Therapeutic targeting of angiogenesis molecular pathways in angiogenesis-dependent diseases

Biomedicine & Pharmacotherapy 110 (2019) 775–785

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Review

Therapeutic targeting of angiogenesis molecular pathways in angiogenesisdependent diseases

T

Asghar Fallaha,b,c, Ali Sadeghiniad,e, Houman Kahrobaf,g, Amin Samadih, Hamid Reza Heidaric, ⁎ Behzad Bradarana, Sirous Zeinalii, Ommoleila Molavib,c,f, a

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran c Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran d Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran e Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran f Molecular Medicine Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran g Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran h Department of Chemical and Materials Engineering, University of Alberta, Edmonton, Canada i Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran b

A R T I C LE I N FO

A B S T R A C T

Keywords: Anti-angiogenesis VEGF–VEGFR system receptors Angiogenesis-dependent diseases Cancer Anti-angiogenic therapeutics

Angiogenesis is a critical step in the progression of almost all human malignancies and some other life-threatening diseases. Anti-angiogenic therapy is a novel and effective approach for treatment of angiogenesis-dependent diseases such as cancer, diabetic retinopathy, and age-related macular degeneration. In this article, we will review the main strategies developed for anti-angiogenic therapies beside their clinical applications, the major challenges, and the latest advances in the development of anti-angiogenesis-based targeted therapies.

1. Angiogenesis Angiogenesis is appointed to spreading of new blood-vessel procedure which plays a central role in human reproduction, organ development, wound healing, and tissue repair. Angiogenesis is also a crucial phenomenon in the progression of various human diseases [1–3]. In normal physiological condition, angiogenesis is tightly regulated by a complex network of angiogenesis growth factors and cytokines which provoke residental endothelial cells (EC) located in the inner surface of vessels as the main site of angiogenesis [4–6]. The angiogenic growth factors and cytokines include vascular endothelial growth factor (VEGF), fibroblast growth factors (FGFs), placental growth factor (PGF), platelet-derived growth factor (PDGF), tumor necrosis factoralpha (TNF-α), transforming growth factor-beta (TGF-β), angiopoietins (Angs), epidermal growth factor (EGF), granulocyte-macrophage colony-stimulating factor/granulocyte colony-stimulating factor (GMCSF)/ G-CSF), hepatocyte growth factor/scatter factor (HGF/SF), interleukin 8 (IL-8), and erythropoietin (EPO) [6–9] (Fig. 1). Angiogenic growth factors and cytokines are produced by different types of cells including endothelial cells, fibroblasts, smooth muscle cells, platelets, inflammatory cells, and cancer cells [10]. Under hypoxia condition,

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hypoxia-inducible factor (HIF) act as an angiogenic factor and cooperates with TNF-α to initiate angiogenesis (Fig. 1). Angiogenesis is triggered by stimulatory angiogenic factors through various mechanisms [10]. VEGF, as the best studied angiogenic growth factor, induce mitogenesis and migration in ECs, and promotes sprouting of ECs and tube formation [10]. The Ang family of angiogenic growth factors including Ang-1, Ang-2, mouse Ang-3, and human Ang4, bind to endothelial receptor tyrosine kinase Tie-2 to promote angiogenesis [11]. Angs also regulate ECs homeostasis through regulation of cell survival, vascular maturation, and vascular stability [11]. While VEGF acts at the early stage of angiogenesis to promote formation of primitive tubular structures, Ang/Tie-2 system function at the later stage of angiogenesis and enhances the recruitment of mural cells (mainly pericytes) and mediates interactions of ECs and pericytes. Ang/ Tie-2 system also promotes stabilization in new vessels due to formation of endothelial tight junctions (Fig. 2) [12]. Pericytes are branched cells elongated around ECs and contribute to vessel maturation through release of angiogenic growth factors which penetrate into basementmembrane to contacts with ECs [5]. Except to the smallest capillaries, angiogenesis is accompanied by the recruitment of smooth muscle cells or pericytes to the vessels and subsequent production of an extracellular

Corresponding author at: Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. E-mail address: [email protected] (O. Molavi).

https://doi.org/10.1016/j.biopha.2018.12.022 Received 6 September 2018; Received in revised form 2 December 2018; Accepted 5 December 2018 0753-3322/ © 2018 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

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Fig. 1. Ligands/Receptors involving in angiogenesis. VEGF–VEGFR system receptors include seven immunoglobulin-autologous domains, one single transmembrane and an intracellular portion having a tyrosine-kinase domain, meanwhile VEGFA/VEGFR2 is an important signal for angiogenesis. VEGF–VEGFR system inhibitors including therapeutics antibody and a small molecule. HIF activates a signaling pathway that up-regulates VEGF expression and hypoxia suppress HIF degradation pathway. TGF-β has been recognized as a pivotal regulator during both developmental and pathophysiological angiogenesis. The angiogenic activity of TGF-β is highly context-dependent and coordinated by many regulatory factors3. TGF-β binds to type II receptor (TβRII), which recruits type I receptors, termed ALKs, to activate downstream signaling. In vascular endothelial cells, the angiogenic activity of TGF-β elicits pro-angiogenic responses. PDGF dimers bind to extracellular regions of PDGFR, triggering the dimerization of PDGFR. The phosphorylated PDGFRs then can initiate various downstream signaling events by recruiting SH2 domain-containing molecules such as ERK kinase, PI3K, FAK, and mTOR. VEGF–VEGFR, Vascular Endothelial Growth Factor-VEGF Receptor; HGF, hepatocyte growth factor; HIF-1α, hypoxia-inducible factor 1α; TGF-β, Transforming growth factor-β; ALKs, activin receptor-like kinase; mTOR, mammalian target of rapamycin; PDGF, platelet-derived growth factor; PDGFR, PDGF Receptor.

