ABSTRACT

In modern medical science, targeting the tumour vasculature instead of the tumour cells is of great interest for the management of tumour associated complications. In context to that, the review was planned to explore the mechanisms of pathological angiogenesis responsible for cancer cell invasion and metastasis. The experimentally proven phytopharmaceuticals having a significant effect to inhibit vasculature development are represented schematically. The scientific literature from authenticated databases (Scopus, PubMed, etc.) search was conducted with emphasis on the previous fifteen years, combining the keywords as selected. Mechanisms of pathological angiogenesis responsible for cancer cell invasion and metastasis have been explained with possible regulatory protein involvement. A total of 97 experimentally proven plant molecules, studied in this review, including 69 plant species among 40 plant families, are summarized in a schematic way.

Hopefully, this review will facilitate the biomedical scientists in setting up the appropriate research questions around the molecular targets discussed in this review for the management of cancer cell invasion and migration and for further proof-ofconcept validation studies for exploring such phytopharmaceuticals.

Keywords: Pathological Angiogenesis; Cancer Cell Invasion; Metastasis; Cell Migration; Experimentally Proven Phytopharmaceutical; Inhibition of Vasculature Development; Modern Target for Cancer treatment

Introduction

The formation of new blood vessels is a vital multistep process in our body with both advantages and disadvantages, as it is responsible for the normal physiological growth on one hand while on the other it accounts for some diseases [1]. Blood vessels aid in oxygen and essential nutrients delivery to the cells and discard catabolic wastes from them [2]. The formation of new blood vessels from a pre-existing one is known as angiogenesis or neovascularization [3]. In 1971, a hypothesis by Judah Folkman first demonstrated that; “the growth of solid neoplasms is always accompanied by neovascularization” [4]. He also isolated a stimulatory factor, Tumour Angiogenesis Factor (TAF), present only in the tumour cells (exception: placenta) [4]. In the absence of angiogenesis, cancer cells cannot grow beyond 2mm3 and may become necrotic or apoptotic [5]. Angiogenesis initiation is triggered by various chemical or physiological factors, among which “Hypoxia” is the key inceptive factor (physiological) [6]. The initiation of angiogenesis, also referred to as “Angiogenic Switch” is a tumour growth and progression process influenced by the tumour type, its microenvironment, and other stimulatory factors, and can eventuate at any stage of a tumour [7]. There are some angiogenic stimulatory factors or pro-angiogenic factors or TAF or Tumour Angiogenesis Factors (VEGF, FGF, EGF, etc.) that assist angiogenesis and some antiangiogenic factors (Thrombospondin-1, statins, etc.) that have inhibitory effects, a gross amount of which leads to tumour dormancy, even for a few years [7].

However, when the normal proportion of pro-angiogenic and antiangiogenic attributes are imbalanced (basically proangiogenics increases largely than anti-angiogenics), angiogenesis triggers, uncontrolled vessel formation starts and the dormant tumour starts proliferating, a phenomenon is known as “Angiogenic Switch” [8]. Among the many angiogenesis affecting factors, vascular endothelial growth factor or VEGF was the first identified (1983) angiogenesis initiator and thrombospondin-1 or TSP-1 was the first identified (1990) angiogenesis inhibitor [8]. White Adipose Tissue (WAT) and Brown Adipose Tissue (BAT) are responsible for angiogenic factor production. WAT maintains vascular growth while BAT is involved with the metabolic processes of tumour growth [9]. Synergistic action of pericytes (perivascular cells that wrap around blood capillaries) and endothelial cells involves some regulators that may be responsible for physiological and pathophysiological conditions like; vasculature development, angiogenesis, and tumour metastasis [10]. Although, the role of pericytes in angiogenic sprouting is not quite clear, pericytetargeted therapies have become very effective these days, to inhibit uncontrolled tumour growth [10]. In this review, we have summarized and explained pathological angiogenesis, its role in cancer cell invasion and metastasis and presented schematically the important experimentally proven phytopharmaceuticals that have been found to be beneficial in inhibiting vasculature development. The review is expected to facilitate the biomedical scientists in setting up appropriate research questions around molecular targets for the management of cancer cell invasion and migration.

