.i39.10956.10956 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 197.Zhang H., Bai M., Deng T., et al. Cell-derived microvesicles mediate the delivery of miR-29a/c to suppress angiogenesis in gastric carcinoma. Cancer Letters . 2016;375(2):331–339. doi: 10.1016/j.canlet.2016.03.026. [DOI] [PubMed] [Google Scholar]
  • 198.Liu H.-T., Xing A.-Y., Chen X., et al. MicroRNA-27b, microRNA-101 and microRNA-128 inhibit angiogenesis by down-regulating vascular endothelial growth factor C expression in gastric cancers. Oncotarget . 2015;6(35):37458–37470. doi: 10.18632/oncotarget.6059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 199.Mei B., Chen J., Yang N., Peng Y. The regulatory mechanism and biological significance of the Snail-miR590-VEGFR-NRP1 axis in the angiogenesis, growth and metastasis of gastric cancer. Cell Death & Disease . 2020;11(4) doi: 10.1038/s41419-020-2428-x.241 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 200.Zhang S., Zhang R., Xu R., Shang J., He H., Yang Q. MicroRNA-574-5p in gastric cancer cells promotes angiogenesis by targeting protein tyrosine phosphatase non-receptor type 3 (PTPN3) Gene . 2020;733 doi: 10.1016/j.gene.2020.144383.144383 [DOI] [PubMed] [Google Scholar]
  • 201.Seo A. N., Jung Y., Jang H., et al. Clinical significance and prognostic role of hypoxia-induced microRNA 382 in gastric adenocarcinoma. PLOS ONE . 2019;14(10) doi: 10.1371/journal.pone.0223608.e0223608 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 202.Liu S., Tian Y., Zhu C., Yang X., Sun Q. High miR-718 suppresses phosphatase and tensin homolog (PTEN) expression and correlates to unfavorable prognosis in gastric cancer. Medical Science Monitor . 2018;24:5840–5850. doi: 10.12659/MSM.909527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 203.Bai M., Li J., Yang H., et al. RETRACTED: miR-135b delivered by gastric tumor exosomes inhibits FOXO1 expression in endothelial cells and promotes angiogenesis. Molecular Therapy . 2019;27(10):1772–1783. doi: 10.1016/j.ymthe.2019.06.018. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 204.Wang Z.-F., Liao F., Wu H., Dai J. Glioma stem cells-derived exosomal miR-26a promotes angiogenesis of microvessel endothelial cells in glioma. Journal of Experimental & Clinical Cancer Research . 2019;38(1) doi: 10.1186/s13046-019-1181-4.201 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 205.He Q., Zhao L., Liu X., et al. MOV10 binding circ-DICER1 regulates the angiogenesis of glioma via miR-103a-3p/miR-382-5p mediated ZIC4 expression change. Journal of Experimental & Clinical Cancer Research . 2019;38 doi: 10.1186/s13046-018-0990-1.9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 206.Li C., Wang X., Song Q. MicroRNA 885-5p inhibits hepatocellular carcinoma metastasis by repressing AEG1. OncoTargets and Therapy . 2020;13:981–988. doi: 10.2147/OTT.S228576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 207.Zhang S., Li G., Liu C., et al. miR-30e-5p represses angiogenesis and metastasis by directly targeting AEG-1 in squamous cell carcinoma of the head and neck. Cancer Science . 2020;111(2):356–368. doi: 10.1111/cas.14259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 208.Niu J., Li Z., Li F. Overexpressed microRNA-136 works as a cancer suppressor in gallbladder cancer through suppression of JNK signaling pathway via inhibition of MAP2K4. American Journal of Physiology-Gastrointestinal and Liver Physiology . 2019;317(5):G670–G681. doi: 10.1152/ajpgi.00055.2019. [DOI] [PubMed] [Google Scholar]
