Biomedicine & Pharmacotherapy 110 (2019) 775–785

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Therapeutic targeting of angiogenesis molecular pathways in angiogenesis- T

dependent diseases
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
b
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

A R T I C LE I N FO A B S T R A C T

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

1. Angiogenesis hypoxia-inducible factor (HIF) act as an angiogenic factor and co-

operates with TNF-α to initiate angiogenesis (Fig. 1).
Angiogenesis is appointed to spreading of new blood-vessel proce- Angiogenesis is triggered by stimulatory angiogenic factors through
dure which plays a central role in human reproduction, organ devel- various mechanisms [10]. VEGF, as the best studied angiogenic growth
opment, wound healing, and tissue repair. Angiogenesis is also a crucial factor, induce mitogenesis and migration in ECs, and promotes
phenomenon in the progression of various human diseases [1–3]. In sprouting of ECs and tube formation [10]. The Ang family of angiogenic
normal physiological condition, angiogenesis is tightly regulated by a growth factors including Ang-1, Ang-2, mouse Ang-3, and human Ang-
complex network of angiogenesis growth factors and cytokines which 4, bind to endothelial receptor tyrosine kinase Tie-2 to promote an-
provoke residental endothelial cells (EC) located in the inner surface of giogenesis [11]. Angs also regulate ECs homeostasis through regulation
vessels as the main site of angiogenesis [4–6]. The angiogenic growth of cell survival, vascular maturation, and vascular stability [11]. While
factors and cytokines include vascular endothelial growth factor VEGF acts at the early stage of angiogenesis to promote formation of
(VEGF), fibroblast growth factors (FGFs), placental growth factor primitive tubular structures, Ang/Tie-2 system function at the later
(PGF), platelet-derived growth factor (PDGF), tumor necrosis factor- stage of angiogenesis and enhances the recruitment of mural cells
alpha (TNF-α), transforming growth factor-beta (TGF-β), angiopoietins (mainly pericytes) and mediates interactions of ECs and pericytes. Ang/
(Angs), epidermal growth factor (EGF), granulocyte-macrophage Tie-2 system also promotes stabilization in new vessels due to formation
colony-stimulating factor/granulocyte colony-stimulating factor (GM- of endothelial tight junctions (Fig. 2) [12]. Pericytes are branched cells
CSF)/ G-CSF), hepatocyte growth factor/scatter factor (HGF/SF), in- elongated around ECs and contribute to vessel maturation through re-
terleukin 8 (IL-8), and erythropoietin (EPO) [6–9] (Fig. 1). Angiogenic lease of angiogenic growth factors which penetrate into basement-
growth factors and cytokines are produced by different types of cells membrane to contacts with ECs [5]. Except to the smallest capillaries,
including endothelial cells, fibroblasts, smooth muscle cells, platelets, angiogenesis is accompanied by the recruitment of smooth muscle cells
inflammatory cells, and cancer cells [10]. Under hypoxia condition, 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: omolavi@ualberta.ca (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/).
A. Fallah et al. Biomedicine & Pharmacotherapy 110 (2019) 775–785

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 rapa-
mycin; PDGF, platelet-derived growth factor; PDGFR, PDGF Receptor.

matrix [13]. TGF-β and PDGF are other angiogenic factors which are network at the subcellular level through ligation to their specific re-
important for the stabilization of new vessels. PDGF is necessary for the ceptors. This network is triggered by RTK and subsequently stimulates
recruitment of smooth muscle cells and pericytes. TGF-β is responsible downstream pathways like Ras/Raf/MAPK, PI3K/Akt/mTOR, and the
for the production of extracellular matrix and the appropriate interac- PKC [19,20]. The details of intracellular singling pathways, the me-
tion between ECs and mural cells [5]. chanism of their activation, and different signaling molecules involved
GM-CSF is another angiogenic factor which plays an important role in signal transduction and function of these pathways has been illu-
in wound healing by promoting angiogenesis [14]. It has been reported strated in Fig. 1.
that GM-CSF enhances VEGF expression, decreases the expression ratio Vasculogenesis and angiogenesis are two main procedures for
of Ang-1/Ang-2, and suppresses the phosphorylation of Tie-2 in the blood-vessel formation. In vasculogenesis which is a developmental
early stages of wound healing leading to the detachment of pericytes process, multipotent mesodermal cells differentiate into angioblasts,
form ECs required for ECs proliferation and migration (Fig. 2) [14,15]. and form ECs. More recent studies have suggested that arterial and
At late stages of wound healing, GM-CSF preserves the high level of venous ECs are derived from different pools of angioblasts which are
VEGF expression while enhancing the expression ratio of Ang-1/Ang-2 originated from mesenchyme (Fig. 2) [5]. In the other hand, angio-
and the phosphorylation of Tie-2, leading to higher pericyte coverage genesis for new vessels is based on pre-existing blood vessels. Angio-
and more integration of the basement membrane which are all required genesis is tightly regulated by molecular pathways of endothelial
for the barrier function of blood vessels [14]. sprouting and non-sprouting microvascular development [21].
FGF1 and FGF2 promote proliferation and physical organization of Endothelial sprouting is a basic sequential multi-step mechanism of
ECs into tube-like structures. Besides, FGF1 and FGF2 induce growth, angiogenesis. In endothelial sprouting, vessel growth is initiated by
differentiation, and survival of blood vessel-associated cells [16]. FGF1 activation of the angiogenic signaling pathways including Notch, Wnt,
plays an important role in induction of angiogenesis in the heart. FGF7, VEGF/VEGFRs, which leads to the morphological remodulation of ECs
KGF2, and FGF10 are keratinocyte growth factors (KGFs) which parti- as stalk cells present in pre-existing blood vessels (Figs. 1,2) [21,22].
cipate in wound healing process [17]. EPO has been also considered as Subsequently activated ECs begin to secret proteases like plasminogen
an angiogenic factor in various studies which have shown the potential activator and matrix metalloproteinase (MMP) to mobilize and recruit
role of EPO in induction of ECs proliferation in normal animals and ECs to the sire of angiogenesis [22]. Sprouts extension is under the
different cancerous tissues. Expression of EPO receptors on ECs support control of adhesion molecules called integrins. As ECs proliferate to-
the notion that EPO is immportant in angiogenesis. It has been also ward surrounding matrix and build microvascular environment, solid
reported that EPO upregulates the expression of VEGF which is a key sprouts provide connections to the neighboring vessels [23]. The se-
regulator of angiogenesis [18]. cretion of growth factors such as VEGF and bFGF accelerate sprouts
Angiogenesis-associated factors establish a complex signaling angiogenesis (Fig. 2). There are other important factors including

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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 micro-
environment. 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 Cancer - infectious diseases - autoimmune disorders

Blood vessels abnormality Vascular malformations - DiGeorge syndrome - HHT- cavernous hemangioma -
atherosclerosis- transplant arteriopathy
Adipose tissue abnormality Obesity - Weight loss by angiogenesis inhibitors
Skin abnormality Psoriasis, warts, allergic dermatitis, scar keloids, pyogenic granulomas, blistering disease, Kaposi sarcoma in AIDS patients
Eye abnormality Persistent hyperplastic vitreous syndrome - diabetic retinopathy- retinopathy of prematurity - choroidal neovascularization
Lung abnormality Primary pulmonary hypertension- asthma - nasal polyps
Intestines abnormality Inflammatory bowel and periodontal disease, ascites, peritoneal adhesions
Reproductive system abnormality Endometriosis- uterine bleeding - ovarian cysts - ovarian hyperstimulation
Bone and joints abnormality Arthritis - synovitis – osteomyelitis - osteophyte formation

PDGF, TGF-β, and Ang-1, that also play a role in sprouts angiogenesis tissue repair, angiogenesis is an important process in the development
[23]. and progress of several human diseases.
Non-sprouting angiogenesis is defined as an intussusceptive angio-
genesis in which pre-existing vessels split into the new vessels by for-
mation of transvacuolar tissue adjoined into the lumen of the vessels 2. Angiogenesis-dependent diseases
[21]. Intussusceptive angiogenesis occur in the zone of contact between
two opposing capillary walls where endothelial cell junction are re- Angiogenesis-dependent diseases were first described in 1971 by
organized as leaky bilayer allowing the penetration of growth factors Judah Folkman who reported that blocking of blood vessel formation in
and cells into the lumen [24]. The leaky contact zone is then filled with tumor cells leads to suppression of cancer cell growth and metastasis.
pericytes and myofibroblasts to build collagen fibers for development of Concurrently, the first treatment of an angiogenesis-dependent pul-
the vessels lumen. Intussusception reorganizes existing cells and in- monary hemangioma by administration of Interferon α-2a, provided
creases the number of capillaries independent of ECs number. During more evidence for the importance of angiogenesis inhibition and its
embryonic development intussusceptive angiogenesis provides avail- potential therapeutic benefits in treatment of neoplasms [25]. Inter-
able microvasculature for new vessel expansion [21,24]. In addition to feron-α is the first anti-angiogenesis agent reported in the 1980s from
the critical role of angiogenesis in reproduction, development, and the Folkman laboratory [1].
Pathological angiogenesis is reported in a range of neovasculature