network at the subcellular level through ligation to their specific receptors. This network is triggered by RTK and subsequently stimulates downstream pathways like Ras/Raf/MAPK, PI3K/Akt/mTOR, and the PKC [19,20]. The details of intracellular singling pathways, the mechanism of their activation, and different signaling molecules involved in signal transduction and function of these pathways has been illustrated in Fig. 1. Vasculogenesis and angiogenesis are two main procedures for blood-vessel formation. In vasculogenesis which is a developmental process, multipotent mesodermal cells differentiate into angioblasts, and form ECs. More recent studies have suggested that arterial and venous ECs are derived from different pools of angioblasts which are originated from mesenchyme (Fig. 2) [5]. In the other hand, angiogenesis for new vessels is based on pre-existing blood vessels. Angiogenesis is tightly regulated by molecular pathways of endothelial sprouting and non-sprouting microvascular development [21]. Endothelial sprouting is a basic sequential multi-step mechanism of angiogenesis. In endothelial sprouting, vessel growth is initiated by activation of the angiogenic signaling pathways including Notch, Wnt, VEGF/VEGFRs, which leads to the morphological remodulation of ECs as stalk cells present in pre-existing blood vessels (Figs. 1,2) [21,22]. Subsequently activated ECs begin to secret proteases like plasminogen activator and matrix metalloproteinase (MMP) to mobilize and recruit ECs to the sire of angiogenesis [22]. Sprouts extension is under the control of adhesion molecules called integrins. As ECs proliferate toward surrounding matrix and build microvascular environment, solid sprouts provide connections to the neighboring vessels [23]. The secretion of growth factors such as VEGF and bFGF accelerate sprouts angiogenesis (Fig. 2). There are other important factors including

matrix [13]. TGF-β and PDGF are other angiogenic factors which are important for the stabilization of new vessels. PDGF is necessary for the recruitment of smooth muscle cells and pericytes. TGF-β is responsible for the production of extracellular matrix and the appropriate interaction between ECs and mural cells [5]. GM-CSF is another angiogenic factor which plays an important role in wound healing by promoting angiogenesis [14]. It has been reported that GM-CSF enhances VEGF expression, decreases the expression ratio of Ang-1/Ang-2, and suppresses the phosphorylation of Tie-2 in the early stages of wound healing leading to the detachment of pericytes form ECs required for ECs proliferation and migration (Fig. 2) [14,15]. At late stages of wound healing, GM-CSF preserves the high level of VEGF expression while enhancing the expression ratio of Ang-1/Ang-2 and the phosphorylation of Tie-2, leading to higher pericyte coverage and more integration of the basement membrane which are all required for the barrier function of blood vessels [14]. FGF1 and FGF2 promote proliferation and physical organization of ECs into tube-like structures. Besides, FGF1 and FGF2 induce growth, differentiation, and survival of blood vessel-associated cells [16]. FGF1 plays an important role in induction of angiogenesis in the heart. FGF7, KGF2, and FGF10 are keratinocyte growth factors (KGFs) which participate in wound healing process [17]. EPO has been also considered as an angiogenic factor in various studies which have shown the potential role of EPO in induction of ECs proliferation in normal animals and different cancerous tissues. Expression of EPO receptors on ECs support the notion that EPO is immportant in angiogenesis. It has been also reported that EPO upregulates the expression of VEGF which is a key regulator of angiogenesis [18]. Angiogenesis-associated factors establish a complex signaling 776

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Fig. 2. Angiogenesis- tumor microenvironment is characterized by recruitment of cells also plays a critical role in resistance to anti-angiogenic therapy, release of soluble factors and hypoxia so that induces angiogenesis. PDGF/PDGFR is necessary for the recruitment of pericytes, the pericytes cells product Ang1for stability of EC and Ang2 is an antagonist. Platelets are recruited to sites of hypoxia, where they become activated and release their stores of stimulatory factors into the tumor microenvironment. EPCs and myeloid cells from the bone marrow move to the tumor microenvironment, where they release even more soluble factors locally. This environment also makes the tumor cells more invasive, allowing them to intravasate into the vasculature or lymphatics for metastasis to distant tissues. Effective strategies for cancer therapy must consider targets on multiple cell types and address issues of poor drug delivery in the leaky and poorly perfused tumor microenvironment. PDGF, platelet-derived growth factor; PDGFR, PDGF Receptor; Ang1/2, Angiopoietin 1/2; EC, Endothelial cells; EPC, Endothelial progenitor cells. Table 1 Angiogenesis-Dependent Diseases. Specific organ

Diseases in mice or humans

Multi-organs abnormality Blood vessels abnormality

Cancer - infectious diseases - autoimmune disorders Vascular malformations - DiGeorge syndrome - HHT- cavernous hemangioma atherosclerosis- transplant arteriopathy Obesity - Weight loss by angiogenesis inhibitors Psoriasis, warts, allergic dermatitis, scar keloids, pyogenic granulomas, blistering disease, Kaposi sarcoma in AIDS patients Persistent hyperplastic vitreous syndrome - diabetic retinopathy- retinopathy of prematurity - choroidal neovascularization Primary pulmonary hypertension- asthma - nasal polyps Inflammatory bowel and periodontal disease, ascites, peritoneal adhesions Endometriosis- uterine bleeding - ovarian cysts - ovarian hyperstimulation Arthritis - synovitis – osteomyelitis - osteophyte formation

Adipose tissue abnormality Skin abnormality Eye abnormality Lung abnormality Intestines abnormality Reproductive system abnormality Bone and joints abnormality

tissue repair, angiogenesis is an important process in the development and progress of several human diseases.

