At the early stage of neoplasm events, tumors present a balance between cell apoptosis and cell proliferation (14). Tumor cells produce pro-angiogenic factors, such as VEGF, PDGF and anti-angiogenic factors, such as angiostatin and thrombospondin. The secretion of these factors is in balance and tumors maintain at the “dormancy state”. However, once the average volume of a tumor exceeds 1-2 mm³, insufficient supply of oxygen and nutrients to tumor tissues will occur. Under hypoxic and/or acidic conditions, this balance is disturbed, and the tumors switch from a non-vascular to a vascular state, which turns on “angiogenic switch”. At this state, hypoxia inducible factor 1 alpha (HIF1-α) is able to bind to hypoxia-regulators and induce the production of VEGF and other pro-angiogenic factors (15). Oncogene Ras and the mutated tumor suppressor gene TP53 also mediate this pro-angiogenic effect. The synthesis of anti-angiogenic factors are found decreased in these tumors (16). Even if only 1% of tumor cells turns on the “angiogenic switch”, tumor growth occurs. In turn, the growth of neoplasm tissues promotes the initiation of angiogenesis (17).

The most well-known receptors for tumor angiogenesis on the membrane of endothelial cells are tyrosine kinase receptors with their co-receptor, neuropilin. These receptors bind to VEGF or bFGF. The transcription of several pro-angiogenic factors can be initiated by the second messenger cascade of these receptors. High levels of VEGF can be found in most tumor types (1, 18). VEGF exerts the key role in the formation of new blood vessels and the proliferation of ECs. There are three tyrosine kinase receptors of VEGF, VEGFR-1 to -3. VEGFR-2 is the most prominent receptor in angiogenesis, which binds to VEGFA with strong tyrosine kinase activity (19). Moreover, latent forms of VEGF ligands are separated in the extracellular matrix, that are regulated by the release and activation of extracellular matrix-degrading proteases (e.g., MMP-9) (20). The up-regulation of other pro-angiogenic signals, such as FGF family, is involved in sustaining tumor angiogenesis (3, 21). Besides the VEGF signaling pathway, other signaling pathways and associated factors are involved in tumor angiogenesis. Angiopoietin 1 (ANGPT1) and ANGPT2 are important ligands from the ANGPT family, that bind to the receptor tyrosine kinase TIE2 on the membrane of ECs. Since ANGPT1 acts as an agonist of TIE2, its function is to promote vessel maturation. The activation of TIE2 mediated by ANGPT2 can induce vascular disruption and increase angiogenesis (22). Another important system that regulates tumor angiogenesis is the Notch-Notch-ligand system. Endothelial-specific ligand Delta-like 4 (DLL4) mediates the formation of the tip and stalk cells following VEGF stimulation (23).

Apparently, neovasculature is strongly governed by ECs apoptosis. Both proangiogenic growth factors and extracellular matrix (ECM) act as the key roles in EC survival and angiogenesis (4). Induction of angiogenic growth factors and associated pathways are capable of inhibiting ECs apoptosis. For instance, ECs sustainment has been demonstrated to be linked with the modulation of cell apoptosis by VEGF (24). By increasing the expression of anti-apoptotic proteins, such as Bcl-2 and survivin, bFGF is able to decrease ECs apoptosis, which guarantees the cells survival (25). Of note, ANGPT1 involves in ECs apoptosis by modulating PI3K/Akt signaling and upregulating the anti-apoptotic protein surviving (26). Regarding the role of cell matrix and cell-cell interactions in angiogenesis, the anti-apoptotic effect of VEGF is dependent on the regulation of αvβ3-integrin and VE-cadherin protein (27, 28). Since the pivotal role of ECs in angiogenesis, many natural products are developed to target EC apoptosis. For example, resveratrol is able to increase Gly-LDL-induced vascular endothelial cell apoptosis (29). Similarly, Physalis alkekengi L. extract can reduce the apoptosis of ECs after exposing to hyperglycemia (30). Overall, angiogenic factors secreted by tumor cells ( Figure 1 ) and EC apoptosis ( Figure 2 ) are of significance in triggering and processing vessel formation in tumor microenvironment.