Angiogenesis and Type of Angiogenesis

Angiogenesis has a great impact on normal physiological growth as well as disease conditions. Physiological angiogenesis is associated with normal tissue growth and vasculogenesis, whereas pathological angiogenesis is associated with illness. Almost all pro-angiogenics are related to various angiogenesis types. Especially, vascular endothelial growth factor (VEGF) plays a key role in both normal angiogenesis (by ensuring endothelial cell proliferation, survival, and metastasis) as well as in angiogenic disorders or pathological angiogenesis (by enhancing the release of proinflammatory cytokines) [11]. Extracellular matrix (ECM) and vascular basement membrane (BM) are key mediators in physiological angiogenesis [12,13]. Vascular or circulatory system is the first physiological system that develops in mammalian embryogenesis [14]. Physiological angiogenesis occurs during wound healing, menstrual cycle, embryo implantation, pregnancy, etc. [15]. There are various in vitro and in silico models (continuum model, cell-based model, hybrid mathematical model) for wound healing angiogenesis, but these have some limitations which need further improvement [16]. Leutial angiogenesis, stimulated and regulated by Macrophages, Polymorphonuclear neutrophils, Eosinophils, etc., occurs almost regularly in the corpus luteum (CL) and is related to the formation and function of the luteal structure, ovulation, peripubertal and postpartum periods, etc. [17,18].

Embryo implantation is regulated by both physiological and pathological angiogenesis in the endometrium [19]. Female reproductive hormones, e.g., Estrogen, Progesterone, Human Chorionic Gonadotrophin (hCG), etc., regulate various stages of endometrium angiogenesis [20]. The imbalance of angiogenic factors during pregnancy may lead to miscarriage, defective placentation, or other pregnancy-related disorders [20]. Mitochondria are also indirectly linked with the angiogenesis process. Mitochondrial Complex III produces mROS (mitochondrial reactive oxygen species) that stabilizes HIF-1α, which then releases VEGF from cells leading to angiogenesis [21]. Skeletal muscle is also driven by the angiogenesis process [22]. Alteration of pro-angiogenics and anti-angiogenics balance leads to the shifting of physiological angiogenesis to pathological angiogenesis, thus resulting in diseased conditions, like; tumor formation and progression, all types of cancers (breast, liver, lung, ovarian, GIT, melanoma, etc.), diabetic retinopathy, cardiovascular diseases, psoriasis etc. in the body [23-24]. Pathological retinal angiogenesis is related to vascular leakage, bleeding and fibrosis, visual impairment, etc. and occurs in disease conditions like; retinopathy of prematurity (ROP) and age-related macular degeneration (AMD caused by angiogenic factor imbalance, by factors like-retinal hypoxia, ischemia or inflammation) [25]. Ocular neovascular disease, a leading cause of vision impairment and blindness, occurs because of IL-17 regulated VEGF and other inflammatory cytokines [26].

Diabetic retinopathy or DR (caused by vascular damage in the retina) is a pathophysiological condition associated with VEGF overexpression and some proinflammatory cytokines (TNF-α, IL 1β, etc.) [27]. Therapeutic angiogenesis is an experimental approach that deals with the external delivery of angiogenic growth factors (like; VEGF, HIF-1) for the treatment of ischemic or injured tissues or fibrosis to promote targeted neovascularization or surgical revascularization process [28]. HIF-1 is used to cure endometriosis and blindness, VEGF can be used (in vivo) in coronary and peripheral artery disease, ischemic ulcers, etc. [15,28]. Particular biomaterials deliver these angiogenic stimulatory factors to our body in some specific manner; example: PEG hydrogel, PEG-fibrinogen hydrogel, PEGDA hydrogel, Porcine pericardium, ECM, PLG microspheresinscaffold, etc. [12]. Gene therapy, stem cell therapy, microvesicle/ exosome therapy, combinational gene stem cell therapy, engineered exosome therapy, etc., are some well-established scientific approaches to therapeutic angiogenesis [29].