PDGF, TGF-β, and Ang-1, that also play a role in sprouts angiogenesis [23]. Non-sprouting angiogenesis is defined as an intussusceptive angiogenesis in which pre-existing vessels split into the new vessels by formation of transvacuolar tissue adjoined into the lumen of the vessels [21]. Intussusceptive angiogenesis occur in the zone of contact between two opposing capillary walls where endothelial cell junction are reorganized as leaky bilayer allowing the penetration of growth factors and cells into the lumen [24]. The leaky contact zone is then filled with pericytes and myofibroblasts to build collagen fibers for development of the vessels lumen. Intussusception reorganizes existing cells and increases the number of capillaries independent of ECs number. During embryonic development intussusceptive angiogenesis provides available microvasculature for new vessel expansion [21,24]. In addition to the critical role of angiogenesis in reproduction, development, and

2. Angiogenesis-dependent diseases Angiogenesis-dependent diseases were first described in 1971 by Judah Folkman who reported that blocking of blood vessel formation in tumor cells leads to suppression of cancer cell growth and metastasis. Concurrently, the first treatment of an angiogenesis-dependent pulmonary hemangioma by administration of Interferon α-2a, provided more evidence for the importance of angiogenesis inhibition and its potential therapeutic benefits in treatment of neoplasms [25]. Interferon-α is the first anti-angiogenesis agent reported in the 1980s from the Folkman laboratory [1]. Pathological angiogenesis is reported in a range of neovasculature 777

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responsive genes (Fig. 1) [41]. Plasminogen activators, proteinases, MMPs, and heparanase families are further factors which modulate angiogenesis by degradation of matrix and activation or secretion of growth factors (bFGF, VEGF, and insulin-like growth factor 1), to provide appropriate circumstances for migration of ECs and tumor cells. MMPs mobilize stromal pro-angiogenic proteins, cause cleavage of endostatin of collagen 18 in the vessel walls, and participate in the cleavage of angiostatin from circulating plasminogen to mediate angiogenesis [42,43]. FGF and PDGF family present in relatively similar quantities in both tumoral and normal cells (Fig. 2). Mesenchymal or inflammatory cells are recruited by FGF. Unlike normal blood vessels, tumor blood vessels are dilated with an irregular shape. As discussed in the following section, the vasculature abnormalities of tumor are significantly altered by antiangiogenesis agents. Dysregulation of angiogenesis in cancer results in an abnormal vascular network which not only reduces the therapeutic efficacy of conventional anticancer therapies but can fuel tumor progression [44]. In tumor microenvironment, the imbalance of angiogenesis promoting factors (e.g., VEGF, bFGF, and Ang-2) and anti-angiogenic factors [e.g., thrombospondin-1 (TSP-1) Ang-1], creates hyper-permeable and immature blood vessels [44]. These abnormalities generate a tumor microenvironment characterized by hypoxia, depleted nutrition, low pH and high interstitial pressure [45]. The vasculature abnormalities and resultant tumor microenvironment reduce the cytotoxicity of systemically administered anticancer drugs by limiting the accessibility of the drugs to cancer cells. Furthermore, a growing number of studies show that the abnormality of tumor vessels make a great contribution to cancer metastasis, immune evasion, and development of drug-resistant cancer cells. Previous studies have shown that the combination of antiVEGF therapy with chemotherapeutic agents has improved the survival of cancer patients that received the combination therapy as compared with those treated with chemotherapy alone [46]. In contrast, antiVEGF monotherapy has not shown promising results [46]. These controversial findings are explained by “vascular normalization” hypothesis which suggests that rather than demolishing vessels, the anti-angiogenic therapies revert abnormal structure and function of vasculature in tumor cells towards a more normal state [47]. Based on this hypothesis, anti-VEGF drugs improve the therapeutic efficacy of chemotherapy by enhancing the accessibility of a tumor to anti-cancer drugs through normalization of blood vessels within the tumor. Previous studies suggest that anti-VEGF therapy can promote transient vascular normalization by induction of a balance between proangiogenic and antiangiogenic factors [44]. Recent studies show that pericytes contribute to tumor progression by induction of angiogenesis and metastasis process [48]. Initially, pericytes were believed to participate in tumor development via angiogenesis [49]. New evidences suggest that residential pericytes of tumor microenvironment function as one of the main regulators of cancer angiogenesis and metastasis. Pericyte cells of tumors indicate more disorderly arrangement, aberrant cell shapes, altered morphologies, and looser vessel attachment [50]. PDGF-B represents the main chemo-attractant for perivascular cells (smooth muscle cells and pericytes) in cancer angiogenesis. Pericytes recruited to tumor, release a variety of angiogenic factors including VEGF, Ang-2 and MMP (Fig. 2) [50]. Recent studies show that during cancer progression, hypoxia can constantly stimulate secretion of VEGF by pericytes via HIF signaling. Under hypoxic condition, pericytes secret Ang-2 and MMP which cause destabilization of vessels and increase permeability of the endothelial barriers in tumor microenvironment [51].