Polyphenols are members of a large family of chemical compounds with several phenolic groups, that can be found in foods and beverages of plant origin, including the spices, dried herbs, tea, red wine, coffee, cocoa products, seeds and nuts, vegetables, and fruits. Polyphenols are usually classified as phenolic acids, flavonoids, stilbenes, lignans, secoiridoids, among others. Polyphenols are of significance in the sustainment of human health. Recent studies have illustrated the pharmacologic functions of polyphenols that include antioxidation, vascular wall protection, improving enterogastric digestion, promoting immune response, and prevention of chronic disorders, such as tumor, atherosclerosis, hypertension, diabetes and so on. In addition to the summary of the chemical structures of polyphenols ( Figure 3 ), the effect of several polyphenols (Ellagic acid, Chlorogenic acid, Quercetin, Catechin, Baicalin, Delphinidin, 6-methoxyequol, et al.) on tumor angiogenesis have also been studied in recent years ( Table 2 ). Ellagic acid can inhibit angiogenesis by inhibiting the expression of VEGFR2 in ECV304 cell line. Moreover, researchers found that ellagic acid was able to regulate angiogenesis by inhibiting VEGF/VEGFR2, PI3K/Akt and MAPK signaling cascades in hamster cheek touch carcinogenesis model (39, 40). Chlorogenic acid is one of the hydroxygenic acid derivatives, which derives from Eucommia ulmoides Oliv. Chlorogenic acid suppressed tumor angiogenesis by blocking HIF-1α/Akt signaling pathway in lung cancer A549 cells (41). Quercetin, a flavanol-like compound, is derived from Quercus iberica. Quercetin reduces angiogenesis by inhibiting ERK phosphorylation and VEGFR-2 mRNA expression, and the calcineurin/NFAT signaling pathway (45, 46). Catechin is a flavanol-like compound and derived from black tea, which can affect angiogenesis by inhibiting VEGF (47). Baicalin, originated from Scutellaria baicalensis Georgi, can also inhibit tumor angiogenesis by regulating VEGFR (51). As for Delphinidin, it regulates angiogenesis by affecting the expression of HIF-1α and VEGF in A549 cells (56). 6-Methoxyquol is an isoflavone-like compound derived from soybean and can affect tumor angiogenesis through MAPK signaling pathway (59).

Polysaccharides are polymeric carbohydrate macromolecules, that are composed of long-chain monosaccharide units connected by glycosidic bonds. As pivotal bioactive macromolecules, polysaccharides are mainly extracted from plants, animals and microorganisms. Polysaccharides are currently applied to various biomedical products and functional foods because of their significant biological functions, such as inhibiting tumor growth, triggering immunity, antioxidation, anti-virus and neuroprotection. Recent studies indicated that polysaccharides extracted from higher plants showed anti-tumor activity by enhancing immunity. In addition to anti-tumor effect through immunomodulation, polysaccharides can directly inhibit tumor angiogenesis. Various polysaccharides, such as dandelion polysaccharide, sulfated polysaccharide, Fucoidan, LEP-2a, and Galactomannan, exert important roles in tumor angiogenesis ( Table 3 ). Dandelion polysaccharide has been proved to inhibit angiogenesis both in vivo and in vitro. The PI3K/Akt signaling pathway is involved in this process, which inhibits the expression of VEGF and HIF-1α (66). Sulfurized polysaccharide is derived from Phellinus ribis. In the Lewis lung carcinoma (LLC) mouse model, sulfurized polysaccharide can inhibit vessel formation by modulating VEGF/VEGFR signaling pathway (67). Fucoidan, extracted from Laminaria japonica, regulates tumor angiogenesis by modulating MAPK and PI3K/Akt signaling pathways (68). Fucoidan is proved to reduce the expression of VEGF and PDGF in two chicken embryo chorioallantoic membrane (CAM) models (69). Moreover, in mice xenografted with DU-145 human prostate cancer cells, fucoidan can decrease tumor growth and angiogenesis by inhibiting JAK/STAT3/VEGF signaling pathway (70). Another important polysaccharide, Lep-2a, can restrain the expression of VEGF, CD105, bFGF, MMP-2 and MMP-9 in hepatocellular carcinoma (72). PSP001 is a galactomannan derived from the fruit rind of Punica granatum L. A recent study found that galactomannan was able to suppress the expression of VEGF, MMP-2 and MMP-9 and up-regulate the expression of TIMP-1 and TIMP-2 in cancer cells (74).