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diseases which are called angiogenesis-dependent diseases (Table. 1). responsive genes (Fig. 1) [41].
Some of the well-studied angiogenic-dependent diseases are cancer, Plasminogen activators, proteinases, MMPs, and heparanase fa-
neovascular age-related macular degeneration (NVAMD), and diabetic milies are further factors which modulate angiogenesis by degradation
retinopathy (DR). In cancers rapid proliferation of cancerous cells of matrix and activation or secretion of growth factors (bFGF, VEGF,
brings an urgent demand for continuous blood and nutrient supply into and insulin-like growth factor 1), to provide appropriate circumstances
the tumor microenvironment. Cancer angiogenesis plays a key role in for migration of ECs and tumor cells. MMPs mobilize stromal pro-an-
providing nutrient to the rapidly dividing cells and tumor progression. giogenic proteins, cause cleavage of endostatin of collagen 18 in the
Therefore tumor angiogenesis is considered as a promising target for vessel walls, and participate in the cleavage of angiostatin from circu-
cancer targeted therapy [3,26,27]. lating plasminogen to mediate angiogenesis [42,43]. FGF and PDGF
Age-related macular degeneration (AMD) is identified as an age- family present in relatively similar quantities in both tumoral and
dependent degenerative disease. Based on severity, AMD is divided into normal cells (Fig. 2). Mesenchymal or inflammatory cells are recruited
early, intermediate, and late subtypes [28]. The late or advanced AMD by FGF. Unlike normal blood vessels, tumor blood vessels are dilated
is consist of two subtypes including wet (choroidal neovascularization; with an irregular shape. As discussed in the following section, the
angiogenesis-dependent) and dry (geographic atrophy; angiogenesis- vasculature abnormalities of tumor are significantly altered by anti-
independent) [29]. Wet advanced AMD is a neurodegenerative disease angiogenesis agents.
of vision loss [28,29]. Advanced-AMD is reported to affect almost 10 Dysregulation of angiogenesis in cancer results in an abnormal
million people worldwide, and the number of affected individuals with vascular network which not only reduces the therapeutic efficacy of
earlier stages are more than 150 million cases. AMD risk factors are conventional anticancer therapies but can fuel tumor progression [44].
obesity, dietary fat, alcohol consumption, aging, and genetic predis- In tumor microenvironment, the imbalance of angiogenesis promoting
positions [30,31]. factors (e.g., VEGF, bFGF, and Ang-2) and anti-angiogenic factors [e.g.,
DR is described as damaged retina blood vessels due to diabetes thrombospondin-1 (TSP-1) Ang-1], creates hyper-permeable and im-
which is a leading cause of blindness. Based on the disease progression, mature blood vessels [44]. These abnormalities generate a tumor mi-
DR is classified as two subtypes; non-proliferative diabetic retinopathy croenvironment characterized by hypoxia, depleted nutrition, low pH
(NPDR) and proliferative diabetic retinopathy (PDR) [32]. NPDR is and high interstitial pressure [45]. The vasculature abnormalities and
known as the early stage of the disease with mild or nonexistent resultant tumor microenvironment reduce the cytotoxicity of systemi-
symptoms related to blood vessels weakness in the retina such as mi- cally administered anticancer drugs by limiting the accessibility of the
croaneurysms, microhemorrhages, and increased permeability of ret- drugs to cancer cells. Furthermore, a growing number of studies show
inal vessels. In PDR, the advanced form of the disease, pathologic an- that the abnormality of tumor vessels make a great contribution to
giogenesis in addition to some clinical symptoms of NPDR are observed. cancer metastasis, immune evasion, and development of drug-resistant
Pathological angiogenesis in PDR is characterized by field fragile blood cancer cells. Previous studies have shown that the combination of anti-
vessels which demonstrate circulation defects and deprive the eye cells VEGF therapy with chemotherapeutic agents has improved the survival
from oxygen and nutrition’s [32]. In PDR, trapped blood within the of cancer patients that received the combination therapy as compared
vitreous obstruct light path into the retina resulting in specks or cloudy with those treated with chemotherapy alone [46]. In contrast, anti-
vision known the main side effect of diabetes mellitus on vision loss VEGF monotherapy has not shown promising results [46]. These con-
worldwide [33–35]. Tien Y. Wong reported one-third of diabetics to troversial findings are explained by “vascular normalization” hypoth-
have DR and DR is regarded as a microvascular disease [36]. esis which suggests that rather than demolishing vessels, the anti-an-
giogenic therapies revert abnormal structure and function of
3. Cancer and angiogenesis vasculature in tumor cells towards a more normal state [47]. Based on
this hypothesis, anti-VEGF drugs improve the therapeutic efficacy of
Cancer is a serious human health challenge for many decades [37]. chemotherapy by enhancing the accessibility of a tumor to anti-cancer
Recent advances in molecular diagnostic techniques has made it pos- drugs through normalization of blood vessels within the tumor. Pre-
sible to detect and assess cancer biomarkers in blood and urine at very vious studies suggest that anti-VEGF therapy can promote transient
early stage of cancer [1,38]. The identification of differences between vascular normalization by induction of a balance between proangio-
angiogenesis processes in cancer and those found in normal cells, had genic and antiangiogenic factors [44].
led to the identification of specific molecules which are only present Recent studies show that pericytes contribute to tumor progression
and active in cancer angiogenesis and can be used in targeted therapy of by induction of angiogenesis and metastasis process [48]. Initially,
cancer [3]. Senger and colleagues for the first time discovered vascular pericytes were believed to participate in tumor development via an-
permeability factor secreted by a guinea pig tumor cell line. In 1989, giogenesis [49]. New evidences suggest that residential pericytes of
Napoleone, Ferrara, and colleagues reported the isolation of VEGF by tumor microenvironment function as one of the main regulators of
protein sequence analyses and confirmed that VEGF is the same mole- cancer angiogenesis and metastasis. Pericyte cells of tumors indicate
cule as the permeability factor reported earlier. Both in vivo and in vitro more disorderly arrangement, aberrant cell shapes, altered morpholo-
studies have showed that VEGF has a decisive role in both physiological gies, and looser vessel attachment [50]. PDGF-B represents the main
and pathological angiogenesis [39,40]. chemo-attractant for perivascular cells (smooth muscle cells and peri-
HIF is an angiogenetic factor which initiates angiogenesis in re- cytes) in cancer angiogenesis. Pericytes recruited to tumor, release a
sponse to hypoxic shocks (Fig. 1). HIF activates signaling pathways that variety of angiogenic factors including VEGF, Ang-2 and MMP (Fig. 2)
up-regulate VEGF expression. Growth factors, produced by HIF-1 sig- [50]. Recent studies show that during cancer progression, hypoxia can
naling, activate MAPK and AKT signaling pathways leading to the constantly stimulate secretion of VEGF by pericytes via HIF signaling.
elevated level of HIF-1 protein which act as proangiogenic factor pro- Under hypoxic condition, pericytes secret Ang-2 and MMP which cause
moting cancer angiogenesis (Fig. 1). HIF-1 promotes oxygen delivery to destabilization of vessels and increase permeability of the endothelial
hypoxic zones of tumor by upregulating the expression of VEGF and barriers in tumor microenvironment [51].
EPO. HIF-1 protein expression is negatively regulated by Von Hippel-
Lindau protein (pVHL). pVHL is an ubiquitin protease which rapidly 4. Anti-angiogenic therapy
degrades HIF-1α following hypoxia states. Under hypoxic condition,
protein level of HIF-1α is stabilized and HIF-1α gets translocated to the The purpose of anti-angiogenesis therapy in cancer is to block
nucleus where it binds to HIF-1β resulting in the formation of tran- oxygen and nutrient supply into cancer cells. Anti-angiogenesis agents
scriptional complex which in turn induce the transcription of hypoxia- are categorized into seven major groups: a) Monoclonal antibodies