diseases which are called angiogenesis-dependent diseases (Table. 1). Some of the well-studied angiogenic-dependent diseases are cancer, neovascular age-related macular degeneration (NVAMD), and diabetic retinopathy (DR). In cancers rapid proliferation of cancerous cells brings an urgent demand for continuous blood and nutrient supply into the tumor microenvironment. Cancer angiogenesis plays a key role in providing nutrient to the rapidly dividing cells and tumor progression. Therefore tumor angiogenesis is considered as a promising target for cancer targeted therapy [3,26,27]. Age-related macular degeneration (AMD) is identified as an agedependent degenerative disease. Based on severity, AMD is divided into early, intermediate, and late subtypes [28]. The late or advanced AMD is consist of two subtypes including wet (choroidal neovascularization; angiogenesis-dependent) and dry (geographic atrophy; angiogenesisindependent) [29]. Wet advanced AMD is a neurodegenerative disease of vision loss [28,29]. Advanced-AMD is reported to affect almost 10 million people worldwide, and the number of affected individuals with earlier stages are more than 150 million cases. AMD risk factors are obesity, dietary fat, alcohol consumption, aging, and genetic predispositions [30,31]. DR is described as damaged retina blood vessels due to diabetes which is a leading cause of blindness. Based on the disease progression, DR is classified as two subtypes; non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) [32]. NPDR is known as the early stage of the disease with mild or nonexistent symptoms related to blood vessels weakness in the retina such as microaneurysms, microhemorrhages, and increased permeability of retinal vessels. In PDR, the advanced form of the disease, pathologic angiogenesis in addition to some clinical symptoms of NPDR are observed. Pathological angiogenesis in PDR is characterized by field fragile blood vessels which demonstrate circulation defects and deprive the eye cells from oxygen and nutrition’s [32]. In PDR, trapped blood within the vitreous obstruct light path into the retina resulting in specks or cloudy vision known the main side effect of diabetes mellitus on vision loss worldwide [33–35]. Tien Y. Wong reported one-third of diabetics to have DR and DR is regarded as a microvascular disease [36]. 3. Cancer and angiogenesis Cancer is a serious human health challenge for many decades [37]. Recent advances in molecular diagnostic techniques has made it possible to detect and assess cancer biomarkers in blood and urine at very early stage of cancer [1,38]. The identification of differences between angiogenesis processes in cancer and those found in normal cells, had led to the identification of specific molecules which are only present and active in cancer angiogenesis and can be used in targeted therapy of cancer [3]. Senger and colleagues for the first time discovered vascular permeability factor secreted by a guinea pig tumor cell line. In 1989, Napoleone, Ferrara, and colleagues reported the isolation of VEGF by protein sequence analyses and confirmed that VEGF is the same molecule as the permeability factor reported earlier. Both in vivo and in vitro studies have showed that VEGF has a decisive role in both physiological and pathological angiogenesis [39,40]. HIF is an angiogenetic factor which initiates angiogenesis in response to hypoxic shocks (Fig. 1). HIF activates signaling pathways that up-regulate VEGF expression. Growth factors, produced by HIF-1 signaling, activate MAPK and AKT signaling pathways leading to the elevated level of HIF-1 protein which act as proangiogenic factor promoting cancer angiogenesis (Fig. 1). HIF-1 promotes oxygen delivery to hypoxic zones of tumor by upregulating the expression of VEGF and EPO. HIF-1 protein expression is negatively regulated by Von HippelLindau protein (pVHL). pVHL is an ubiquitin protease which rapidly degrades HIF-1α following hypoxia states. Under hypoxic condition, protein level of HIF-1α is stabilized and HIF-1α gets translocated to the nucleus where it binds to HIF-1β resulting in the formation of transcriptional complex which in turn induce the transcription of hypoxia-

4. Anti-angiogenic therapy The purpose of anti-angiogenesis therapy in cancer is to block oxygen and nutrient supply into cancer cells. Anti-angiogenesis agents are categorized into seven major groups: a) Monoclonal antibodies 778

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Table 2 Anti-angiogenic strategies and Clinical and preclinical application. Anti-angiogenic strategies

Clinical and preclinical application

Monoclonal Antibody MicroRNAs (miRNAs) / Small interfering RNAs (siRNA) Aptamers Gene Therapy Small molecular Angiostatin and Endostatin

Bevacizumab [40], Cetuximab [64], Ranibizumab [20], Aflibercept [72], miR126 [75], miR143and miR145 [74], VEGF siRNA–PEG/PEI PEC micelles [78] Pegaptanib sodium [80] VEGF scFv Adenovirus, VEGFR2 AAVand VEGF AAV [84], AAVrh.10 bevacizumab Sorafenib, sunitinib, Everolimusand Temsirolimus [113], Regorafenib [91] Recombinant Human Endostatin Adenovirus (RetinoStat) [99], Lentiviral Vector Gene Transfer of Endostatin/ Angiostatin [120] CAR-modified T lymphocytes with human VEGFR-1 specificity (V-1 CAR) [122]

Chimeric Antigen Receptor T cells (CAR-T) Cell therapy

(mAbs), b) MicroRNAs (miRNAs) / Small interfering RNAs (siRNA), c) Aptamers, d) Gene Therapy, e) Small molecular, f) Angiostatin and endostatin, and g) Chimeric antigen receptor T cells (CAR-T) cell therapy (Table. 2) [52]. Small molecule inhibitors of angiogenesis and mAbs are two important groups of anti-angiogenic drugs which are approved by US food and drug administration (FDA) for treatment of cancer and some other angiogenesis-dependent diseases (Tablet. 2) [4,38,53]. Further candidates for anti-angiogenesis therapy such as gene therapy, RNA interference (RNAi) therapy, and CAR-T cell therapy are also novel and promising therapeutic approaches [53,54]. Since 1971, anti-angiogenesis related studies have begun turning their attention to personalized medicine to translate research-based outcomes of anti-angiogenic therapeutics into clinical targeted therapeutics [55]. In personalized medicine, the best treatment based on the characteristics of disease, specific complexity and variability of tumors is considered. Genetic polymorphisms, the presence of specific mutations, individual cancer types, their specific metabolic, and hemodynamic, could directly influence vascular homeostasis. For instance, the metastatic colorectal cancer patients with mutations in KRAS, NRAS, BRAF, and PIK3CA show poor response to cetuximab, an anti-EGFR inhibitor, regardless of high expression of EGFR. Cetuximab can be only used for treatment of colon cancer with wild-type KRAS. The full genome sequencing of cancer patients is stepping forward to personalized medicine. The Cancer Genome Atlas, via whole-genome deep sequencing, is revealing that hundreds of coding genes may be mutated in each cancer type/subtype [56–58]. Diseases that have been treated more effectively using personalized medicine approaches include cancer, DR, and NVAMD [59,60]. Angiogenesis molecular mechanisms in a variety of biological processes are appealing candidates for targeting in cancer therapy [40]. Anti-angiogenic therapy initially targets micro-vascular ECs within a tumor bed, which have been activated by tumor cells. In fact suppression of tumor microenvironment ECs responsiveness to angiogenic proteins such as endostatin and angiostatins secreted by cancer cells, can suppress ECs proliferation. Anti-angiogenic therapies targeting EGFR receptor (using Tarceva) or VEGF by either anti-VEGF mAbs (i.e bevacizumab) or VEGF siRNA have been found to exert anticancer effects through induction of cell death in cancer cells) (Fig. 3) [1,38,42,61,62]. Anti-angiogenic therapies are usually used in combination with chemotherapy to boost survival rate [63].