Mode of Vessel Formation and Branching

Circulatory or cardiovascular system maintains body homeostasis along with other physiological process like- supply of blood cells, essential nutrients, oxygen, and elimination of waste materials by creating a blood vessel network all over our body [30]. Blood vessel formation occurs mainly via Vasculogenesis and Angiogenesis, two different processes of vascularization consisting of various molecules and signalling pathways [30,31]. Mainly Embryonic development triggers vasculogenesis, whereas angiogenesis can be triggered by hypoxia and some other factors [31]. Vasculogenesis results in the formation of vascular network in embryonic stage followed by the expansion of those blood vessels by angiogenesis [31]

However, some factors responsible for both vasculogenesis and angiogenesis includesa.

HIF-1α stimulation by Lactate in endothelial cells (EC) under normoxic conditions leads to hypoxia whereas Lactate mediated vascular endothelial growth factor (VEGF pathway) upregulation results in vasculogenesis and tumour angiogenesis [32,33].

b. Endothelial Ca2+ signalling induces both angiogenesis and vasculogenesis [34].

c. CD27-CD70 T cell co-stimulation in lymphoid organs results in neovascularization in the human body [35].

d. Vessel branching process mainly occurs through two distinct mechanisms.

I. By bud or sprout formation of pre-existing vessels or sprouting angiogenesis and,

II. By forming of pillar or tube-like new vessels from endothelial cells or non-sprouting angiogenesis or splitting angiogenesis or intussusceptive angiogenesis [36,37].

Sprouting angiogenesis (SA), mechanized with the budding process, undergoes three main steps; proliferation or dilation, elongation, stabilization, where elongation further consists of cell migration, basement membrane degradation, lumen formation [38,39]. In such angiogenesis, the endothelial cell (EC) is proliferated and initiates sprouting with the help of VEGFAngiopoietin factor [38]. Two significant cellular phenotypes, tip cells and stock cells, and some factors like platelet-derived growth factor-β (PDGF-β), matrix metalloproteinases (MMPs) play a vital role in vessel elongation and tube formation, [38,39]. The stock cells work in a proliferative way while tip cells as migratory units in lumen formation to form a vascular network [39]. Angiopoietins and their receptors (Tie-1 and Tie-2) then decrease the pericyteendothelial cell interactions and stabilize these newly formed vessels [38]. In a recent study, it has been shown that a transcription factor, myocyte enhancer factors-2 (MEF2) significantly regulated SA by upregulating Delta-like ligand-4 (Dll4) factor [40].

Meanwhile, intussusceptive angiogenesis (IA), coordinated by the ‘intussusception’ process, may be defined as the transluminal tube formation and splitting longitudinally into two vessels from a preexisting single blood vessel [41]. The term ‘intussusception’ signifies ‘growth within itself’ [42]. Mainly, eruption and branching of new vessels occur due to cytoplasmic partial pressure [38]. IA undergoes a very complicated series of process

a. Expansion of blood vessels by intussusceptive microvascular growth (IMG) mechanism,

b. Isolation of new vessels by intussusceptive arborization (IAR) mechanism,

c. Augmentation through intussusceptive branching remodelling (IBR) [43]. Due to the fast and unpredictive nature of the mechanism, the vascular network is reconstructed now and then [41].

The general interrelations between SA and IA are shown in Table 1. Although, sprouting angiogenesis is a standard antiangiogenic therapy target for treating malignant and non-malignant human diseases, intussusceptive angiogenesis (IA) is also a significant target in controlling tumour growth for some reasons.

• It is a rapid but low energy consuming branching process with approximately 50% of the total vasculature in certain types of cancers originated through IA. Therefore, it can be an important druggable target.

• IA also assists in tumour regrowth and expands the vascular network rapidly in local or organ specific, even after antiangiogenic therapy.

• Angiogenic switch plays a key role in the development of antiangiogenic therapy and tumour resistance. Angiogenic switch from SA to IA heavily depends upon some pro-angiogenic factors (NO VEGF signalling, etc.) [38].