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

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

(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 ther-
apeutics [55]. In personalized medicine, the best treatment based on Fig. 3. Anti-angiogenic therapy mechanism and main clinical and preclinical
the characteristics of disease, specific complexity and variability of factors (red lines) (For interpretation of the references to colour in this figure
tumors is considered. Genetic polymorphisms, the presence of specific legend, the reader is referred to the web version of this article.).
mutations, individual cancer types, their specific metabolic, and he-
modynamic, could directly influence vascular homeostasis. For in- therapy of metastatic colorectal cancer, has been shown to improve
stance, the metastatic colorectal cancer patients with mutations in treatment outcome by 5-flrouracil leucovorin and progression-free
KRAS, NRAS, BRAF, and PIK3CA show poor response to cetuximab, an survival (PFS) in patients with metastatic colorectal cancer as compared
anti-EGFR inhibitor, regardless of high expression of EGFR. Cetuximab with group that received 5-fluorouracil leucovorin alone [66]. Bev-
can be only used for treatment of colon cancer with wild-type KRAS. acizumab has been also used in combination with paclitaxel as a first-
The full genome sequencing of cancer patients is stepping forward to line treatment for adult patients with metastatic breast cancer
personalized medicine. The Cancer Genome Atlas, via whole-genome [19,20,40]. Cetuximab is another commonly used angiogenesis in-
deep sequencing, is revealing that hundreds of coding genes may be hibitor which directly blocks an EGFR-dependent mitogenic pathway
mutated in each cancer type/subtype [56–58]. Diseases that have been and inhibits RAS-ERK pathway. Suppression of RAS-ERK pathway in-
treated more effectively using personalized medicine approaches in- hibits the production of various pr vb -angiogenic factor which utilize
clude cancer, DR, and NVAMD [59,60]. the TGFα/EGFR pathway to markedly upregulate VEGF production and
Angiogenesis molecular mechanisms in a variety of biological pro- tumor angiogenesis [1,39,67,68].
cesses are appealing candidates for targeting in cancer therapy [40]. Ramucirumab is a recombinant human IgG1 mAb that binds to
Anti-angiogenic therapy initially targets micro-vascular ECs within a VEGFR-2 and blocks VEGF-A–stimulated proliferation and migration of
tumor bed, which have been activated by tumor cells. In fact suppres- ECs leading to suppression of tumor angiogenesis and progression
sion of tumor microenvironment ECs responsiveness to angiogenic (Fig. 1) [69]. Ranibizumab (Lucentis) is a mAb fragment (Fab) which
proteins such as endostatin and angiostatins secreted by cancer cells, binds to all isoforms of VEGF-A with high affinity and prevents VEGF-A
can suppress ECs proliferation. Anti-angiogenic therapies targeting binding into the VEGFR-1-2 (Fig. 1). Ranibizumab is approved for
EGFR receptor (using Tarceva) or VEGF by either anti-VEGF mAbs (i.e treatment of "wet" type of AMD [70,71]. Aflibercept (Eylea) and Ziv-
bevacizumab) or VEGF siRNA have been found to exert anticancer ef- aflibercept (Zaltrap) are initially named as VEGF Trap-eye. Aflibercept
fects through induction of cell death in cancer cells) (Fig. 3) and Ziv-aflibercept are synthetic fully humanized fusion proteins
[1,38,42,61,62]. Anti-angiogenic therapies are usually used in combi- composed of the second binding domain of VEGFR-1 and the third
nation with chemotherapy to boost survival rate [63]. binding domain of VEGFR-2, conjugated with the Fc portion of human
IgG1. Aflibercept and Ziv-aflibercept act as a soluble decoy VEGF re-
4.1. Monoclonal antibodies (mAbs) ceptors which neutralize VEGF protein and prevents its biological
function (Fig. 1) [72]. Aflibercept is used for treatment of neovascular
Anti-angiogenic mAbs bind to three different kinds of targets in- AMD, visual impairment due to diabetic macular edema (DME), and
cluding VEGF protein, VEGF decoy receptors, and signaling molecules visual impairment due to macular edema secondary to retinal vein
of VEGF signal transduction pathway. Napoleone Ferrara and collea- occlusion [(RVO), branch and central RVO]. Ziv-aflibercept is used for
gues in the Genentech laboratory used the Folkman theory to develop treatment metastatic colorectal cancer [72,73].
bevacizumab. Bevacizumab is a mAb that inhibits tumor angiogenesis
by blocking VEGF-A165 isoform which binds into the VEGFR2 (Fig. 1) 4.2. MicroRNAs/small interfering RNAs
[40]. Previous studies show that combinational therapy with anti-an-
giogenic mAbs and chemotherapy or radiotherapy results is better MicroRNAs have significant effects as modulators in angiogenesis
therapeutic effects as compared with the therapeutic efficacy of each animal model studies in vitro [74]. Shusheng Wang and colleagues have
treatment on its own [64,65]. For instance, bevacizumab, the first-line tested the effects of miR-126 (miR-126-3p and -5p) in a mouse model of

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neovascular AMD and found that miR-126 is critical for retinal vascular 4.5. Inhibition of angiogenesis by small-molecules
development. MiR-126 has been also shown to have a dual function in
pathological angiogenesis. It has been reported that overexpression of Small molecule inhibitors of angiogenesis work by targeting a
miR-126-5p in ECs promotes angiogenesis, while the silencing of miR- variety of molecules involved in the process of angiogenesis. Afinitor
126-3p inhibits angiogenesis [75]. Another study in retinal pigment (everolimus) and torisel (temsirolimus) are two small molecules which
epithelial cells showed that miR-126-3p inhibits angiogenesis by a new act as inhibitors of the mTOR intracellular metabolic pathway. Afinitor
mechanism that directly targets the 3′-untranslated region of VEGF-A. (everolimus) and torisel have been found to be effective in down-reg-
This finding reveals that cell-specific function of miR-126 in angio- ulation of angiogenesis in many cancers. Sorafenib (Nexavar) and su-
genesis, depends on the disease condition [75,76]. MiR143/145 cluster nitinib, targeting VEGF and PDGF receptor tyrosine kinases (i.e
have been found to function a tumor suppressors in colon and pan- VEGFR1–3, PDGFRβ, and RET), have been approved by the FDA for the
creatic cancer. Preclinical studies have shown that the growth in- treatment of gastrointestinal stromal tumors (GIST), pancreatic neu-
hibitory effects of miR143/145 result from its binding to the mRNAs of roendocrine, and metastatic renal cell cancers (Fig. 1) [86,87]. Sor-
KRAS, ERK5, VEGF, and EGFR, leading to reduction in the expression afenib, have also been approved for hepatocellular cancer [88]. With-
level of these oncogenic proteins [74,77]. aferin A is another compound which shows anti-angiogenic and
Small interfering RNAs are effective tools for silencing gene ex- antitumor activity. While the anti-angiogenic effects of withaferin A are
pression. Researchers have used poly(ethylene glycol)/poly- related to the inhibition of chymotrypsin, the induction of apoptosis by
ethylenimine polyelectrolyte complex (PEG/PEI PEC) micelles loaded this compound is due to the inhibition of protein kinase C. Some studies
with VEGF siRNA to target VEGF mRNA for degradation. VEGF have reported the activation of caspase-3 by withaferin, which can be
siRNA–PEG/PEI PEC micelles are suggested to have a greater stability another possible mechanism by which withaferin A induces apoptosis
compared to naked VEGF siRNA against enzymatic degradation. VEGF [89]. TNP-470, a synthetic analog of the antibiotic fumagillin, is an-
siRNA–PEG/PEI PEC micelles have found to effectively silence VEGF other compound which is believed to exert its anticancer activity
gene expression in prostate carcinoma cells (PC-3) up to 96.5% under through the suppression of cancer angiogenesis. TNP-470 has been
an optimized condition. These studies suggest that VEGF siRNA–PEG/ shown to bind and irreversibly inactivate methionine aminopeptidase-2
PEI PEC micelles have a great potential for RNAi-based anti-angiogenic (MetAP2), resulting in ECs cell cycle arrest late in the G1 phase and
treatment in human malignancies (Fig. 3) [76,78]. inhibition of tumor angiogenesis. Another possible mechanism for TNP-
470 is the induction of p53 pathway, which results in up-regulation of
cyclin-dependent kinase inhibitor p21 [90]. Regorafenib is a kinase
4.3. Aptamers
inhibitor which have been shown to increase the overall survival of
patients with metastatic colorectal cancer. Regorafenib, as a multi-
Aptamers are oligonucleotide ligands that bind to a specific target
kinase inhibitor, interferes with different kinases involved in the reg-
with high-affinity [79]. In 1994, for the first time, aptamers against
ulation of tumor angiogenesis (VEGFR1, VEGFR2 [KDR], VEGFR3
VEGF were isolated and reported as in vitro bioactive molecules [80].
[FLT4], TIE2 [TEK]), and oncogenesis (KIT, RET, RAF1, BRAF, and
Pegaptanib sodium (Macugen) is an RNA aptamer directed against a
BRAFV600E) [91].
VEGF isoform (VEGF-165) which plays a key role in pathological an-
giogenesis such as neovascular AMD. Pegaptanib, an oligonucleotide
with high-affinity binding to VEGF-165, is the first therapeutic aptamer
4.6. Angiostatin and endostatin
approved in 2004 for the treatment of AMD. Pegaptanib development
was carried out by SELEX methodology. F-substituted nucleotides and
Primary tumors have the potential of stimulating angiogenesis in
NH2-substituted nucleotides were applied to reduce the sensitivity of
their own vascular bed and they also can prevent angiogenesis in sec-
these aptamers to nuclease attack [80,81].
ondary metastatic lesions [39,92]. Angiostatin and endostatin are cir-
culating factors made up by the primary tumor. Angiostatin and en-
4.4. Gene therapy dostatin are anti-angiogenic agents and they are accountable for
prevention of distant tumor growth. Endostatin is a cleavage product of
Gene therapy introduces genetic materials (DNA or RNA) into the collagen XVIII and angiostatin is a cleavage product of plasminogen
target cells to reprogram their behavior. Benefits of gene therapy, as [42]. Previously published papers have shown that angiostatin and
opposed to other protein-based treatments, include less im- endostatin can function as suppressors of tumor growth and metastases
munogenicity and more effective penetration into solid tumors [64,82]. in vivo [93]. Endostatin blocks the binding of VEGF to ECs thereby in-
The first report of anti-angiogenic gene therapy was published in 1994 hibit their growth and migration, leading to the suppression of tube
when a dominant negative mutant of the VEGF receptor was used to formation. Direct injection of endostatin mRNA to Xenopus embryos
suppress angiogenesis in glioblastoma [83]. Anti-angiogenic gene models has been shown to inhibit WTn signaling with B-catenin [94].
therapy approaches are aimed at stopping new vessel formation and Many other studies involving gene transfer of endostatin/angiostatin
inactivation of pre-existing ones [84]. A major challenge in the field of have also provided evidence for the viability of these therapies as anti-
gene therapy is sustaining the effect of gene therapy in target cells for a angiogenesis therapeutic agents. In one study by Wang Min and col-
period of time which is long enough for effective treatment of the in- leagues, the injection of formulated genes encoding the secreted form of
tended disorder. A study looking at developing a sustained anti-angio- endostatin to skeletal muscle resulted in the long-term expression and
genic effect, used a recombinant adeno-associated virus-2 (rAAV) liberation of endostatin into the bloodstream [62,95–97]. Monitoring
vector to encode the human soluble FMS-like tyrosine kinase receptor 1 the blood level of endostatin, indicated sufficient inhibition of angio-
(sFlt-1) for long-term expression without vector-associated immunity or genesis at distant sites by a mouse cornea assay. In this study, in-
toxicity [85]. Anti-VEGF therapy using rAAV which encodes sFlt-1 tramuscular administration of the formulated endostatin gene showed
system showed significant growth inhibitory activity in human umbi- anti-angiogenic activity in both the primary tumors and metastatic
lical vein endothelial cell proliferation (HUVEC) in vitro and increased growths in murine models [93,98]. A clinical trial used a lentiviral
disease-free survival in xenograft models as confirmed by im- Equine Infectious Anemia Virus (EIAV) vector expressing endostatin
munohistochemistry and in-situ hybridization analyses. These studies and angiostatin (RetinoStat®) for long-term anti-angiogenic activity in
indicate that rAAV-mediated sFlt-1 gene therapy may be a promising Macular Degeneration patient [99].
approach for inhibiting tumor angiogenesis, particularly as an adjuvant
therapy [85].