Fig. 3. Anti-angiogenic therapy mechanism and main clinical and preclinical factors (red lines) (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.).

therapy of metastatic colorectal cancer, has been shown to improve treatment outcome by 5-flrouracil leucovorin and progression-free survival (PFS) in patients with metastatic colorectal cancer as compared with group that received 5-fluorouracil leucovorin alone [66]. Bevacizumab has been also used in combination with paclitaxel as a firstline treatment for adult patients with metastatic breast cancer [19,20,40]. Cetuximab is another commonly used angiogenesis inhibitor which directly blocks an EGFR-dependent mitogenic pathway and inhibits RAS-ERK pathway. Suppression of RAS-ERK pathway inhibits the production of various pr vb -angiogenic factor which utilize the TGFα/EGFR pathway to markedly upregulate VEGF production and tumor angiogenesis [1,39,67,68]. Ramucirumab is a recombinant human IgG1 mAb that binds to VEGFR-2 and blocks VEGF-A–stimulated proliferation and migration of ECs leading to suppression of tumor angiogenesis and progression (Fig. 1) [69]. Ranibizumab (Lucentis) is a mAb fragment (Fab) which binds to all isoforms of VEGF-A with high affinity and prevents VEGF-A binding into the VEGFR-1-2 (Fig. 1). Ranibizumab is approved for treatment of "wet" type of AMD [70,71]. Aflibercept (Eylea) and Zivaflibercept (Zaltrap) are initially named as VEGF Trap-eye. Aflibercept and Ziv-aflibercept are synthetic fully humanized fusion proteins composed of the second binding domain of VEGFR-1 and the third binding domain of VEGFR-2, conjugated with the Fc portion of human IgG1. Aflibercept and Ziv-aflibercept act as a soluble decoy VEGF receptors which neutralize VEGF protein and prevents its biological function (Fig. 1) [72]. Aflibercept is used for treatment of neovascular AMD, visual impairment due to diabetic macular edema (DME), and visual impairment due to macular edema secondary to retinal vein occlusion [(RVO), branch and central RVO]. Ziv-aflibercept is used for treatment metastatic colorectal cancer [72,73].

4.1. Monoclonal antibodies (mAbs) Anti-angiogenic mAbs bind to three different kinds of targets including VEGF protein, VEGF decoy receptors, and signaling molecules of VEGF signal transduction pathway. Napoleone Ferrara and colleagues in the Genentech laboratory used the Folkman theory to develop bevacizumab. Bevacizumab is a mAb that inhibits tumor angiogenesis by blocking VEGF-A165 isoform which binds into the VEGFR2 (Fig. 1) [40]. Previous studies show that combinational therapy with anti-angiogenic mAbs and chemotherapy or radiotherapy results is better therapeutic effects as compared with the therapeutic efficacy of each treatment on its own [64,65]. For instance, bevacizumab, the first-line

4.2. MicroRNAs/small interfering RNAs MicroRNAs have significant effects as modulators in angiogenesis animal model studies in vitro [74]. Shusheng Wang and colleagues have tested the effects of miR-126 (miR-126-3p and -5p) in a mouse model of 779

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4.5. Inhibition of angiogenesis by small-molecules

neovascular AMD and found that miR-126 is critical for retinal vascular development. MiR-126 has been also shown to have a dual function in pathological angiogenesis. It has been reported that overexpression of miR-126-5p in ECs promotes angiogenesis, while the silencing of miR126-3p inhibits angiogenesis [75]. Another study in retinal pigment epithelial cells showed that miR-126-3p inhibits angiogenesis by a new mechanism that directly targets the 3′-untranslated region of VEGF-A. This finding reveals that cell-specific function of miR-126 in angiogenesis, depends on the disease condition [75,76]. MiR143/145 cluster have been found to function a tumor suppressors in colon and pancreatic cancer. Preclinical studies have shown that the growth inhibitory effects of miR143/145 result from its binding to the mRNAs of KRAS, ERK5, VEGF, and EGFR, leading to reduction in the expression level of these oncogenic proteins [74,77]. Small interfering RNAs are effective tools for silencing gene expression. Researchers have used poly(ethylene glycol)/polyethylenimine polyelectrolyte complex (PEG/PEI PEC) micelles loaded with VEGF siRNA to target VEGF mRNA for degradation. VEGF siRNA–PEG/PEI PEC micelles are suggested to have a greater stability compared to naked VEGF siRNA against enzymatic degradation. VEGF siRNA–PEG/PEI PEC micelles have found to effectively silence VEGF gene expression in prostate carcinoma cells (PC-3) up to 96.5% under an optimized condition. These studies suggest that VEGF siRNA–PEG/ PEI PEC micelles have a great potential for RNAi-based anti-angiogenic treatment in human malignancies (Fig. 3) [76,78].