Angiogenic Stimulatory Factors

Various mechanical, chemical or molecular factors trigger the angiogenesis process.

Mechanical Stimulatory Factors

Researchers found clear evidence on the impact of mechanical microenvironment on tumor angiogenesis, however their mechanism processes are still confusing and controversial [44,45].

However, recently it has been identified that,

I. Fluid shear stress of blood capillaries.

II. Increased muscle contraction led to the rise of NO level.

III. Increased Collagen Matrix and Endothelial-Cell-Matrix (ECM) stiffening can introduce mechanical stimulation in tissue angiogenesis [44,45].

Molecular Stimulatory Factors

A number of chemical factors and pathways also have a great impact on angiogenesis. Some of them are summarized here

VEGF: The vascular endothelial growth factor (VEGF) is the key mediator of angiogenesis along with cancer cell proliferation, invasion, and metastasis [46]. VEGF belongs to a heparin-binding glycoprotein family, consisting of VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PLGF) and shows affinity towards 3 types of receptors, VEGFR1 (binds with VEGF-A, B and PLGF), VEGFR2 (binds with VEGF-A), and VEGFR3 (binds with VEGF-C and VEGF-D) [47]. Many studies support the presence of VEGFRs in liquid and solid tumours like; NSCLC, melanoma, prostate cancer, leukaemia, breast cancer, etc. which on subsequent stimulation by VEGF regulates tumour cell proliferation [48]. VEGF shows both neurotrophic and neuroprotective effects on glial and neuronal cells; apparently, they actively participate in neuronal vessel development in CNS and PNS [49]. It is also associated with ocular neovascularization [50]. Often, VEGF-a overexpression results in Hepatocellular carcinoma and lung cancer [46,51]. VEGF and SEMA4D synergistically showed an angiogenic effect on ovarian cancer [52]. PIN2/TRF1-interacting telomerase inhibitor-1 or PinX1 can suppress renal cancer angiogenesis through downregulation of VEGF expression in the mir-125a-3p/VEGF signalling pathway [53]. PR1P, a novel therapeutic peptide, binds with VEGF, which on further overexpression promotes fibrosis or revascularization of injured tissue [54].

HIF-1: Hypoxia, a principal physiological state of our body, is caused by the unrestrained replication of cancer cells, the development of nonfunctional vasculature in solid tumoursetc. and noticed when a shortage of adequate supply of oxygen in body tissue fails to meet oxygen demand [55,56]. HIF or hypoxiainducible factor, which is a heterodimeric transcriptional factor, consists of α and β (also known as aryl hydrocarbon receptor nuclear translocator or ARNT) subunits which are further subdivided into (1) HIF-1α or HIF-1, (2) HIF-2α or HIF-2, (3) HIF- 3α or HIF-3 and (1) ARNT1, (2) ARNT2, (3) ARNT3 [55,57]. Among all, the α subunit (especially HIF-1α), is more oxygen-sensitive and the key mediator of a hypoxic response that produces angiogenic growth factors and various cytokines leading to angiogenesis [58]. HIF-1α plays a pivotal roles in cardiac hypertrophy and end-stage heart failure, whereas the development of HIF-2α by myocardial hypoxia can play a protective role in cardiac failure [58]. The HIF- 1α expression regulates every step involved in tumorigenesis towards cancer like; cell cycle regulation, glucose metabolism, angiogenesis, erythropoiesis, cell proliferation and invasion, etc., and radio resistance neovascularization by releasing the pro-angiogenic cytokine (i.e.-VEGF) although HIF-1-dependent tumour cell apoptosis has inhibitory effect on tumour growth by promoting glucose deprivation [59]. HIF-1α is also involved in pulmonary hypertension, critical limb ischaemia (CLI), retinopathy, diabetic ulcer, ageing, etc [60]. HIF-1α along with its downstream factors regulate metabolic reprogramming and angiogenesis in cutaneous tumours like; Merkel cell carcinoma, melanoma, basal cell carcinoma, and squamous cell carcinoma [61].