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4.7. Chimeric antigen receptor T cells (CAR-T) cell therapy PlGF, leading to suppression of angiogenesis. Ziv-aflibercept has been
shown to significantly improve the overall survival of metastatic col-
CAR-T cell therapy is a method of cancer treatment which uses orectal cancer patients when it is co-administered with Camptosar re-
engineered T cells with a complex receptor on their surface to recognize gimen as compared with those received oxaliplatin or Camptosar re-
cancer-associated antigens. Recognition of cancer-associated antigens gimen alone [115,116]. Ramucirumab has been approved by FDA for
by CAR-T cells results in destruction of cancer cells. CAR-T cell therapy administration in metastatic colorectal cancer as the second-line drug
is considered as a personalized medicine approach [100,101]. Scientists which is applied in combination with 5FU, leucovorin, and irinotecan
at the National Institutes of Health (NIH) have looked at treating cancer (FOLFIRI) [117]. Helena Verdaguer and et al. have shown that com-
with anti-angiogenic CAR-T cells. They have developed CARs that have bination of ramucirumab with FOLFIRI regimen boosts overall survival
a high affinity for VEGFR2 which is expressed on both cancer cells and of metastatic colorectal cancer [117]. Ramucirumab combined with
ECs. Therefore anti-VEGFR2 CAR-T cells serve as a dual purpose tar- docetaxel, has been approved by FDA for treatment of NSCLC patients
geted therapy which targets tumor cells as well as ECs [102]. In this [118]. Phase III clinical trial studies evaluating the therapeutic efficacy
study, the antigen binding domain of the KDR-1121 and DC101 anti- of ramucirumab and docetaxel combinational therapy have shown
bodies, that have high-affinity portions for human and mouse VEGFR2 improved progression-free survival and overall survival in NSCLC pa-
respectively, were used. To prepare anti-VEGFR2 CAR-T cells, the NIH tients [118]. Ramucirumab has been approved by FDA for treatment of
designed antibody construct is joined to the transmembrane and in- NSCLC patients, however, severe toxicity has been reported in some
tracellular signaling domains of the T cell receptor (TCR). Indeed the patients [118].
designed CARs associate a high-affinity antibody portion against Another anti-angiogenic strategy which is showing optimistic re-
VEGFR2 with the target cell killing activity of T cells expressing an sults in clinical trials is gene therapy for head and neck cancers [119]. A
activated TCR, to provide a more effective anti-cancer therapy. Infusion phase II clinical trial study of endostatin gene therapy using E10 A (a
of these VEGFR2-specific CAR-T cells into cancer patients is considered recombinant human endostatin adenovirus), has demonstrated safety
a novel and powerful immunotherapeutic approach for blocking an- and efficacy for patients with advanced head and neck squamous cell
giogenesis in cancer through killing tumors cells overexpressing carcinoma or nasopharyngeal carcinoma [120]. The high costs of gene
VEGFR2 [103–105]. therapies is a challenge for large-scale application in clinical settings
[119]. CAR-T cells designed to target tumor antigens and VEGFR2 are
5. Clinical and preclinical evidence for the success of anti- also being tested in preclinical models [104]. The results of these pre-
angiogenic therapy in cancer and other diseases clinical studies show that the CAR T-cell therapy targeting VEGFR2
effectively suppresses metastasis in metastatic melanoma and renal
5.1. Cancer animal cancer models [104,121]. CAR-T lymphocytes modified for
human VEGFR-1 (V-1 CAR) has shown improved cytotoxic effect on
Metastasis accounts for more than 90% of cancer-related mortality. target cells in a VEGFR-1- dependent manner [122].
Metastasis is a multistep process that occurs cancer cells detaches from
the primary tumor niche and invades to other sites in the body. In 5.2. Neovascular age-related macular degeneration
metastatic site, cancer cells initiate colonization and usually use pre-
existing blood vessels to form new tumors. [106,107]. The tumor mi- Anti-angiogenic therapies targeting VEGFA, have been successful in
croenvironment is a complex system with a variety of molecules present improvement of central vision and eye-catching vision loss in almost
in novel concentrations that differ from the physiological norm such as 30% and 94% of patients (compared with 62% of sham-treated pa-
extracellular matrix, macrophages, fibroblasts, stem cells, and ECs. tients), respectively [30,31]. A study of endostatin gene therapy in
Tumor microenvironment play a critical role in tumor growth and AMD rabbit model showed a positive effect on vision after gene
metastasis [108,109]. Given the significance of angiogenesis in cancer therapy. Another study show that while gene therapy with endostatin
progression and metastasis, anti-angiogenic therapy is believed to be a using lentiviral vectors improved vision in patients with AMD, several
promising strategy for cancer treatment. The main therapeutic goal of injections of gene delivery system were required for achieving the de-
anti-angiogenic therapy is to suppress metastasis in high-risk patients sirable therapeutic effects, most probably due to gene silencing over
and to prevent the recurrence of additional metastases in patients with time [99,123].
higher stage cancers. The success of anti-angiogenesis therapy depends Current anti-VEGF therapies, such as ranibizumab and aflibercept,
on the type of cancer and the stage of cancer at the time of diagnosis. are used as standard treatments for neovascular AMD. Aflibercept and
Some studies have shown the better therapeutic efficacy of anti-an- ranibizumab have shown good clinical outcome in treatment of neo-
giogenic therapy in cancer patients when it is combined with other vascular (‘wet’) AMD, visual impairment due to DME, and macular
immunotherapy strategies [109,110]. In Non-Small-Cell Lung cancer edema due to retinal vein occlusion (RVO) [124]. Some clinical trial
patients, administration of bevacizumab in combination with erlotinib, studies have shown that combinational therapy with anti-PDGF-B and
has been shown to result in a better clinical response, as compared with anti-VEGFA mAbs results in a significant decrease in choroidal neo-
the clinical outcome of monotherapy with each drug alone [111]. Based vascularization in neovascular AMD patients [113]. Other studies have
on the results of clinical trials, erlotinib/bevacizumab has been used as reported that the co-administration of anti-PDGF-B aptamer pegpler-
the first-line treatment of cancer patients with EGFR-mutated NSCLC anib with ranibizumab in AMD patients improve visual acuity as
[112]. compared with those received ranibizumab alone [113].
Anti-VEGF/VEGFR antibodies such as bevacizumab, Ziv-aflibercept,
and ramucirumab, are the most common antiangiogenic drugs in the 5.3. Diabetic retinopathy
clinical settings [73,113]. While the ultimate goal of antibody-based
therapies is similar, there are some difference in the pharmacodynamics PDR, the advanced form of DR, can be treated using laser photo-
and biological effects of therapeutic antibodies in tumor micro- coagulation, anti-VEGF mAbs, intravitreal (IVT) steroid, and vitrectomy
environment [114]. Anti- VEGF/VEGFR antibodies are being used for [125]. Intraocular delivery of anti-VEGF drugs is now widely used to
the treatment of colorectal cancer. In the United States, colorectal treat advanced DR [125]. Some studies have reported vision loss after
cancer accounted for 9% of all cancer mortality in 2012. Bevacizumab anti-VEGF therapy in patients with diabetic macular edema. Never-
is administrated in combination with 5-Fluorouracil (5FU) as the first- theless, FDA has approved two anti-VEGF mAbs including aflibercept
line treatment of metastatic colorectal cancer [19,20,110]. Ziv-afli- and ranibizumab for treatment of DR patients [126,127]. Angiopoietin
bercept is a VEGF trap fusion protein which binds to VEGF-A, -B and is exalted in patients with PDR as compared with either control group