Small molecule inhibitors of angiogenesis work by targeting a variety of molecules involved in the process of angiogenesis. Afinitor (everolimus) and torisel (temsirolimus) are two small molecules which act as inhibitors of the mTOR intracellular metabolic pathway. Afinitor (everolimus) and torisel have been found to be effective in down-regulation of angiogenesis in many cancers. Sorafenib (Nexavar) and sunitinib, targeting VEGF and PDGF receptor tyrosine kinases (i.e VEGFR1–3, PDGFRβ, and RET), have been approved by the FDA for the treatment of gastrointestinal stromal tumors (GIST), pancreatic neuroendocrine, and metastatic renal cell cancers (Fig. 1) [86,87]. Sorafenib, have also been approved for hepatocellular cancer [88]. Withaferin A is another compound which shows anti-angiogenic and antitumor activity. While the anti-angiogenic effects of withaferin A are related to the inhibition of chymotrypsin, the induction of apoptosis by this compound is due to the inhibition of protein kinase C. Some studies have reported the activation of caspase-3 by withaferin, which can be another possible mechanism by which withaferin A induces apoptosis [89]. TNP-470, a synthetic analog of the antibiotic fumagillin, is another compound which is believed to exert its anticancer activity through the suppression of cancer angiogenesis. TNP-470 has been shown to bind and irreversibly inactivate methionine aminopeptidase-2 (MetAP2), resulting in ECs cell cycle arrest late in the G1 phase and inhibition of tumor angiogenesis. Another possible mechanism for TNP470 is the induction of p53 pathway, which results in up-regulation of cyclin-dependent kinase inhibitor p21 [90]. Regorafenib is a kinase inhibitor which have been shown to increase the overall survival of patients with metastatic colorectal cancer. Regorafenib, as a multikinase inhibitor, interferes with different kinases involved in the regulation of tumor angiogenesis (VEGFR1, VEGFR2 [KDR], VEGFR3 [FLT4], TIE2 [TEK]), and oncogenesis (KIT, RET, RAF1, BRAF, and BRAFV600E) [91].

4.3. Aptamers Aptamers are oligonucleotide ligands that bind to a specific target with high-affinity [79]. In 1994, for the first time, aptamers against VEGF were isolated and reported as in vitro bioactive molecules [80]. Pegaptanib sodium (Macugen) is an RNA aptamer directed against a VEGF isoform (VEGF-165) which plays a key role in pathological angiogenesis such as neovascular AMD. Pegaptanib, an oligonucleotide with high-affinity binding to VEGF-165, is the first therapeutic aptamer approved in 2004 for the treatment of AMD. Pegaptanib development was carried out by SELEX methodology. F-substituted nucleotides and NH2-substituted nucleotides were applied to reduce the sensitivity of these aptamers to nuclease attack [80,81].

4.6. Angiostatin and endostatin Primary tumors have the potential of stimulating angiogenesis in their own vascular bed and they also can prevent angiogenesis in secondary metastatic lesions [39,92]. Angiostatin and endostatin are circulating factors made up by the primary tumor. Angiostatin and endostatin are anti-angiogenic agents and they are accountable for prevention of distant tumor growth. Endostatin is a cleavage product of collagen XVIII and angiostatin is a cleavage product of plasminogen [42]. Previously published papers have shown that angiostatin and endostatin can function as suppressors of tumor growth and metastases in vivo [93]. Endostatin blocks the binding of VEGF to ECs thereby inhibit their growth and migration, leading to the suppression of tube formation. Direct injection of endostatin mRNA to Xenopus embryos models has been shown to inhibit WTn signaling with B-catenin [94]. Many other studies involving gene transfer of endostatin/angiostatin have also provided evidence for the viability of these therapies as antiangiogenesis therapeutic agents. In one study by Wang Min and colleagues, the injection of formulated genes encoding the secreted form of endostatin to skeletal muscle resulted in the long-term expression and liberation of endostatin into the bloodstream [62,95–97]. Monitoring the blood level of endostatin, indicated sufficient inhibition of angiogenesis at distant sites by a mouse cornea assay. In this study, intramuscular administration of the formulated endostatin gene showed anti-angiogenic activity in both the primary tumors and metastatic growths in murine models [93,98]. A clinical trial used a lentiviral Equine Infectious Anemia Virus (EIAV) vector expressing endostatin and angiostatin (RetinoStat®) for long-term anti-angiogenic activity in Macular Degeneration patient [99].

4.4. Gene therapy Gene therapy introduces genetic materials (DNA or RNA) into the target cells to reprogram their behavior. Benefits of gene therapy, as opposed to other protein-based treatments, include less immunogenicity and more effective penetration into solid tumors [64,82]. The first report of anti-angiogenic gene therapy was published in 1994 when a dominant negative mutant of the VEGF receptor was used to suppress angiogenesis in glioblastoma [83]. Anti-angiogenic gene therapy approaches are aimed at stopping new vessel formation and inactivation of pre-existing ones [84]. A major challenge in the field of gene therapy is sustaining the effect of gene therapy in target cells for a period of time which is long enough for effective treatment of the intended disorder. A study looking at developing a sustained anti-angiogenic effect, used a recombinant adeno-associated virus-2 (rAAV) vector to encode the human soluble FMS-like tyrosine kinase receptor 1 (sFlt-1) for long-term expression without vector-associated immunity or toxicity [85]. Anti-VEGF therapy using rAAV which encodes sFlt-1 system showed significant growth inhibitory activity in human umbilical vein endothelial cell proliferation (HUVEC) in vitro and increased disease-free survival in xenograft models as confirmed by immunohistochemistry and in-situ hybridization analyses. These studies indicate that rAAV-mediated sFlt-1 gene therapy may be a promising approach for inhibiting tumor angiogenesis, particularly as an adjuvant therapy [85]. 780

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PlGF, leading to suppression of angiogenesis. Ziv-aflibercept has been shown to significantly improve the overall survival of metastatic colorectal cancer patients when it is co-administered with Camptosar regimen as compared with those received oxaliplatin or Camptosar regimen alone [115,116]. Ramucirumab has been approved by FDA for administration in metastatic colorectal cancer as the second-line drug which is applied in combination with 5FU, leucovorin, and irinotecan (FOLFIRI) [117]. Helena Verdaguer and et al. have shown that combination of ramucirumab with FOLFIRI regimen boosts overall survival of metastatic colorectal cancer [117]. Ramucirumab combined with docetaxel, has been approved by FDA for treatment of NSCLC patients [118]. Phase III clinical trial studies evaluating the therapeutic efficacy of ramucirumab and docetaxel combinational therapy have shown improved progression-free survival and overall survival in NSCLC patients [118]. Ramucirumab has been approved by FDA for treatment of NSCLC patients, however, severe toxicity has been reported in some patients [118]. Another anti-angiogenic strategy which is showing optimistic results in clinical trials is gene therapy for head and neck cancers [119]. A phase II clinical trial study of endostatin gene therapy using E10 A (a recombinant human endostatin adenovirus), has demonstrated safety and efficacy for patients with advanced head and neck squamous cell carcinoma or nasopharyngeal carcinoma [120]. The high costs of gene therapies is a challenge for large-scale application in clinical settings [119]. CAR-T cells designed to target tumor antigens and VEGFR2 are also being tested in preclinical models [104]. The results of these preclinical studies show that the CAR T-cell therapy targeting VEGFR2 effectively suppresses metastasis in metastatic melanoma and renal animal cancer models [104,121]. CAR-T lymphocytes modified for human VEGFR-1 (V-1 CAR) has shown improved cytotoxic effect on target cells in a VEGFR-1- dependent manner [122].

