Angiogenesis in gastrointestinal stromal tumors: From bench to bedside

Table 1 The basic mechanisms of angiogenesis

Angiogenetic mechanism	Function	Implicated signaling/ pathways
Sprouting angiogenesis	Vessel formation from a parental one as a sprout outgrowth	VEGF, Dll4/notch pathways and neuropilins
Intussusceptive Angiogenesis	Splitting of a parental vessel into two newly formed	VEGF, PDGF pathways and erythropoietin
Vasculogenesis/Endothelial progenitor cells	Vessel formation from endothelial progenitor cells differentiating into mature endothelial cells	VEGF pathway, chemokines
Vasculogenic mimicry	Vessel-like formations without endothelial cells	HGFR
Trans-differentiation of CSCs	CSC give rise to endothelial cells	Tie-2, TGF-, CXCL12/CXCR4

PDGF-R: Platelet-derived growth factor receptor; VEGF: Vascular endothelial growth factor; HGFR: Hepatocyte growth factor receptor; TGF-: Transforming growth factor-; CSCs: Cancer stem cells, CXCL12: C-x-c motif chemokine ligand 12; CXCR4: C-x-c motif chemokine receptor 4.

Table 2 A brief presentation of several angiogenetic molecules in disease progression

Ref.	Sample size	Molecule/methods	Outcomes
Zhao et al[59]	124 patients-62, 50% in stomach, 22.6% in small intestine	HIF-1α/IHC	Association with disease-free survival (P = 0.03)
		VEGF/IHC	Association with disease-free survival (P = 0.002)
		MVD/IHC	Association with disease-free survival (P < 0.001)
Kang et al[60]	213 patients-63% in stomach, 25.3% in small intestine	634G/C	Superior OS than 634 G/G (P = 0.054)
			Superior RFS than 634 G/G (P = 0.082)
Mu et al[22]	20 patients	BRD4/mRNA, IHC	Increased BRD4 expression compared with normal tissue
		BRD4/IHC	Associated with poor OS (P < 0.01)
			Associated with poor DFS (P < 0.01)
Toda-Ishii et al[61]	94 patients–mean follow-up period 65 mo	PPP2R1A mutations/PCR	Lower OS (P < 0.05)
			Lower DFS (P < 0.05)
Liu et al[62]	52 patients–27 malignant cases–11 borderline–14 benign	MMP-9, COX-2, VEGF/IHC	Enhance metastasis (P = 0.014, P = 0.010, P = 0.032 respectively)
			Higher mitotic count (P = 0.021, P = 0.027, P = 0.009 respectively)
			Higher incidence of central necrosis (P < 0.01)
Takahashi et al[63]	53 patients: 21 cases < 30 mm-9 cases with liver metastasis	VEGF/IHC	Association with liver metastasis (P < 0.01)
		VEGF/IHC	Poor 10-yr OS (P < 0.05)
		MVD/IHC	Association with liver metastasis (P < 0.05)
Verboom et al[64]	227 patients-36 SNPs-18 genes, median PFS 39 mo–median OS 86.5 mo	rs1570360 polymorphism in VEGFA gene	Association with poorer PFS (P = 0.015)
		rs1870377 polymorphism in VEGFR2 gene	Association with lower PFS (P = 0.037)
Chen et al[65]	62 patients: 31 high risk–31 low risk	HIF-1α/IHC	Association with high risk disease (P < 0.0001)
			Association with GIST recurrence or metastasis (P = 0.009)
Basilio-de-Oliveira and Pannain[66]	54 patients	VEGF/IHC	Association with survival (P < 0.001)
		CD105/IHC	Association with prognosis (P < 0.001)
Imamura et al[67]	95 patients: 64 cases in stomach–31 in small intestine	MVD/IHC	Association with tumor grade (P = 0.036)
			Association with VEGF expression (P < 0.0001)
			Association with DFS after surgery (P = 0.0028)
Wang et al[68]	68 patients: 20 low risk cases–48 high risk cases	Soluble VEGF	Association with lower DSS (P < 0.05)
		VEGF/IHC
		MVD/IHC

OS: Overall survival; DSS: Disease-specific survival; DFS: Disease-free survival; PFS: Progression-free survival; VEGF: Vascular endothelial growth factor; IHC: Immunohistochemistry; MVD: Microvascular density; HIF: Hypoxia-inducible factor.