TNF-α: Tumour Necrosis Factor (TNF) is an inflammatory cytokine (protein), derived from monocytes, other immunological or parenchymal cells [62,63]. TNF was first reported about 45 years ago, in mid-1975, by Carswell et al.; although TNF was first observed in the 1960s [64]. Carswell et al. reported that an endotoxin tutor necrosis factor (TNF) acts indirectly by causing the host to release a substance, that mimics the tumour necrotic action of endotoxin and is selectively toxic for malignant cells [64]. Gradually TNF became a rapidly growing prototype family or superfamily with more than 20 ligands and over 29 receptors [65]. There is main two types of membrane-bound receptors- TNFR-1 (expressed by almost all mammalian cell types), TNFR-2 (expressed by mainly immune cells and endothelial cells); that activates through a soluble TNF-a ligand stimulus [64,66]. TNF plays a conflicted role in cancer biology by promoting and suppressing tumour, by promoting angiogenesis along with some other biological activity through various signalling pathways [67,68].

TGF-β: The regulatory cytokine family, transforming growth factor-β (TGF-β) plays multiple roles in embryogenesis, adult angiogenesis and cancer [69]. TGF-β exists as 3 isoforms- TGF-β1, TGF-β2, and TGF-β3 and shows dual roles in both cancer and angiogenesis [69]. There are several specific stromal activators (MMPs, Integrins, ROS, ECM protein, TSP-1 or thrombospondin-1, bone morphogenetic protein 1 or BMP1 etc.) and inhibitors (Proteoglycans, Fibrillin’s, Fibulins, Fibronectin, etc.) that operate latent TGF-β activation and suppression [70]. Although the exact mechanism of TGF-β’s role in angiogenesis is still unclear, but from some preclinical studies it has been observed that tumour angiogenesis stimulates through plasminogen-dependent activation of TGFβRI/ SMAD1/5 [70]. Besides, in the tumour microenvironment, angiogenesis is inhibited when enhanced TGF-β concentration upregulates fibronectin through TGFβRI/ SMAD2/3 signalling pathway [70,71]. Studies in animal models revealed, at early stages of neovascular age-related macular degeneration or nAMD, TGF-β concentration in the aqueous humour decreases and shows protective and antiangiogenic stimulation, while later, in the diseased stage, it shows pro-angiogenic effects, and in human patients, it inhibits tumour development in early stages, whereas in later stages, it supports tumour invasion and metastasis [72-74]. TGF-β1 secreted from radial glia (RG) cells of the brain regulates RG and endothelial cell interaction to form blood vessels resulting in the development of the cerebral cortex [75]. It also regulates melanoma distal metastase, hepatic angiogenesis [76,77]. Leucinerich α-2 glycoprotein (LRG) and Interleukin-37 (IL-37) promote lung fibrosis and angiogenesis, respectively, via TGF-β signalling [78,79]. Besides, TGF-β represses VEGFA-mediated angiogenesis in colon cancer metastasis, breast cancer bone metastase, but stimulate glioblastoma through VEGFR signalling [80,82]. A study on bovine ovaries proved that TGF-β has an inhibitory effect on both the angiogenesis in female reproductive organs and steroidogenesis (formation of steroids) [83]. Studies revealed transforming growth factor-β1 overexpression can cause airway remodelling and lung fibrosis by enhancing collagen Ⅰ and Ⅲ, in mustard lung [84].

PARP-1: PARP (Poly (ADP-ribose) polymerase), recently known as ARTs or ADP-ribosyl transferases, is a protein family including 17 members that have diverse structures, enzymatic activity, subcellular localization and functions [85-87]. Among all, the first discovered and extensively discussed member is PARP-1 or ART-1, a DNA-dependent nuclear enzyme [86,88,89]. Structurally, it consists of 3 domains- 1) DNA-binding region, 2) auto modification region, and 3) catalytic region or the PARP site [90]. In essence, the catalytic region of PARP-1 is associated with DNA damage repair, but in case of severe damage, it induces cell death by NAD+ and ATP depletion [90,91]. It is already proven that PARP and angiogenesis are correlated and PARP-1 inhibitors can suppress the angiogenesis process [92]. The impact of PARP-1 overexpression in cancer angiogenesis is shown in Table 2 [93-96].