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or patients with NPDR [33]. The combination of AKB-9778 (a small- 6. Conclusion

molecule inhibitor of vascular endothelial protein tyrosine phosphatase
that is a negative regulator of Tie2) with ranibizumab added important The identification of VEGF–VEGFR system as the main angiogenic
advantage over monotherapy with ranibizumab, indicated by a sig- modulator, has revolutionized our vision to the field of anti-angiogenic
nificantly greater decrease in diabetic macular edema in patient re- therapy and normal physiology of angiogenesis. The achievements
ceived combinational therapy in comparison with those received rani- gained by targeting VEGFA with bevacizumab, ranibizumab, and afli-
bizumab alone [128]. An important advantage of AKB-9778 is ease of bercept in the treatment of cancer and retinopathy, have paved the path
use. AKB-9778 is given subcutaneously therefore it can be easily self- for the development of new targeted therapies for angiogenesis-de-
administered by patients [129]. pendent 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
5.4. Anti-angiogenesis therapy in personalized medicine major challenge for clinical use of these drugs.
An important strategy for overcoming the off-target effects of anti-
Personalized medicine is a new field aimed at more precise and angiogenic agents is targeted delivery of this agents to the diseased
efficient diagnosis and treatment of human diseases. Personalized tissue. These days with the advances in molecular angiogenesis, novel
medicine requires accurate molecular information concerning with the molecular targets which are overexpressed in diseased tissue (such as
pathology of human diseases at the DNA, RNA, and protein levels integrins and microRNAs) have been identified. Conjugation of anti-
[130,131]. Bio-profiles like proteomics, genomics, and metabolomics, VEGF agents with targeting moieties specific for molecular targets
accompanied by other bioinformatics techniques, could be a promising overexpressed in diseased tissues, is being evaluated in preclinical
future tool for healthcare system [60]. Precision Medicine started by studies as a strategy to improve the therapeutic efficacy of anti-angio-
Human Genome Project that introduced genomic nucleotide sequence genesis therapy and reduce their off-target side effects.
of human, followed by the Hap Map project, Encyclopedia of DNA Another strategy for enhancing the clinical benefits of anti-angio-
Elements (ENCODE), and the Thousand Genome Project. The aim of genic drugs is to optimize the schedule and dosage of combinational
these projects is to provide bio-profile databases on different human therapies included with anti-angiogenic therapy [136]. There is evi-
genomes to map possible differences [60,131]. Personalized medicine dence showing that anti-VEGF therapy enhances the anticancer effects
can indicate the correct drug for the correct patient at the correct time, of chemotherapy. While the exact mechanism for the synergistic effects
so it could significantly enhance the quality of treatment and reduce of anti-VEGF therapy and chemotherapy is not well known, the vascular
healthcare costs [130] remodeling, lower interstitial pressure, and increased blood flow re-
A growing number of studies show that dysregulation of angio- sulted from anti-VEGF therapy are suggested to be the reason behind
genesis (the formation of either extravagant or inadequate blood ves- this potentiating effect [46,136].
sels) plays a central role in the pathogenesis of several human diseases Another obstacle to anti-angiogenic therapy is the development of
including cancer, a number of ocular conditions, certain skin diseases, drug resistance in the patients treated with these drugs. Some of the
as well as impaired wound healing [61]. Personalized medicine ap- suggested mechanisms for resistance to VEGF-targeted therapies in-
proaches such as pharmacogenomics base on bio-profile data can clude microenvironment adaptation, tumor heterogeneity and micro-
identify effective and cost-effective treatments for angiogenesis-asso- vascular heterogeneity [137]. Preclinical data showed that some
ciated diseases [132]. adaptive mechanisms through genetic aberrations (i.e. loss of p53
Current challenges in anti-angiogenic therapy is the heterogeneous function), by adapting their metabolism, or by autophagy, all of which
nature of angiogenesis-dependent diseases, predominantly cancer reduce dying of certain cancer cells under stress conditions [137]. The
[133,134]. While angiogenesis plays a role in the pathology of angio- identification of specific factors involved in resistance of cancer cells to
genesis-dependent diseases, it is also a natural physiological process anti-angiogenic therapy can lead to better planning for treatment of
that must be kept in balance to ensure the maintenance of homeostasis cancer with a combination therapy included with an anti-angiogenic
within the organism. Thus we need to identify biomarkers specific for agent and another drug to suppress the key molecules responsible for
pathological angiogenesis and develop ligands for targeted treatment resistance to anti-angiogenic therapy.
which are expected to causes insignificant/no damage to healthy organ.
Angiogenesis-dependent diseases such as neovascular AMD and DME References
patients, require treatment modalities with long-lasting anti-angiogenic
effects (such as gene therapy) due to the cost and need for chronic [1] J. Folkman, Angiogenesis: an organizing principle for drug discovery? Nat. Rev.
therapy of these diseases. Another main obstacle is how to improve the Drug Discov. 6 (4) (2007) 273–286.
[2] D. Ribatti, The history of angiogenesis inhibitors, Leukemia 21 (8) (2007) 1606.
efficacy of angiogenic targeting. The identification of predictive bio- [3] M. Potente, T. Mäkinen, Vascular heterogeneity and specialization in development
markers is considered to be a promising approach for development of and disease, Nat. Rev. Mol. Cell Biol. (2017).
an effective anti-angiogenesis targeted therapy. Nevertheless, successful [4] N. Ferrara, R.S. Kerbel, Angiogenesis as a therapeutic target, Nature 438 (7070)
(2005) 967–974.
targeting of angiogenesis using the identified biomarkers require the [5] J. Rouwkema, A. Khademhosseini, Vascularization and angiogenesis in tissue
deep insight in the molecular mechanisms by which these biomarkers engineering: beyond creating static networks, Trends Biotechnol. 34 (9) (2016)
mediate angiogenesis. Moreover characterization of the mechanisms of 733–745.
[6] A. Luttun, M. Tjwa, P. Carmeliet, Placental growth factor (PlGF) and its receptor
resistance to anti-angiogenic agents based on bio-profiles data, can
Flt‐1 (VEGFR‐1), Ann. N. Y. Acad. Sci. 979 (1) (2002) 80–93.
reveal additional underlying disease mechanisms in angiogenesis-de- [7] C. De Vries, J.A. Escobedo, H. Ueno, K. Houck, N. Ferrara, L.T. Williams, The fms-
pendent diseases. like tyrosine kinase, a receptor for vascular endothelial growth factor, Science
(1992) 989–991.
Although anti-angiogenic therapies have a significant effect on im-
[8] F.Z. Shahneh, B. Baradaran, F. Zamani, L. Aghebati-Maleki, Tumor angiogenesis
provement of cancer patient’s life quality, making a treatment plan and anti-angiogenic therapies, Hum. Antibodies 22 (1–2) (2013) 15–19.
based on personal molecular information, refining molecular targeting, [9] D. Ribatti, The discovery of angiogenic growth factors: the contribution of Italian
incorporating biomarkers, and selecting appropriate combinations with scientists, . 6 (1) (2014) 8.
[10] A.A. Ucuzian, A.A. Gassman, A.T. East, H.P. Greisler, Molecular mediators of an-
other therapies, can greatly improve the anti-angiogenic therapeutic giogenesis, J. Burn Care Res. 31 (1) (2010) 158–175.
efficacy in the next decade. While application of new anti-angiogenic [11] E. Fagiani, G. Christofori, Angiopoietins in angiogenesis, Cancer Lett. 328 (1)
therapy such as gene and cell therapy seems to be a promising approach (2013) 18–26.
[12] H.G. Augustin, G.Y. Koh, G. Thurston, K. Alitalo, Control of vascular morpho-
for treatment of angiogenesis-dependent diseases, the cost of such genesis and homeostasis through the angiopoietin–tie system, Nat. Rev. Mol. Cell
treatment is still a major challenge [113].