Alkaloids are a group of natural compounds with nitrogen structure and physiological function. Many alkaloids have complex nitrogen heterocyclic structures, and several compounds are organic amines with non-nitrogen heterocycles. Alkaloids have the properties of alkali, that are important active ingredients in Chinese herbal medicine. Although certain vitamins, amino acids and peptides from natural sources are also nitrogenous compounds, they are not included in the category of alkaloids. Alkaloids are ubiquitous in nature, especially in the plant kingdom. Alkaloids have been reported in at least 140 species of plants, especially in Papaveraceae, tetrandridae, Solanaceae, Leguminosae, Apocynaceae, Ranunculaceae, and tillering family, et al. The common alkaloids include pyrrole, pyridine, quinoline, isoquinoline, indole, imidazole, purine, anisodamine, terpenoids, steroids, organic amines, and so on and the chemical structures of these alkaloids are shown in Figure 4 . Current studies proved the biological activities of alkaloids, including anti-tumor, anti-bacterial, anti-inflammatory, antiviral, antiarrhythmic, analgesic, and antispasmodic effects. Voacangine is an indole-like compound, which is rich in Ervatamia Stapf. Treatment with voacangine decreases the VEGFR2 kinase activity in athymic nude mice bearing glioblastoma tumors and HUVECs, suggesting that its anti-angiogenic role is closely associated with VEGFR2 (81). Evodiamine is an indoloquinazoline-like compound, which is derived from Euodia rutaecarpa (Juss.). Evodiamine is able to modulate angiogenesis by inhibiting the expression of VEGF through the c-Mer/Src/STAT3 signaling pathway (82). By inhibiting β-catenin, which reduces VEGF-A expression, Le Shi et al. found the anti-angiogenic role of evodiamine (83). As an isocarbostyril compound, narciclasine regulates HUVECs proliferation by a RhoA-independent activation of the Rho kinase Rock (84). Tetromethylpyrazine is an amide alkaloid, which is extracted from Ligusticum chuanxiong hort. Tetromethylpyrazine combined with paclitaxel inhibited angiogenesis both in vivo and in vitro through blocking ERK1/2 and AKT signaling pathways (85). Previous studies found that harmine, a β-carboline alkaloid, suppressed bladder cancer growth by its anti-angiogenic effect, which was linked to VEGFR2 signaling pathway (86). Oxysophocarpine is a quinolizidine alkaloid and it reduces the levels of HO-1, VEGF, MMP-9 and HIF-1 in OSCC cells (87). 3-acetyl-norerthrophlamide is a cassaditerpene alkaloid, which comes from Erythrophleum fordii. 3-acetyl-norerthrophlamide and exerts the anti-angiogenic function by inhibiting the eNOS activation and NO production (88). Many alkaloids, such as chuanbeinone, halofuginone, tetrandrine, also play significant roles in tumor angiogenesis ( Table 4 ).