4.7. Chimeric antigen receptor T cells (CAR-T) cell therapy CAR-T cell therapy is a method of cancer treatment which uses engineered T cells with a complex receptor on their surface to recognize cancer-associated antigens. Recognition of cancer-associated antigens by CAR-T cells results in destruction of cancer cells. CAR-T cell therapy is considered as a personalized medicine approach [100,101]. Scientists at the National Institutes of Health (NIH) have looked at treating cancer with anti-angiogenic CAR-T cells. They have developed CARs that have a high affinity for VEGFR2 which is expressed on both cancer cells and ECs. Therefore anti-VEGFR2 CAR-T cells serve as a dual purpose targeted therapy which targets tumor cells as well as ECs [102]. In this study, the antigen binding domain of the KDR-1121 and DC101 antibodies, that have high-affinity portions for human and mouse VEGFR2 respectively, were used. To prepare anti-VEGFR2 CAR-T cells, the NIH designed antibody construct is joined to the transmembrane and intracellular signaling domains of the T cell receptor (TCR). Indeed the designed CARs associate a high-affinity antibody portion against VEGFR2 with the target cell killing activity of T cells expressing an activated TCR, to provide a more effective anti-cancer therapy. Infusion of these VEGFR2-specific CAR-T cells into cancer patients is considered a novel and powerful immunotherapeutic approach for blocking angiogenesis in cancer through killing tumors cells overexpressing VEGFR2 [103–105]. 5. Clinical and preclinical evidence for the success of antiangiogenic therapy in cancer and other diseases 5.1. Cancer Metastasis accounts for more than 90% of cancer-related mortality. Metastasis is a multistep process that occurs cancer cells detaches from the primary tumor niche and invades to other sites in the body. In metastatic site, cancer cells initiate colonization and usually use preexisting blood vessels to form new tumors. [106,107]. The tumor microenvironment is a complex system with a variety of molecules present in novel concentrations that differ from the physiological norm such as extracellular matrix, macrophages, fibroblasts, stem cells, and ECs. Tumor microenvironment play a critical role in tumor growth and metastasis [108,109]. Given the significance of angiogenesis in cancer progression and metastasis, anti-angiogenic therapy is believed to be a promising strategy for cancer treatment. The main therapeutic goal of anti-angiogenic therapy is to suppress metastasis in high-risk patients and to prevent the recurrence of additional metastases in patients with higher stage cancers. The success of anti-angiogenesis therapy depends on the type of cancer and the stage of cancer at the time of diagnosis. Some studies have shown the better therapeutic efficacy of anti-angiogenic therapy in cancer patients when it is combined with other immunotherapy strategies [109,110]. In Non-Small-Cell Lung cancer patients, administration of bevacizumab in combination with erlotinib, has been shown to result in a better clinical response, as compared with the clinical outcome of monotherapy with each drug alone [111]. Based on the results of clinical trials, erlotinib/bevacizumab has been used as the first-line treatment of cancer patients with EGFR-mutated NSCLC [112]. Anti-VEGF/VEGFR antibodies such as bevacizumab, Ziv-aflibercept, and ramucirumab, are the most common antiangiogenic drugs in the clinical settings [73,113]. While the ultimate goal of antibody-based therapies is similar, there are some difference in the pharmacodynamics and biological effects of therapeutic antibodies in tumor microenvironment [114]. Anti- VEGF/VEGFR antibodies are being used for the treatment of colorectal cancer. In the United States, colorectal cancer accounted for 9% of all cancer mortality in 2012. Bevacizumab is administrated in combination with 5-Fluorouracil (5FU) as the firstline treatment of metastatic colorectal cancer [19,20,110]. Ziv-aflibercept is a VEGF trap fusion protein which binds to VEGF-A, -B and

5.2. Neovascular age-related macular degeneration Anti-angiogenic therapies targeting VEGFA, have been successful in improvement of central vision and eye-catching vision loss in almost 30% and 94% of patients (compared with 62% of sham-treated patients), respectively [30,31]. A study of endostatin gene therapy in AMD rabbit model showed a positive effect on vision after gene therapy. Another study show that while gene therapy with endostatin using lentiviral vectors improved vision in patients with AMD, several injections of gene delivery system were required for achieving the desirable therapeutic effects, most probably due to gene silencing over time [99,123]. Current anti-VEGF therapies, such as ranibizumab and aflibercept, are used as standard treatments for neovascular AMD. Aflibercept and ranibizumab have shown good clinical outcome in treatment of neovascular (‘wet’) AMD, visual impairment due to DME, and macular edema due to retinal vein occlusion (RVO) [124]. Some clinical trial studies have shown that combinational therapy with anti-PDGF-B and anti-VEGFA mAbs results in a significant decrease in choroidal neovascularization in neovascular AMD patients [113]. Other studies have reported that the co-administration of anti-PDGF-B aptamer pegpleranib with ranibizumab in AMD patients improve visual acuity as compared with those received ranibizumab alone [113]. 5.3. Diabetic retinopathy PDR, the advanced form of DR, can be treated using laser photocoagulation, anti-VEGF mAbs, intravitreal (IVT) steroid, and vitrectomy [125]. Intraocular delivery of anti-VEGF drugs is now widely used to treat advanced DR [125]. Some studies have reported vision loss after anti-VEGF therapy in patients with diabetic macular edema. Nevertheless, FDA has approved two anti-VEGF mAbs including aflibercept and ranibizumab for treatment of DR patients [126,127]. Angiopoietin is exalted in patients with PDR as compared with either control group 781

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6. Conclusion

or patients with NPDR [33]. The combination of AKB-9778 (a smallmolecule inhibitor of vascular endothelial protein tyrosine phosphatase that is a negative regulator of Tie2) with ranibizumab added important advantage over monotherapy with ranibizumab, indicated by a significantly greater decrease in diabetic macular edema in patient received combinational therapy in comparison with those received ranibizumab alone [128]. An important advantage of AKB-9778 is ease of use. AKB-9778 is given subcutaneously therefore it can be easily selfadministered by patients [129].