MMP: MMPs or matrix metalloproteinases are zinc-dependent catalytic enzyme groups that have a significant contribution in both physiological as well as pathological processes of the human body [97]. There are mainly 24 human MMPs under 6 subfamilies which are associated with the formation of vasculature, destruction of some extracellular matrix (ECM) proteins, like; collagen, etc. and activation of some inflammatory cytokines as well [98]. MMPs are mainly secreted by platelets, fibroblasts, leukocytes, endothelial cells, and vascular smooth muscle as proenzymes [99,100]. Some findings suggest that MMPs promote angiogenesis by activating some signalling pathways and receptors or by enzyme overexpression; besides, it can inhibit angiogenesis related vascular sprouting by converting large proangiogenic molecules into relatively smaller antiangiogenic proteins [101]. Expression of MMPs is a risk factor of cardiovascular disease (CVD), chronic kidney disease (CKD), and Peripheral Vascular Disease (PVD) [99]. MMPs, are also associate with tumour maturity-proliferation-migration and several types of cancer subtypes [101] (Table 3) [102-122]. There are some natural modulators in our body that randomly bind to any MMP in 1:1 ratio and inhibits MMPS, known as tissue inhibitors of metalloproteinases or TIMPs and few synthetic MMP-inhibitors like; metal ions (Cu2+, Mg2+, Mn2+ etc), doxycycline (only MMPi approved by FDA) acts by reducing MMP secretion.

VASH-2: Vasohibin (VASH) consisting of two subfamilies with - VASH-1 and VASH-2, are recently discovered angiogenesis regulator genes that show antipathic effects on tumour angiogenesis; by inhibiting angiogenesis (VASH-1) and by stimulating angiogenesis (VASH-2), although there are 52.5% similarities between full-length human VASH-1 and VASH-2 genes at the amino acid level [123]. VASH-2 generally on exposure to mononuclear cells of bone marrow starts angiogenesis as a chemical stimulator [124]. Studies revealed that VASH-2 can be used as a biomarker in oesophageal squamous cell carcinoma (ESCC) as the plasma concentration level and tumour expression level of VASH-2 were found to increase at a proportional rate [125]. Epigenetic mechanism involving transcriptional start site (TSS) upregulation and activation of histone modifications occurs -354 to -10 region of VASH-2 gene, which probably leads to VASH-2 overexpression following increased angiogenesis in hepatocellular carcinoma (HCC) [126]. VASH-2 expression is related to angiogenesis in human retinal microvascular endothelial cells or HMVEC [127]. VASH-2 promotes tumour angiogenesis by altering gene expression and metastasis by tubulin de-tyrosination of PDAC or Pancreatic Ductal Adenocarcinoma cells [128]. Two growth factors; fibroblast growth factor-2 (FGF-2) and growth/ differentiation factor-15 (GDF-15) overexpression leads to VASH- 2 induced breast cancer cell proliferation [129]. Overexpression of VASH2 indicated as a predictor in oesophageal squamous cell carcinoma (ESCC) and accelerated tumour angiogenesis in some specific types of ovarian cancer by enhancing tumour growth and peritoneal dissemination of tumour cells [130,131].

Experimentally Proven Phytopharmaceutical to Inhibit Vasculature Development

Experimentally proven phytopharmaceuticals inhibiting vasculature development are summarized based on most impacted and cited literature published in the last 15 years; 2005- 2020) as searched from the authenticated databases (Scopus, PubMed, etc), including the keywords like- Pathological Angiogenesis, Cancer Cell Invasion, Metastasis, Cell Migration, Experimentally Proven Phytopharmaceutical, Inhibition of Vasculature Development, Modern Target for Cancer treatment in Table 4. [132-245] A total of 97 plant molecules, studied in this review, including 69 plant species among 40 plant families are summarized in a schematic way. The respective compounds/ extracts are included with their respective sources/ families and the specific protocols/ methodologies used for the experimental proof-of-of-concept studies are tabularized in Table 3 [102-122].

