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.

Table 2 Overview of phase-III clinical trials in gastric cancer including vascular endothelial growth factor, vascular endothelial growth factor receptor and vascular endothelial growth factor receptor tyrosine kinase inhibitor blockers

Tar-get C Cate-gory	Blockers	Country	Cancer type	Setting	Treat-ment	N	ORR (%)	DCR (%)	PFS (mo)	OS (mo)	Top 5 adverse events	Ref.
							HR (95% CI)P value	P value	HR (95% CI)P value	HR (95% CI)P value
Anti-VEGF	Bevaci-zumab (Mono-clonal Ab)	Multieth-nic	●Metasta-tic GC	1st-line	Bevaci-zumab	387	46%	76.90%	6.7	12.1	Neutro-penia	AVA-GAST[114]
		Asia-Pacific	Unresec-table locally advanced GC		+Cis/Cap						Febrile neutrope-nia
		Europe	Recurrent GC								Anemia
		Pan-America	Gastro-esophageal junction GC		Placebo	387	37.40%	67.70%	5.3	10.1	Decreased appetite
					+Cis/Cap		P = 0.0315	ND	P = 0.0037	P = 0.1002	Diarrhea
		China	Metastatic GC	1st-line	Bevacizumab	100	40.70%	75.30%	6.3	10.5	Vomiting	AVA-TAR[115]
			Unresectable locally advanced GC		+Cis/Cap						Neutrope-nia
			Recurrent GC								Nausea
			Gastro-esophageal junction GC								Anemia
					Placebo	102	33.70%	72.10%	6	11.4	Intestinal obstruc-tion
					+Cis/Cap
							P = 0.348	ND	P = 0.4709	P = 0.5567
		China	Unresectable locally advanced GC	1st-line	Bevacizumab	40	65%	30%	15.2	17.6	Nausea	[116]
					+Doc/Oxa/5-FU						Vomiting
											Sensory neuropa-thy
					Placebo	40	42.50%	42.50%	12.3	16.4	Leukope-nia
					+Doc/Oxa/5-FU		P = 0.0436	ND	P = 0.013	P = 0.776	Decreased hemoglo-bin
		United Kingdom	Resectable GC	Peri-operative	Bevacizumab	530	ND	ND	ND	48.10%	Lethargy	(United Kingdoms Medical Research Council ST03) [117]
			Esophagogastric junction GC		+Cis/Cap/Epi						Nausea
			Lower esophageal GC								Neutropenia
											Diarrhea
					Placebo	533	ND	ND	ND	50.30%	Alopecia
					+Cis/Cap/Epi		ND	ND	P = 0.56	P = 0.36
Anti-VEGFR	Ramucirumab	Multieth-nic	Advanced gastric GC	2nd-line	Ramucirumab	238	3%	49%	2.1	5.2	Fatigue	REG-ARD[118]
	(Monoclonal Ab)	North America, Europe, Australia,	Gastro-esophageal junction GC		+ Pla/5-Fu						Abdomi-nal pain
		New Zealand									Decreased appetite
		Asia									Vomiting
		South and Central America, India, South Africa, Middle East			Placebo	117	3%	23%	1.3	3.8	Constipa-tion
					+ Pla/5-Fu
							ND	P = 0.76	P < 0.0001	P = 0.047
		Multieth-nic	Advanced gastric GC	2nd-line	Ramucirumab	330	28%	80%	4.4	9.63	Fatigue	RAIN-BOW[119]
		North and South America	Gastro-esophageal junction GC		+ Pac						Neuropa-thy
		Europe									Decreased appetite
		Australia,			Placebo	335	16%	64%	2.86	7.4	Abdomi-nal pain
		Asia			+ Pac						Nausea
							P < 0.0001	P = 0.0001	P < 0.0001	P = 0.0169
		Multieth-nic	Metastatic GC	1st-line	Ramucirumab	326	41.10%	81.90%	10.2	11.2	Neutropenia	RAIN-FALL[120]
		North America	Gastro-esophageal junction GC		+ Cis/5-Fu						Anaemia
		Europe									Hypertension
		Japan			Placebo	319	36.40%	76.50%	9.2	10.7	Palmar-plantar erythrodysesthesia syndrome
					+ Cis/5-Fu						Fatigue
							P = 0.17	P = 0.095	P = 0.4	P = 0.68
VEGF	apatinib	China	Metastatic GC	3rd-line	Apatinib	176	2.84	42.05	2.6	6.5	Hand-foot syndrome	[121]
TKI			Advanced GC								Proteinu-ria
			Gastro-esophageal junction GC								Hyperten-sion
					Placebo	91	0	8.79	1.8	4.7	Myelosuppression
							P < 0.001	P = 0.1695	P < 0.001	P = 0.0149	Nausea and vomiting

A P value less than 0.05 indicates statistical significance according to the Mann-Whitney U test. VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; TKI: Tyrosine kinase inhibitor; ORR: Median overall response rate; DCR: Median disease control rate; PFS: Median progression-free survival; OS: Median overall survival; Cis: Cisplatin; Cap: Capecitabine; Doc: Docetaxel; Oxa: Oxaliplatin; 5-FU: 5-Fluoropyrimidin; Epi: Epirubicine; Pla: Polylactic acid; Pac: Paclitaxel; HR: Hazard ratio; CI: Confidence interval.