Issues of origin, morphology and clinical significance of tumor microvessels in gastric cancer

Table 1 Factors associated with the activation of tumor angiogenesis

Factor	Signaling pathways	Effects	Ref.
EGF and EGFR	p38 MAPK, HIF-1α, VEGF	Enhanced angiogenesis, increased VEGF expression, and MMP-1	[38]
	EGFR	EMT activation	[39]
	PI3K/Akt/mTOR	EMT activation	[40]
	Notch and MAPK	Enhanced ECs proliferation, vascular growth and development, increased vascular permeability, inhibition of apoptosis	[41]
		Increased expression level in GC patients with peritoneal metastases	[42]
PIGF	VEGF/VEGFR	A high level of PIGF in plasma is associated with enhanced ECs proliferation and decreased survival of GC patients	[4]
Angs (Ang-1, -2, -3, -4)	Ang/Tie	The formation of blood vessels from preexisting, maturation of blood vessels, migration, adhesion, and survival of ECs	[43]
		Plasma Ang-2 level correlated with liver metastases in patients with GC	[44]
		A high level of angiopoietin-like protein 2 in serum is associated with a high risk of early recurrence of GC	[45]
PDGF-β; PDGF-D; PDGF-BB and other		In the intestinal-type GC, higher MVD was correlated to overexpression, intensity, and proportion of PDGF-B, but not of VEGF-A. PDGF-B plays a more important role in angiogenesis in intestinal-type gastric carcinomas than VEGF-A	[46]
	STAT3, AKT, ERK1/2, mTOR and GSK-3β	PDGF-D promoted the migration, proliferation, adhesion, and tube formation of endothelial progenitor cells	[47]
	STAT3, AKT, ERK1/2, mTOR and GSK-3β	PDGF-BB could activate VEGF-A expression	[48]
		A high level of PDGFR-β gene expression in tumor is associated with decreased 5-year overall survival rate in GC patients	[49]
FGFs and FGFR	AKT and Notch	Increased VEGF expression	[50]
	Snail	The effect of FGF-1 on ECs culture is associated with overexpression of Snai1, increased expression of CD31, CD34, and VWF, and formation of tubes	[51]
	WNT and Twist1	EMT activation	[52]
		Serum FGF level was related to MVD, tumor size, infiltration degree, TNM staging, lymph node metastasis, and distant metastasis	[53]
		High levels of FGF2 expression in the tumor is associated with advanced TNM stage and decreased survival of GC patients	[54]
Tryptase	AKT and ERK, PAR-2 and MAPK	The density of mast cells positive to tryptase is associated MVD in GC patients	[55-57]
IL-8	Src/Vav2/Rac1/PAK1	Induction of expression of VEGF-A, VEGFR-1, and VEGFR-2; stimulation of proliferation, survival, and migration of ECs, activation of MMP production	[58]
		Stimulation of ECs migration	[59]
HER2		Expression of HER2 (2+ and 3+) in gastric tumors is associated with an increase in MVD	[60]
		Expression of HER2 in a tumor is associated with an increase in MVD and a decrease in the survival rate of GC patients	[61]
ITGAX	PI3k/Akt	Overexpression of ITGAX in HUVEC is associated with induction of VEGF-A and VEGFR-2 expression, enhanced HUVEC proliferation, migration, and tube formation, as well as promoted angiogenesis and ovarian tumor growth	[62]
IGF2 and IGF1R		Enhances sprouting angiogenesis and affects tip cell phenotype	[63]
MCU		MCU was related with the activation of EMT mechanisms and HIF-1α and VEGF expression. High level of MCU expression in the tumor was associated with the advanced TNM stage and decreased survival of GC patients	[64]
Helicobacter pylori	Wnt/beta-catenin	VEGF and MVD levels were significantly higher in H. pylori-positive tissues	[65]
Epstein-Barr virus	PI3K/AKT/mTOR/HIF-1α	EBV is associated with the formation of vasculogenic mimicry	[66,67]

AKT: Protein kinase B; Ang: Angiopoietin; ECs: Endothelial cells; EGF: Epidermal growth factor; EGFR: Epidermal growth factor receptor; EMT: Epithelial-endothelial transition; ERK: Extracellular signal-regulated kinase; FGF: Fibroblast growth factor; FGFR: Fibroblast growth factor receptor; GC: Gastric cancer; HER2: Human epidermal growth factor receptor 2; HIF: Hypoxia-inducible factor; HUVEC: Human umbilical vein endothelial cells; IGF2: Insulin-like growth factor 2; IGF1R: Insulin-like growth factor 1 receptor; IL-8: Interleukin-8; ITGAX: Integrin alpha x; MAPK: Mitogen-activated protein kinase; MCU: Mitochondrial calcium uniporter; MMP: Matrix metalloproteinase; MVD: Microvessel density; PAR: Protease-activated receptor; PI3K: Phosphoinositide 3-kinase; PIGF: Placental grow factor; PDGF: Platelet-derived growth factors; STAT3: Signal transducer and activator of transcription 3; VEGF: Vascular endothelial growth factor; VWF: Von Willebrand factor.