The identification of VEGF–VEGFR system as the main angiogenic modulator, has revolutionized our vision to the field of anti-angiogenic therapy and normal physiology of angiogenesis. The achievements gained by targeting VEGFA with bevacizumab, ranibizumab, and aflibercept in the treatment of cancer and retinopathy, have paved the path for the development of new targeted therapies for angiogenesis-dependent diseases [113,135]. Despite all the progresses made in the development of anti-angiogenic agents, the off-target effects of this agents in the suppression of angiogenesis in healthy tissues remains a major challenge for clinical use of these drugs. An important strategy for overcoming the off-target effects of antiangiogenic agents is targeted delivery of this agents to the diseased tissue. These days with the advances in molecular angiogenesis, novel molecular targets which are overexpressed in diseased tissue (such as integrins and microRNAs) have been identified. Conjugation of antiVEGF agents with targeting moieties specific for molecular targets overexpressed in diseased tissues, is being evaluated in preclinical studies as a strategy to improve the therapeutic efficacy of anti-angiogenesis therapy and reduce their off-target side effects. Another strategy for enhancing the clinical benefits of anti-angiogenic drugs is to optimize the schedule and dosage of combinational therapies included with anti-angiogenic therapy [136]. There is evidence showing that anti-VEGF therapy enhances the anticancer effects of chemotherapy. While the exact mechanism for the synergistic effects of anti-VEGF therapy and chemotherapy is not well known, the vascular remodeling, lower interstitial pressure, and increased blood flow resulted from anti-VEGF therapy are suggested to be the reason behind this potentiating effect [46,136]. Another obstacle to anti-angiogenic therapy is the development of drug resistance in the patients treated with these drugs. Some of the suggested mechanisms for resistance to VEGF-targeted therapies include microenvironment adaptation, tumor heterogeneity and microvascular heterogeneity [137]. Preclinical data showed that some adaptive mechanisms through genetic aberrations (i.e. loss of p53 function), by adapting their metabolism, or by autophagy, all of which reduce dying of certain cancer cells under stress conditions [137]. The identification of specific factors involved in resistance of cancer cells to anti-angiogenic therapy can lead to better planning for treatment of cancer with a combination therapy included with an anti-angiogenic agent and another drug to suppress the key molecules responsible for resistance to anti-angiogenic therapy.

5.4. Anti-angiogenesis therapy in personalized medicine Personalized medicine is a new field aimed at more precise and efficient diagnosis and treatment of human diseases. Personalized medicine requires accurate molecular information concerning with the pathology of human diseases at the DNA, RNA, and protein levels [130,131]. Bio-profiles like proteomics, genomics, and metabolomics, accompanied by other bioinformatics techniques, could be a promising future tool for healthcare system [60]. Precision Medicine started by Human Genome Project that introduced genomic nucleotide sequence of human, followed by the Hap Map project, Encyclopedia of DNA Elements (ENCODE), and the Thousand Genome Project. The aim of these projects is to provide bio-profile databases on different human genomes to map possible differences [60,131]. Personalized medicine can indicate the correct drug for the correct patient at the correct time, so it could significantly enhance the quality of treatment and reduce healthcare costs [130] A growing number of studies show that dysregulation of angiogenesis (the formation of either extravagant or inadequate blood vessels) plays a central role in the pathogenesis of several human diseases including cancer, a number of ocular conditions, certain skin diseases, as well as impaired wound healing [61]. Personalized medicine approaches such as pharmacogenomics base on bio-profile data can identify effective and cost-effective treatments for angiogenesis-associated diseases [132]. Current challenges in anti-angiogenic therapy is the heterogeneous nature of angiogenesis-dependent diseases, predominantly cancer [133,134]. While angiogenesis plays a role in the pathology of angiogenesis-dependent diseases, it is also a natural physiological process that must be kept in balance to ensure the maintenance of homeostasis within the organism. Thus we need to identify biomarkers specific for pathological angiogenesis and develop ligands for targeted treatment which are expected to causes insignificant/no damage to healthy organ. Angiogenesis-dependent diseases such as neovascular AMD and DME patients, require treatment modalities with long-lasting anti-angiogenic effects (such as gene therapy) due to the cost and need for chronic therapy of these diseases. Another main obstacle is how to improve the efficacy of angiogenic targeting. The identification of predictive biomarkers is considered to be a promising approach for development of an effective anti-angiogenesis targeted therapy. Nevertheless, successful targeting of angiogenesis using the identified biomarkers require the deep insight in the molecular mechanisms by which these biomarkers mediate angiogenesis. Moreover characterization of the mechanisms of resistance to anti-angiogenic agents based on bio-profiles data, can reveal additional underlying disease mechanisms in angiogenesis-dependent diseases. Although anti-angiogenic therapies have a significant effect on improvement of cancer patient’s life quality, making a treatment plan based on personal molecular information, refining molecular targeting, incorporating biomarkers, and selecting appropriate combinations with other therapies, can greatly improve the anti-angiogenic therapeutic efficacy in the next decade. While application of new anti-angiogenic therapy such as gene and cell therapy seems to be a promising approach for treatment of angiogenesis-dependent diseases, the cost of such treatment is still a major challenge [113].

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