782
A. Fallah et al. Biomedicine & Pharmacotherapy 110 (2019) 775–785

Biol. 10 (3) (2009) 165. [46] I.F. Nerini, M. Cesca, F. Bizzaro, R. Giavazzi, Combination therapy in cancer: ef-
[13] M. De Palma, D. Biziato, T.V. Petrova, Microenvironmental regulation of tumour fects of angiogenesis inhibitors on drug pharmacokinetics and pharmacodynamics,
angiogenesis, Nat. Rev. Cancer 17 (8) (2017) 457. Chin. J. Cancer 35 (1) (2016) 61.
[14] J. Zhao, L. Chen, B. Shu, J. Tang, L. Zhang, J. Xie, S. Qi, Y. Xu, Granulocyte/ [47] S. Goel, A.H.-K. Wong, R.K. Jain, Vascular normalization as a therapeutic strategy
macrophage colony-stimulating factor influences angiogenesis by regulating the for malignant and nonmalignant disease, Cold Spring Harb. Perspect. Med. 2 (3)
coordinated expression of VEGF and the Ang/Tie system, PLoS One 9 (3) (2014) (2012) a006486.
e92691. [48] K. Hosaka, Y. Yang, T. Seki, C. Fischer, O. Dubey, E. Fredlund, J. Hartman,
[15] V. Siavashi, R. Sariri, S.M. Nassiri, M. Esmaeilivand, S. Asadian, H. Cheraghi, P. Religa, H. Morikawa, Y. Ishii, Pericyte–fibroblast transition promotes tumor
M. Barekati-Mowahed, R. Rahbarghazi, Angiogenic activity of endothelial pro- growth and metastasis, Proc. Natl. Acad. Sci. 113 (38) (2016) E5618–E5627.
genitor cells through angiopoietin-1 and angiopoietin-2, Anim. Cells Syst. 20 (3) [49] J. Lu, A.K. Shenoy, Epithelial-to-pericyte transition in cancer, Cancers 9 (7)
(2016) 118–129. (2017) 77.
[16] C.M. Teven, E.M. Farina, J. Rivas, R.R. Reid, Fibroblast growth factor (FGF) sig- [50] D. Ferland-McCollough, S. Slater, J. Richard, C. Reni, G. Mangialardi, Pericytes, an
naling in development and skeletal diseases, Genes Dis. 1 (2) (2014) 199–213. overlooked player in vascular pathobiology, Pharmacol. Ther. 171 (2017) 30–42.
[17] Y.-R. Yun, J.E. Won, E. Jeon, S. Lee, W. Kang, H. Jo, J.-H. Jang, U.S. Shin, H.- [51] Z. Chen, X. Xu, J. Hu, Role of pericytes in angiogenesis: focus on cancer angio-
W. Kim, Fibroblast growth factors: biology, function, and application for tissue genesis and anti-angiogenic therapy, Neoplasma 63 (2) (2016) 173–182.
regeneration, J. Tissue Eng. 1 (1) (2010) 218142. [52] A.M. Abdalla, L. Xiao, M.W. Ullah, M. Yu, C. Ouyang, G. Yang, Current challenges
[18] P. Kimáková, P. Solár, Z. Solárová, R. Komel, N. Debeljak, Erythropoietin and its of cancer anti-angiogenic therapy and the promise of nanotherapeutics,
angiogenic activity, Int. J. Mol. Sci. 18 (7) (2017) 1519. Theranostics 8 (2) (2018) 533.
[19] N. Ferrara, VEGF and intraocular neovascularization: from discovery to therapy, [53] B. Leader, Q.J. Baca, D.E. Golan, Protein therapeutics: a summary and pharma-
Transl. Vis. Sci. Technol. 5 (2) (2016) 10. cological classification, Nat. Rev. Drug Discov. 7 (1) (2008) 21–39.
[20] N. Ferrara, L. Damico, N. Shams, H. Lowman, R. Kim, Development of ranibi- [54] J.R. Ohlfest, Z.L. Demorest, Y. Motooka, I. Vengco, S. Oh, E. Chen,
zumab, an anti–vascular endothelial growth factor antigen binding fragment, as F.A. Scappaticci, R.J. Saplis, S.C. Ekker, W.C. Low, Combinatorial antiangiogenic
therapy for neovascular age-related macular degeneration, Retina 26 (8) (2006) gene therapy by nonviral gene transfer using the sleeping beauty transposon
859–870. causes tumor regression and improves survival in mice bearing intracranial human
[21] F. Hillen, A.W. Griffioen, Tumour vascularization: sprouting angiogenesis and glioblastoma, Mol. Ther. 12 (5) (2005) 778–788.
beyond, Cancer Metastasis Rev. 26 (3-4) (2007) 489–502. [55] J.S. de BONO, A. Ashworth, Translating cancer research into targeted ther-
[22] D. Ribatti, E. Crivellato, “Sprouting angiogenesis”, a reappraisal, Dev. Biol. 372 (2) apeutics, Nature 467 (7315) (2010) 543.
(2012) 157–165. [56] M. De Palma, D. Hanahan, The biology of personalized cancer medicine: facing
[23] K.-A. Norton, A.S. Popel, Effects of endothelial cell proliferation and migration individual complexities underlying hallmark capabilities, Mol. Oncol. 6 (2) (2012)
rates in a computational model of sprouting angiogenesis, Sci. Rep. 6 (2016). 111–127.
[24] S.J. Mentzer, M.A. Konerding, Intussusceptive angiogenesis: expansion and re- [57] A.A. Mangoni, R.J. Woodman, G. Kichenadasse, A. Rowland, M.J. Sorich, Anti-
modeling of microvascular networks, Angiogenesis 17 (3) (2014) 499–509. VEGF-Induced Hypertension and Cancer Outcomes: Translating Research Into
[25] K. Kimura, T. Hashiguchi, T. Deguchi, S. Horinouchi, T. Uto, H. Oku, S. Setoyama, Clinical Practice, Taylor & Francis, 2016.
I. Maruyama, M. Osame, K. Arimura, Serum VEGF—as a prognostic factor of [58] S. Tabchi, N. Blais, Antiangiogenesis for advanced non-small-cell lung cancer in
atherosclerosis, Atherosclerosis 194 (1) (2007) 182–188. the era of immunotherapy and personalized medicine, Front. Oncol. 7 (2017).
[26] R.S. Kerbel, Tumor angiogenesis, N. Engl. J. Med. 358 (19) (2008) 2039–2049. [59] K. Pavelić, T. Martinović, S.K. Pavelić, Do we understand the personalized medi-
[27] S.M. Weis, D.A. Cheresh, Tumor angiogenesis: molecular pathways and ther- cine paradigm? EMBO Rep. 16 (2) (2015) 133–136.
apeutic targets, Nat. Med. 17 (11) (2011) 1359–1370. [60] D.E. Pritchard, F. Moeckel, M.S. Villa, L.T. Housman, C.A. McCarty, H.L. McLeod,
[28] F. Bandello, R. Sacconi, L. Querques, E. Corbelli, M.V. Cicinelli, G. Querques, Strategies for integrating personalized medicine into healthcare practice, Per.
Recent advances in the management of dry age-related macular degeneration: a Med. 14 (2) (2017) 141–152.
review, F1000Research 6 (2017). [61] P. Carmeliet, Angiogenesis in life, disease and medicine, Nature 438 (7070) (2005)
[29] J. Ambati, B.J. Fowler, Mechanisms of age-related macular degeneration, Neuron 932–936.
75 (1) (2012) 26–39. [62] W. Luo, Y. Shih, W. Lo, H. Chen, S. Wang, C. Wang, C. Chien, C. Chiang,
[30] A.G. Consortium, Seven new loci associated with age-related macular degenera- Y. Chuang, Y. Hu, Baculovirus vectors for antiangiogenesis-based cancer gene
tion, Nat. Genet. 45 (4) (2013) 433–439. therapy, Cancer Gene Ther. 18 (9) (2011) 637–645.
[31] S.L. Doyle, M. Campbell, E. Ozaki, R.G. Salomon, A. Mori, P.F. Kenna, G.J. Farrar, [63] F. Fleetwood, S. Klint, M. Hanze, E. Gunneriusson, F.Y. Frejd, S. Ståhl, J. Löfblom,
A.-S. Kiang, M.M. Humphries, E.C. Lavelle, NLRP3 has a protective role in age- Simultaneous targeting of two ligand-binding sites on VEGFR2 using biparatopic
related macular degeneration through the induction of IL-18 by drusen compo- Affibody molecules results in dramatically improved affinity, Sci. Rep. 4 (2014).
nents, Nat. Med. 18 (5) (2012) 791–798. [64] Q. Zhang, G. Chen, X. Liu, Q. Qian, Monoclonal antibodies as therapeutic agents in
[32] E.J. Duh, J.K. Sun, A.W. Stitt, Diabetic retinopathy: current understanding, me- oncology and antibody gene therapy, Cell Res. 17 (2) (2007) 89–99.
chanisms, and treatment strategies, JCI Insight 2 (14) (2017). [65] G. Niu, X. Chen, Vascular endothelial growth factor as an anti-angiogenic target
[33] M.T. Bolinger, D.A. Antonetti, Moving past anti-VEGF: novel therapies for treating for cancer therapy, Curr. Drug Targets 11 (8) (2010) 1000–1017.
diabetic retinopathy, Int. J. Mol. Sci. 17 (9) (2016) 1498. [66] J.W. Zinser-Sierra, S. Rodríguez-Ramírez, R. Villalobos-Valencia, M. Ramírez-
[34] R. Gale, P.H. Scanlon, M. Evans, F. Ghanchi, Y. Yang, G. Silvestri, M. Freeman, Márquez, Use of Bevacizumab in metastatic colorectal cancer, Drugs R & D 11 (2)
A. Maisey, J. Napier, Action on diabetic macular oedema: achieving optimal pa- (2011) 101–111.
tient management in treating visual impairment due to diabetic eye disease, Eye [67] L.M. Weiner, R. Surana, S. Wang, Monoclonal antibodies: versatile platforms for
31 (2017) S1–S20. cancer immunotherapy, Nat. Rev. Immunol. 10 (5) (2010) 317–327.
[35] S.Z. Safi, R. Qvist, S. Kumar, K. Batumalaie, I.S.B. Ismail, Molecular mechanisms of [68] C. Pozzi, A. Cuomo, I. Spadoni, E. Magni, A. Silvola, A. Conte, S. Sigismund,
diabetic retinopathy, general preventive strategies, and novel therapeutic targets, P.S. Ravenda, T. Bonaldi, M.G. Zampino, The EGFR-specific antibody cetuximab
Biomed Res. Int. 2014 (2014). combined with chemotherapy triggers immunogenic cell death, Nat. Med. 22 (6)
[36] T. Curtis, T. Gardiner, A. Stitt, Microvascular lesions of diabetic retinopathy: clues (2016) 624–631.
towards understanding pathogenesis? Eye 23 (7) (2009) 1496–1508. [69] A.D. Singh, S. Parmar, Ramucirumab (Cyramza): a breakthrough treatment for
[37] S. Committee, Cancer progress report, Clin. Cancer Res. 21 (19 Suppl) (2015) S1. gastric cancer, Pharm. Therapeut. 40 (7) (2015) 430.
[38] O. Benny, O. Fainaru, A. Adini, F. Cassiola, L. Bazinet, I. Adini, E. Pravda, [70] J. Li, Z. Zhu, Research and development of next generation of antibody-based
Y. Nahmias, S. Koirala, G. Corfas, An orally delivered small-molecule formulation therapeutics, Acta Pharmacol. Sin. 31 (9) (2010) 1198–1207.
with antiangiogenic and anticancer activity, Nat. Biotechnol. 26 (7) (2008) [71] M. Tolentino, Systemic and ocular safety of intravitreal anti-VEGF therapies for
799–807. ocular neovascular disease, Surv. Ophthalmol. 56 (2) (2011) 95–113.
[39] J. Folkman, Tumor angiogenesis: therapeutic implications, N. Engl. J. Med. 285 [72] C. Balaratnasingam, E. Dhrami-Gavazi, J.T. McCann, Q. Ghadiali, K.B. Freund,
(21) (1971) 1182–1186. Aflibercept: a review of its use in the treatment of choroidal neovascularization
[40] N. Ferrara, K.J. Hillan, H.-P. Gerber, W. Novotny, Discovery and development of due to age-related macular degeneration, Clin. Ophthalmol. (Auckland, NZ) 9
bevacizumab, an anti-VEGF antibody for treating cancer, Nat. Rev. Drug Discov. 3 (2015) 2355.
(5) (2004) 391–400. [73] S.C. Stanel, J. Sjöberg, T. Salmonson, P. Foggi, M. Caleno, D. Melchiorri,
[41] G.N. Masoud, W. Li, HIF-1α pathway: role, regulation and intervention for cancer I. Gravanis, K. Tzogani, F. Pignatti, European Medicines Agency approval sum-
therapy, Acta Pharm. Sin. B 5 (5) (2015) 378–389. mary: zaltrap for the treatment of patients with oxaliplatin-resistant metastatic
[42] M.S. O’Reilly, T. Boehm, Y. Shing, N. Fukai, G. Vasios, W.S. Lane, E. Flynn, colorectal cancer, ESMO Open 2 (2) (2017) e000190.
J.R. Birkhead, B.R. Olsen, J. Folkman, Endostatin: an endogenous inhibitor of [74] R. Rupaimoole, F.J. Slack, MicroRNA therapeutics: towards a new era for the
angiogenesis and tumor growth, Cell 88 (2) (1997) 277–285. management of cancer and other diseases, Nat. Rev. Drug Discov. 16 (3) (2017)
[43] Z. Shen, C. Yao, Z. Wang, L. Yue, Z. Fang, H. Yao, F. Lin, H. Zhao, Y.-J. Sun, X.- 203–222.
w. Bian, Vastatin, an endogenous antiangiogenesis polypeptide that is lost in he- [75] Q. Zhou, C. Anderson, J. Hanus, F. Zhao, J. Ma, A. Yoshimura, S. Wang, Strand and
patocellular carcinoma, effectively inhibits tumor metastasis, Mol. Ther. 24 (8) cell type-specific function of microRNA-126 in angiogenesis, Mol. Ther. 24 (10)
(2016) 1358–1368. (2016) 1823–1835.
[44] S. Goel, D.G. Duda, L. Xu, L.L. Munn, Y. Boucher, D. Fukumura, R.K. Jain, [76] N. Laham-Karam, M. Lalli, N. Leinonen, S. Ylä-Herttuala, Differential regulation of
Normalization of the vasculature for treatment of cancer and other diseases, vascular endothelial growth factors by promoter-targeted shRNAs, Mol. Ther.-
Physiol. Rev. 91 (3) (2011) 1071–1121. Nucleic Acids 4 (2015) e243.
[45] K. Eales, K. Hollinshead, D. Tennant, Hypoxia and metabolic adaptation of cancer [77] J.R. van Beijnum, E. Giovannetti, D. Poel, P. Nowak-Sliwinska, A.W. Griffioen,
cells, Oncogenesis 5 (1) (2016) e190. miRNAs: micro-managers of anticancer combination therapies, Angiogenesis

