Tumor progression-dependent angiogenesis in gastric cancer and its potential application

Table 1 Regulators of tumor angiogenesis in gastric cancer and their use in antiangiogenic therapy

Biological category	Gene name	Regulator of pro-/anti angiogenic types	Antiangiogenic drug	Drug direct target	Preclinical trials; cell line (in vitro)/animal (in vivo)	Clinical application
						Expression levels in GC patients	Prognostic factors (proangiogenic biomarker)
Transcription factor	Hypoxia	Activator	NSAID[82]	COX-1, COX-2 inhibitor	●	ND	ND
	HIF[16-19,22-25]
Growth factor	VEGF family[26-38]	Activator	Aflibercept[22]	Anti-VEGF-A	●	VEGF-A, C	Lymph node metastasis
						overexpres-sion[21,41-47]	(VEGF-A, C)
							Distant metastasis
				Anti-PIGF			(VEGF-A)
							Poor survival
							(VEGF-A)
			Bevacizumab[83-89]	Anti-VEGF-A	●	ND	ND
			IFN[90]	Anti-IFNR	●	ND	ND
			Rapamycin[91]	Anti-rapamycin kinase	●	ND	ND
			Neovastat[92]	Anti-VEGF	●	ND	ND
	PIGF[29,30,35,48]	Activator	Aflibercept[22]	Anti-VEGF-A	●	PIGF	ND
				Anti-PIGF		overexpres-sion[49-51]
	FGF, EGF, HGF, IGF[31,52-55]	Activator	IFN[93]	Anti-IFNR	●	ND	ND
	PDGF[56,57]	Activator	SU6668	Multiple receptor	●	ND	ND
			Orantinib[94]	TKI
Growth factor receptor	VEGFR[32,33]	Activator	Ramuci-rumab[95-97]	Anti-VEGFR2	●	ND	ND
			Regorafenib[98,99]	VEGFR TKI	●	ND	ND
			Apatinib[98,99]	VEGFR TKI	●	ND	ND
			Foretinib[98,99]	VEGFR TKI	●	ND	ND
			SU5416	Multiple receptor (KDR/FGFR/PDGFR)	●	ND	ND
			SU6668
			Orantinib[94]
			Pazopanib[100]	Multiple receptor TKI	●	ND	ND
			Sorafenib (Nexavar)[101,102]	Multikinase inhibitor (the serine/threonine kinase Raf and receptor tyrosine kinases)	●	ND	ND
			Sunitinib	Multitargeting TKI	●	ND	ND
			(Sutent)[103,104]
			Telatinib	Multitargeting TKI	●	ND	ND
			Erbitux (Cetuximab)[105]
	GP130	Activator	ND	ND	●	ND	ND
	IL-6R[58]
	Her2/	Activator	Trastuzumab[59,62]	Anti-Her2/Neu	●	ND	ND
	Neu[59-62]
Cytokine	Ang-1,3,4[63,64,66-73]	Activator	ND	ND	●	Ang-1,2	Lymph node metastasis
						overexpres-sion[74-77]	Liver metastasis
	Ang-2[65,66]	Activator					Poor survival
		Inhibitor
	IL-6 [58]	Activator	ND	ND	●	ND	ND
	IL-8[37,106]	Activator	ND	ND	●	ND	ND
	IL-17[78]	Activator	ND	ND	●	ND	ND
	Tryptase[79,80]	Activator	ND	ND	●	Tryptase overexpres-sion[81]	ND
ECM	MMP[92],[107,108]	Activator	Marimastat[107,108]	MMP inhibitor	●	ND	ND
			Bay 12-9566
			AG3340
			Neovastat[92]

GC: Gastric cancer; ND: Not determined; ●: Determined; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; TKI: Tyrosine kinase inhibitor.