  • 209.Fan B., Jin Y., Zhang H., et al. MicroRNA-21 contributes to renal cell carcinoma cell invasiveness and angiogenesis via the PDCD4/c-Jun (AP-1) signalling pathway. International Journal of Oncology . 2019;56:178–192. doi: 10.3892/ijo.2019.4928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 210.Carthew R. W., Sontheimer E. J. Origins and mechanisms of miRNAs and siRNAs. Cell . 2009;136(4):642–655. doi: 10.1016/j.cell.2009.01.035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 211.Li F., Wang Y., Chen W.-L., et al. Co-delivery of VEGF siRNA and etoposide for enhanced anti-angiogenesis and anti-proliferation effect via multi-functional nanoparticles for orthotopic non-small cell lung cancer treatment. Theranostics . 2019;9(20):5886–5898. doi: 10.7150/thno.32416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 212.Lu P., Liang W., Li J., et al. A cost-effectiveness analysis: first-line avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. Frontiers in Pharmacology . 2020;11 doi: 10.3389/fphar.2020.00619.619 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 213.Mazahir F., Pathak A., Gupta U., Yadav A. K. Therapeutic Nanocarriers in Cancer Treatment: Challenges and Future Perspective . Bentham Science Publisher; 2023. Nanotechnology for cancer treatment: an introduction; pp. 31–63. [DOI] [Google Scholar]
  • 214.Soni N., Jain K., Gupta U., Jain N. K. Controlled delivery of gemcitabine hydrochloride using mannosylated poly(propyleneimine) dendrimers. Journal of Nanoparticle Research . 2015;17(11):1–17. doi: 10.1007/s11051-015-3265-1. [DOI] [Google Scholar]
  • 215.Goel S., Duda D. G., Xu L., et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiological Reviews . 2011;91(3):1071–1121. doi: 10.1152/physrev.00038.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 216.Regmi P., Hu H.-J., Lv T.-R., et al. Efficacy and safety of sorafenib plus hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma. Surgical Oncology . 2021;39 doi: 10.1016/j.suronc.2021.101663.101663 [DOI] [PubMed] [Google Scholar]
  • 217.Al-Husein B., Abdalla M., Trepte M., DeRemer D. L., Somanath P. R. Antiangiogenic therapy for cancer: an update. Pharmacotherapy . 2012;32(12):1095–1111. doi: 10.1002/phar.1147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 218.Khan M. A., Jain V. K., Rizwanullah M., Ahmad J., Jain K. PI3K/AKT/mTOR pathway inhibitors in triple-negative breast cancer: a review on drug discovery and future challenges. Drug Discovery Today . 2019;24(11):2181–2191. doi: 10.1016/j.drudis.2019.09.001. [DOI] [PubMed] [Google Scholar]
  • 219.Yang H., Wang Y., Cheryan V. T., et al. Withaferin A inhibits the proteasome activity in mesothelioma in vitro and in vivo. PLOS ONE . 2012;7(8) doi: 10.1371/journal.pone.0041214.e41214 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 220.Grothey A., Cutsem E. V., Sobrero A., et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. The Lancet . 2013;381(9863):303–312. doi: 10.1016/S0140-6736(12)61900-X. [DOI] [PubMed] [Google Scholar]
  • 221.Zhang W., Fulci G., Buhrman J. S., et al. Bevacizumab with angiostatin-armed oHSV increases antiangiogenesis and decreases bevacizumab-induced invasion in U87 glioma. Molecular Therapy . 2012;20(1):37–45. doi: 10.1038/mt.2011.187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 222.Vasudev N. S., Reynolds A. R. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis . 2014;17(3):471–494. doi: 10.1007/s10456-014-9420-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 223.Sweeney C. J., Miller K. D., Sledge G. W., Jr. Resistance in the anti-angiogenic era: nay-saying or a word of caution? Trends in Molecular Medicine . 2003;9(1):24–29. doi: 10.1016/S1471-4914(02)00007-2. [DOI] [PubMed] [Google Scholar]
  • 224.Reiter R., Rosales-Corral S., Tan D.-X., et al. Melatonin, a full service anti-cancer agent: inhibition of initiation, progression and metastasis. International Journal of Molecular Sciences . 2017;18(4) doi: 10.3390/ijms18040843.843 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 225.Ma Q., Reiter R. J., Chen Y. Role of melatonin in controlling angiogenesis under physiological and pathological conditions. Angiogenesis . 2020;23(2):91–104. doi: 10.1007/s10456-019-09689-7. [DOI] [PubMed] [Google Scholar]
  • 226.Park S.-Y., Jang W.-J., Yi E.-Y., et al. Melatonin suppresses tumor angiogenesis by inhibiting HIF-1α stabilization under hypoxia. Journal of Pineal Research . 2010;48(2):178–184. doi: 10.1111/j.1600-079X.2009.00742.x. [DOI] [PubMed] [Google Scholar]