783
A. Fallah et al. Biomedicine & Pharmacotherapy 110 (2019) 775–785

(2017) 1–17. cell therapy of solid tumors, Immunol. Cell Biol. (2016).
[78] S.H. Kim, J.H. Jeong, S.H. Lee, S.W. Kim, T.G. Park, PEG conjugated VEGF siRNA [106] P.S. Steeg, Targeting metastasis, Nat. Rev. Cancer 16 (4) (2016) 201–218.
for anti-angiogenic gene therapy, J. Control. Release 116 (2) (2006) 123–129. [107] Y. Kubota, Tumor angiogenesis and anti-angiogenic therapy, Keio J. Med. 61 (2)
[79] N. Alizadeh, M.Y. Memar, S.R. Moaddab, H.S. Kafil, Aptamer-assisted novel (2012) 47–56.
technologies for detecting bacterial pathogens, Biomed. Pharmacother. 93 (2017) [108] N.S. Vasudev, A.R. Reynolds, Anti-angiogenic therapy for cancer: current progress,
737–745. unresolved questions and future directions, Angiogenesis 17 (3) (2014) 471–494.
[80] E.W. Ng, D.T. Shima, P. Calias, E.T. Cunningham, D.R. Guyer, A.P. Adamis, [109] L.M. Ellis, D.J. Hicklin, VEGF-targeted therapy: mechanisms of anti-tumour ac-
Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease, Nat. Rev. tivity, Nat. Rev. Cancer 8 (8) (2008) 579–591.
Drug Discov. 5 (2) (2006) 123–132. [110] G. Ranieri, R. Patruno, E. Ruggieri, S. Montemurro, P. Valerio, D. Ribatti, Vascular
[81] C.A. Trujillo, A.A. Nery, J.M. Alves, A.H. Martins, H. Ulrich, Development of the endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the
anti-VEGF aptamer to a therapeutic agent for clinical ophthalmology, Clin. biology to the clinic, Curr. Med. Chem. 13 (16) (2006) 1845–1857.
Ophthalmol. 1 (4) (2007) 393–402. [111] R.S. Herbst, V.J. O’Neill, L. Fehrenbacher, C.P. Belani, P.D. Bonomi, L. Hart,
[82] L. Sanz, B. Blanco, L. Alvarez-Vallina, Antibodies and gene therapy: teaching old O. Melnyk, D. Ramies, M. Lin, A. Sandler, Phase II study of efficacy and safety of
‘magic bullets’ new tricks, Trends Immunol. 25 (2) (2004) 85–91. bevacizumab in combination with chemotherapy or erlotinib compared with
[83] B. Millauer, L.K. Shawver, K.H. Plate, W. Risaui, A. Ullrich, Glioblastoma growth chemotherapy alone for treatment of recurrent or refractory non–small-cell lung
inhibited in vivo by a dominant-negative Flk-1 mutant, Nature 367 (1994) 576. cancer, J. Clin. Oncol. 25 (30) (2007) 4743–4750.
[84] I. Guijarro-Munoz, M. Compte, L. Alvarez-Vallina, L. Sanz, Antibody gene therapy: [112] Y.-L. Wu, EGFR as a pharmacological target in EGFR-mutant non-small-cell lung
getting closer to clinical application? Curr. Gene Ther. 13 (4) (2013) 282–290. cancer: where do we stand now? Trends Pharmacol. Sci. 37 (11) (2016) 887–903.
[85] G. Mahendra, S. Kumar, T. Isayeva, P.J. Mahasreshti, D.T. Curiel, C.R. Stockardt, [113] N. Ferrara, A.P. Adamis, Ten years of anti-vascular endothelial growth factor
W.E. Grizzle, V. Alapati, R. Singh, G.P. Siegal, Antiangiogenic cancer gene therapy therapy, Nat. Rev. Drug Discov. 15 (6) (2016) 385–404.
by adeno-associated virus 2-mediated stable expression of the soluble FMS-like [114] J. Clarke, H. Hurwitz, F. Rangwala, Understanding the mechanisms of action of
tyrosine kinase-1 receptor, Cancer Gene Ther. 12 (1) (2005) 26–34. antiangiogenic agents in metastatic colorectal cancer: a clinician’s perspective,
[86] B. Al‐Husein, M. Abdalla, M. Trepte, D.L. DeRemer, P.R. Somanath, Cancer Treat. Rev. 40 (9) (2014) 1065–1072.
Antiangiogenic therapy for cancer: an update, Pharmacotherapy 32 (12) (2012) [115] J. Tabernero, E. Van Cutsem, R. Lakomý, J. Prausová, P. Ruff, G.A. van Hazel,
1095–1111. V.M. Moiseyenko, D.R. Ferry, J.J. McKendrick, K. Soussan-Lazard, Aflibercept
[87] P. Saharinen, L. Eklund, K. Pulkki, P. Bono, K. Alitalo, VEGF and angiopoietin versus placebo in combination with fluorouracil, leucovorin and irinotecan in the
signaling in tumor angiogenesis and metastasis, Trends Mol. Med. 17 (7) (2011) treatment of previously treated metastatic colorectal cancer: prespecified sub-
347–362. group analyses from the VELOUR trial, Eur. J. Cancer 50 (2) (2014) 320–331.
[88] E.A. Kuczynski, R.S. Kerbel, Implications of vessel co-option in sorafenib-resistant [116] G. Folprecht, C. Pericay, M.P. Saunders, A. Thomas, R. Lopez Lopez, J. Roh,
hepatocellular carcinoma, Chin. J. Cancer 35 (2016) 97. V. Chistyakov, T. Höhler, J.-S. Kim, R.-D. Hofheinz, Oxaliplatin and 5-FU/folinic
[89] H. Yang, Y. Wang, V.T. Cheryan, W. Wu, C.Q. Cui, L.A. Polin, H.I. Pass, Q.P. Dou, acid (modified FOLFOX6) with or without aflibercept in first-line treatment of
A.K. Rishi, A. Wali, Withaferin a inhibits the proteasome activity in mesothelioma patients with metastatic colorectal cancer: the AFFIRM study, Ann. Oncol. 27 (7)
in vitro and in vivo, PLoS One 7 (8) (2012) e41214. (2016) 1273–1279.
[90] Y. Zhang, E.C. Griffith, J. Sage, T. Jacks, J.O. Liu, Cell cycle inhibition by the anti- [117] H. Verdaguer, J. Tabernero, T. Macarulla, Ramucirumab in metastatic colorectal
angiogenic agent TNP-470 is mediated by p53 and p21WAF1/CIP1, Proc. Natl. cancer: evidence to date and place in therapy, Ther. Adv. Med. Oncol. 8 (3) (2016)
Acad. Sci. 97 (12) (2000) 6427–6432. 230–242.
[91] A. Grothey, E. Van Cutsem, A. Sobrero, S. Siena, A. Falcone, M. Ychou, [118] O. Arrieta, Z.L. Zatarain-Barrón, A.F. Cardona, A. Carmona, M. Lopez-Mejia,
Y. Humblet, O. Bouché, L. Mineur, C. Barone, Regorafenib monotherapy for pre- Ramucirumab in the treatment of non-small cell lung cancer, Expert Opin. Drug
viously treated metastatic colorectal cancer (CORRECT): an international, multi- Saf. 16 (5) (2017) 637–644.
centre, randomised, placebo-controlled, phase 3 trial, Lancet 381 (9863) (2013) [119] H. Deng, Y. Wang, Q. Ding, D. Li, Y.-q. Wei, Gene therapy research in Asia, Gene
303–312. Ther. 24 (9) (2017) 572–577.
[92] U. Folkman, R. Kalluri, Beginning of Angiogenesis Research, Holland-frei Cancer [120] W. Ye, R. Liu, C. Pan, W. Jiang, L. Zhang, Z. Guan, J. Wu, X. Ying, L. Li, S. Li,
Medicine, (2003). Multicenter randomized phase 2 clinical trial of a recombinant human endostatin
[93] R.C. Murthy, T.J. McFarland, J. Yoken, S. Chen, C. Barone, D. Burke, Y. Zhang, adenovirus in patients with advanced head and neck carcinoma, Mol. Ther. 22 (6)
B. Appukuttan, J.T. Stout, Corneal transduction to inhibit angiogenesis and graft (2014) 1221–1229.
failure, Invest. Ophthalmol. Vis. Sci. 44 (5) (2003) 1837–1842. [121] J. Xu, K. Tian, H. Zhang, L. Li, H. Liu, J. Liu, Q. Zhang, J. Zheng, Chimeric antigen