Terpenoids are natural products that derive from mevalonic acid. Terpenoids are composed of multiple isoprene (C5) units with the general formula of (C₅H₈)_n. More than 20,000 terpenoids exist in nature and are widely distributed in the plant kingdom, such as Compositae, Ranunculaceae, Araliaceae, Oleaceae, Magnoliaceae, Lauraceae, Aristolochiaceae, and more. Based on the different molecular structures ( Figure 5 ), terpenoids are divided into five groups: monoterpenes, sesquiterpenes, diterpenoids, triterpenoids and terpenes compound. Most of the bioactive terpenoids have been isolated from medicinal plants. For example, monoterpenes and sesquiterpenes are extracted from essential oils of medicinal plants and triterpenes are primarily available in balsams and resins. Recent studies have found that terpenoids have a variety of biological functions, including the regulation of enzyme system, cell surface signaling transduction, immune function, cell differentiation, tumor proliferation and angiogenesis. Important terpenoids (Perillyl Alcohol, β-elemene, Alantolactone, Tanshinone IIA, Triptolide, Ursolic acid, Koetjapic acid, et al) and their molecular signaling pathways participate in modulating tumor angiogenesis ( Table 5 ). Perillyl Alcohol, hugely available in the essential oils of several plants (Lavendin, Mints, Cherries, etc.), possesses the anti-angiogenic property, the mechanism of which is probably to decrease the release of VEGF in cancer cells and stimulate the expression of Ang2 in endothelial cells (98). β-elemene is a sesquiterpene compound isolated from Curcuma Zedoaria. It inhibits the proliferation and metastasis of melanoma by suppressing VEGF-mediated angiogenesis (102). Alantolactone is also a sesquiterpene compound extracted from Inula Helenium. Alantolactone inhibits angiogenesis by reducing the phosphorylation of VEGFR2 and its downstream protein kinases, including PLCγ1, FAK, Src, and Akt in breast cancer (106). Tanshinone IIA is the key compound of Diterpene, isolated from Salvia Miltiorrhiza Bunge. Tanshinone IIA has anti-angiogenic activity in human EPCs, which is associated with the regulation of VEGF, PLC, Akt and JNK signaling pathways (109). Triptolide is also a Diterpene compound, derived from Tripterygium Wilfordii. Triptolide exerts the anti-angiogenic role in breast cancer by inhibiting ERK1/2-HIF1-α-VEGFA signaling pathway both in vitro and in vivo (113). As an important Triterpene compound, ursolic acid is able to decrease the expression of VEGF and iNOS in ehrlich ascites carcinoma (114). Koetjapic acid is also a significant Triterpene compound. Koetjapic acid is found to reduce the expression of VEGF in various angiogenic models, such as rat aortic ring, CAM and HUVECs (116).

Saponins are composed of sapogenins and sugars. The sapogenins are triterpenes or spirostanes and the make-up sugars are commonly glucose, galactose, rhamnose, arabinose, xylose, glucuronic acid and galacturonic acid. Lipophilic sapogenins and hydrophilic sugar chains make the saponin an excellent surfactant. Saponins are mainly distributed in terrestrial higher plants and marine organisms, such as starfish and sea cucumber. Many Chinese herbal medicines, such as Ginseng, Polygala Tenuifolia, Platycodon grandiflorum, licorice, Anemarrhena and Bupleurum, contain saponins as the main active ingredients. According to the different structures of sapogenins, saponins have the biological functions of anti-tumor, hypoglycemic, cholesterol lowering, liver protection, immune regulation, anti-inflammatory and anti-microbial effects. The chemical structures ( Figure 6 ) and anti-angiogenic property of several saponins (Timosaponin AIII, Ginsenoside Rg3, β-Escin, sea cucumber saponins, et al) has been identified in recent years ( Table 6 ). Timosaponin AIII is a steroidal saponin, derived from Anemarrhena asphodeloides Bge. It exerts anti-angiogenic effect through VEGF/PI3K/Akt/MAPK signaling pathway in the zebrafish embryos model (119). Ginsenoside Rg3 is a triterpene saponin, isolated from Panax ginseng. Ginsenoside Rg3 can decrease the expression of MMP-2, MMP-9 and VEGF in B16 cell tumor mouse model and in vitro B16 cell model (122). β-escin is also a kind of triterpene saponin, extracted from Aesculus hippocastanum seeds. β-escin can inhibit melanoma angiogenesis by increasing the expression of TIMP-1 and TIMP-2 (123). Sea cucumber saponins are crude saponins, that are prevalent in Holothuria leucospilota. The saponins extracted from sea cucumber can inhibit the expression of VEGF-D and TGF-β in MCF7 cells (126).