  • 227.Wang R.-X., Liu H., Xu L., Zhang H., Zhou R.-X. Melatonin downregulates nuclear receptor RZR/RORγ expression causing growth-inhibitory and anti-angiogenesis activity in human gastric cancer cells in vitro and in vivo. Oncology Letters . 2016;12(2):897–903. doi: 10.3892/ol.2016.4729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 228.Jardim-Perassi B. V., Arbab A. S., Ferreira L. C., et al. Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer. PLOS ONE . 2014;9(1) doi: 10.1371/journal.pone.0085311.e85311 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 229.Kim K.-J., Choi J.-S., Kang I., Kim K.-W., Jeong C.-H., Jeong J.-W. Melatonin suppresses tumor progression by reducing angiogenesis stimulated by HIF-1 in a mouse tumor model. Journal of Pineal Research . 2013;54(3):264–270. doi: 10.1111/j.1600-079X.2012.01030.x. [DOI] [PubMed] [Google Scholar]
  • 230.Carbajo-Pescador S., Ordoñez R., Benet M., et al. Inhibition of VEGF expression through blockade of Hif1α and STAT3 signalling mediates the anti-angiogenic effect of melatonin in HepG2 liver cancer cells. British Journal of Cancer . 2013;109(1):83–91. doi: 10.1038/bjc.2013.285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 231.Cho S.-Y., Lee H.-J., Jeong S.-J., et al. Sphingosine kinase 1 pathway is involved in melatonin-induced HIF-1α inactivation in hypoxic PC-3 prostate cancer cells. Journal of Pineal Research . 2011;51(1):87–93. doi: 10.1111/j.1600-079X.2011.00865.x. [DOI] [PubMed] [Google Scholar]
  • 232.Zonta Y., Martinez M., Camargo I., et al. Melatonin reduces angiogenesis in serous papillary ovarian carcinoma of ethanol-preferring rats. International Journal of Molecular Sciences . 2017;18(4) doi: 10.3390/ijms18040763.763 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 233.Liu R., Wang H.-L., Deng M.-J., et al. Melatonin inhibits reactive oxygen species-driven proliferation, epithelial–mesenchymal transition, and vasculogenic mimicry in oral cancer. Oxidative Medicine and Cellular Longevity . 2018;2018:13. doi: 10.1155/2018/3510970.3510970 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 234.Goncalves N., Rodrigues R., Jardim-Perassi B., et al. Molecular markers of angiogenesis and metastasis in lines of oral carcinoma after treatment with melatonin. Anti-Cancer Agents in Medicinal Chemistry . 2014;14(9):1302–1311. doi: 10.2174/1871520614666140812110246. [DOI] [PubMed] [Google Scholar]
  • 235.Goradel N. H., Asghari M. H., Moloudizargari M., Negahdari B., Haghi-Aminjan H., Abdollahi M. Melatonin as an angiogenesis inhibitor to combat cancer: mechanistic evidence. Toxicology and Applied Pharmacology . 2017;335:56–63. doi: 10.1016/j.taap.2017.09.022. [DOI] [PubMed] [Google Scholar]
  • 236.Alvarez-García V., González A., Alonso-González C., Martínez-Campa C., Cos S. Regulation of vascular endothelial growth factor by melatonin in human breast cancer cells. Journal of Pineal Research . 2013;54(4):373–380. doi: 10.1111/jpi.12007. [DOI] [PubMed] [Google Scholar]
  • 237.Menéndez-Menéndez J., Martínez-Campa C. Melatonin: an anti-tumor agent in hormone-dependent cancers. International Journal of Endocrinology . 2018;2018:20. doi: 10.1155/2018/3271948.3271948 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 238.Pal A. K., Sharma P., Zia A., et al. Metabolomics and EMT markers of breast cancer: a crosstalk and future perspective. Pathophysiology . 2022;29(2):200–222. doi: 10.3390/pathophysiology29020017. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

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Data Availability Statement

The authors confirm that all the data supporting the findings of this study are presented within the article. If any further information is required, then it may be provided upon reasonable request.


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