Expert Opinion on the Recent Perspectives on Cancer Management

It has been observed that the growth and progression of cancerous tumours beyond a certain size require pathogenic angiogenesis, and therefore angiogenesis inhibition can prove to be an effective strategy in cancer management [246,247]. Typically, the focus on cancer management by angiogenesis inhibition in the recent past has been to develop inhibitors against its stimulant molecules like VEGFR-2, protease inhibitors, etc. [248, 249]. This further with angiogenesis imaging procedures aiding in tumour vasculature characterisation, identification of various biomarkers with the potential to diagnose cancer and even identify patients likely to benefit as well as those with the possibility to develop resistance and/or adverse events from antiangiogenic treatment makes it a promising therapy [250,251]. There is an abundance of experimental phytopharmaceuticals inhibiting angiogenesis however, limited clinical effectivity and high toxicity call for further research in such area [252]. The review presents the physiology of angiogenesis, its stimulants at the molecular level which are basically molecular targets for drug development, mechanisms of angiogenesis, contribution to cancer progression, and a summary of numerous plant compounds/ extracts inhibiting vasculature development along with their families. While the schematic representation of compounds/ extracts having potential anti-vasculature activity together with methods for extraction and development will aid scientists in the timely selection of phytopharmaceuticals for further experimentation, the summarisation of the respective phytochemicals with the plant source/ family would help to trace the origin and provide further scope to identify new plants having potential vasculature development inhibitory activity. Overall, this review will assist in exploring phytopharmaceuticals targeted towards cancer treatment specifically inhibiting vasculature development.

Conclusion

Targeting the tumour vasculature instead of the tumour cells directly is of great interest for tumour management. With regards to this, the review scientifically explained the pathological angiogenesis mechanism responsible for cancer cell invasion and metastasis, and in a similar line, the experimentally proven phytopharmaceuticals having a significant effect inhibiting vasculature development have been represented schematically. Hopefully, this review will facilitate the biomedical scientists in setting up the appropriate research questions around the molecular targets explained here for the management of cancer cell invasion and migration. Therefore, further proof-of-concept validation studies for exploring such phytopharmaceuticals can be possible.

Conflict of Interest

The authors confirm that this article content has no conflicts of interest.

Acknowledgement

The Director and Principal I/C of Guru Nanak Institute of Pharmaceutical Science and Technology are acknowledged. National Institute of Pharmaceutical Education and Research (NIPER), Hajipur, India and “Department of Pharmaceutical, Ministry of Chemical and Fertilizer, Govt. of India” are also acknowledged for providing the M.S. Fellowship to Mr. Antarip Sinha and Ms. Debanjana Das.

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ABSTRACT

In modern medical science, targeting the tumour vasculature instead of the tumour cells is of great interest for the management of tumour associated complications. In context to that, the review was planned to explore the mechanisms of pathological angiogenesis responsible for cancer cell invasion and metastasis. The experimentally proven phytopharmaceuticals having a significant effect to inhibit vasculature development are represented schematically. The scientific literature from authenticated databases (Scopus, PubMed, etc.) search was conducted with emphasis on the previous fifteen years, combining the keywords as selected. Mechanisms of pathological angiogenesis responsible for cancer cell invasion and metastasis have been explained with possible regulatory protein involvement. A total of 97 experimentally proven plant molecules, studied in this review, including 69 plant species among 40 plant families, are summarized in a schematic way.

Hopefully, this review will facilitate the biomedical scientists in setting up the appropriate research questions around the molecular targets discussed in this review for the management of cancer cell invasion and migration and for further proof-ofconcept validation studies for exploring such phytopharmaceuticals.

Keywords: Pathological Angiogenesis; Cancer Cell Invasion; Metastasis; Cell Migration; Experimentally Proven Phytopharmaceutical; Inhibition of Vasculature Development; Modern Target for Cancer treatment