[94] J.-i. Hanai, J. Gloy, S.A. Karumanchi, S. Kale, J. Tang, G. Hu, B. Chan, receptor-T cell therapy for solid tumors require new clinical regimens, Expert Rev.
R. Ramchandran, V. Jha, V.P. Sukhatme, Endostatin is a potential inhibitor of Wnt Anticancer Ther. (2017) (just-accepted).
signaling, J. Cell Biol. 158 (3) (2002) 529–539. [122] W. Wang, Y. Ma, J. Li, H. Shi, L. Wang, F. Guo, J. Zhang, D. Li, B. Mo, F. Wen,
[95] X.-Y. Wen, Y. Bai, A.K. Stewart, Adenovirus-mediated human endostatin gene Specificity redirection by CAR with human VEGFR-1 affinity endows T lympho-
delivery demonstrates strain-specific antitumor activity and acute dose-dependent cytes with tumor-killing ability and anti-angiogenic potency, Gene Ther. 20 (10)
toxicity in mice, Hum. Gene Ther. 12 (4) (2001) 347–358. (2013) 970–978.
[96] C.-H. Kuo, B.-I. Chang, F.-T. Lee, P.-K. Chen, J.-S. Lee, G.-Y. Shi, H.-L. Wu, [123] M. Parker, J. Bellec, T. McFarland, V. Scripps, B. Appukuttan, M. Hartzell,
Development of recombinant adeno-associated virus serotype 2/8 carrying kringle A. Yeager, T. Hady, K.A. Mitrophanous, T. Stout, Suppression of neovasculariza-
domains of human plasminogen for sustained expression and cancer therapy, tion of donor corneas by transduction with equine infectious anemia virus-based
Hum. Gene Ther. 26 (9) (2015) 603–613. lentiviral vectors expressing endostatin and angiostatin, Hum. Gene Ther. 25 (5)
[97] A.L. Feldman, H.R. Alexander, S.M. Hewitt, D. Lorang, C.E. Thiruvathukal, (2014) 408–418.
E.M. Turner, S.K. Libutti, Effect of retroviral endostatin gene transfer on sub- [124] H. Almuhtaseb, S. Kanavati, S. Rufai, A. Lotery, One-year real-world outcomes in
cutaneous and intraperitoneal growth of murine tumors, J. Natl. Cancer Inst. 93 patients receiving fixed-dosing aflibercept for neovascular age-related macular
(13) (2001) 1014–1020. degeneration, Eye 31 (6) (2017) 878–883.
[98] P. Blezinger, J. Wang, M. Gondo, A. Quezada, D. Mehrens, M. French, A. Singhal, [125] J. Nirmal, K. Radhakrishnan, M. Moreno, J.V. Natarajan, A. Laude, T.H. Lim,
S. Sullivan, A. Rolland, R. Ralston, Systemic inhibition of tumor growth and tumor S. Venkatraman, R. Agrawal, Drug, delivery and devices for diabetic retinopathy
metastases by intramuscular administration of the endostatin gene, Nat. (3Ds in DR), Expert Opin. Drug Deliv. 13 (11) (2016) 1625–1637.
Biotechnol. 17 (4) (1999) 343–348. [126] F. Semeraro, F. Morescalchi, S. Duse, F. Parmeggiani, E. Gambicorti,
[99] P.A. Campochiaro, A.K. Lauer, E.H. Sohn, T.A. Mir, S. Naylor, M.C. Anderton, C. Costagliola, Aflibercept in wet AMD: specific role and optimal use, Drug Des.
M. Kelleher, R. Harrop, S. Ellis, K.A. Mitrophanous, Lentiviral vector gene transfer Devel. Ther. 7 (2013) 711–722.
of endostatin/angiostatin for macular degeneration (GEM) study, Hum. Gene [127] J. Lee, K.E. Kim, D.-K. Choi, J.Y. Jang, J.-J. Jung, H. Kiyonari, G. Shioi, W. Chang,
Ther. 28 (1) (2017) 99–111. T. Suda, N. Mochizuki, Angiopoietin-1 guides directional angiogenesis through
[100] A.J. Smith, J. Oertle, D. Warren, D. Prato, Chimeric antigen receptor (CAR) T cell integrin α v β 5 signaling for recovery of ischemic retinopathy, Sci. Transl. Med. 5
therapy for malignant cancers: summary and perspective, J. Cell. Immunother. 2 (203) (2013) 203ra127-203ra127.
(2) (2016) 59–68. [128] P.A. Campochiaro, A. Khanani, M. Singer, S. Patel, D. Boyer, P. Dugel, S. Kherani,
[101] H.-h. Sha, D.-d. Wang, D.-l. Yan, Y. Hu, S.-j. Yang, S.-w. Liu, J.-f. Feng, Chimaeric B. Withers, L. Gambino, K. Peters, Enhanced benefit in diabetic macular edema
antigen receptor T-cell therapy for tumour immunotherapy, Biosci. Rep. 37 (1) from AKB-9778 Tie2 activation combined with vascular endothelial growth factor
(2017) BSR20160332. suppression, Ophthalmology 123 (8) (2016) 1722–1730.
[102] T.R. Holzer, A.D. Fulford, D.M. Nedderman, T.S. Umberger, R.R. Hozak, A. Joshi, [129] A. Das, P.G. McGuire, F. Monickaraj, Novel pharmacotherapies in diabetic re-
S.A. Melemed, L.E. Benjamin, G.D. Plowman, A.E. Schade, Tumor cell expression tinopathy: Current status and what’s in the horizon? Indian J. Ophthalmol. 64 (1)
of vascular endothelial growth factor receptor 2 is an adverse prognostic factor in (2016) 4.
patients with squamous cell carcinoma of the lung, PLoS One 8 (11) (2013) [130] J.C. Davis, L. Furstenthal, A.A. Desai, T. Norris, S. Sutaria, E. Fleming, P. Ma, The
e80292. microeconomics of personalized medicine: today’s challenge and tomorrow’s
[103] P. Carmeliet, R.K. Jain, Angiogenesis in cancer and other diseases, Nature 407 promise, Nat. Rev. Drug Discov. 8 (4) (2009) 279–286.
(6801) (2000) 249–257. [131] S. Jakka, M. Rossbach, An economic perspective on personalized medicine, Hugo
[104] D. Chinnasamy, Z. Yu, M.R. Theoret, Y. Zhao, R.K. Shrimali, R.A. Morgan, J. 7 (1) (2013) 1.
S.A. Feldman, N.P. Restifo, S.A. Rosenberg, Gene therapy using genetically mod- [132] D. Henderson, L.A. Ogilvie, N. Hoyle, U. Keilholz, B. Lange, H. Lehrach,
ified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic Personalized medicine approaches for colon cancer driven by genomics and sys-
tumors in mice, J. Clin. Invest. 120 (11) (2010) 3953–3968. tems biology: OncoTrack, Biotechnol. J. 9 (9) (2014) 1104–1114.
[105] C.S. Yong, V. Dardalhon, C. Devaud, N. Taylor, P.K. Darcy, M.H. Kershaw, CAR T- [133] A.D. Weston, L. Hood, Systems biology, proteomics, and the future of health care:

784
A. Fallah et al. Biomedicine & Pharmacotherapy 110 (2019) 775–785

toward predictive, preventative, and personalized medicine, J. Proteome Res. 3 (2) [136] L. Moserle, G. Jiménez-Valerio, O. Casanovas, Antiangiogenic therapies: going
(2004) 179–196. beyond their limits, Cancer Discov. 4 (1) (2014) 31–41.
[134] R. Chen, M. Snyder, Systems biology: personalized medicine for the future? Curr. [137] G. Lupo, N. Caporarello, M. Olivieri, M. Cristaldi, C. Motta, V. Bramanti, R. Avola,
Opin. Pharmacol. 12 (5) (2012) 623–628. M. Salmeri, F. Nicoletti, C.D. Anfuso, Anti-angiogenic therapy in cancer: down-
[135] R.S. Samant, L.A. Shevde, Recent advances in anti-angiogenic therapy of cancer, sides and new pivots for precision medicine, Front. Pharmacol. 7 (2017) 519.
Oncotarget 2 (3) (2011) 122–134.

785