Table 4.

Relevant studies of NCTD anti-angiogenesis, anti-VM, and anti-lymphangiogenesis

Anticancer activities	Cancers	Cell lines	Basic mechanisms	Pathways	Accompanying roles	Experiment	References
Anti-angiogenesis	Gallbladder cancer	GBC-SD	Inhibiting capillary-like tube formation of HUVECs in vitro; destroying angiogenesis and CAM capillaries; decreasing xenograft MVD and vascular perfusion in vivo; downregulating VEGF, Ang-2; upregulating TSP, TIMP-2		Prolonging xenograft-mice survival	In vitro	[84]
		GBC-SD	Lower MVD and PCNA/apoptosis ratio, smaller tumor volume; down-regulating VEGF and Ang-2, and up-regulating TSP and TIMP2; MVD positively correlating with VEGF, Ang-2n and negatively correlating with TSP and TIMP2			In vitro In vivo	[83]
	Colorectal cancer	HCT116	Inhibiting xenograft growth and tumor angiogenesis in vivo; reducing migration, adhesion and vascular network tube formation of HUVECs in vitro; downregulating VEGF and VEGFR-2	Downregulating VEGF and VEGFR-2		In vivo	[85]
		CT26	Inhibiting viability, adhesion, migration, capillary-like tube formation of HUVECs, and the release of pro-angiogenic factors from HUVECs; inducing anoikis; down-regulating VEGF, integrin β1, vimentin, p-JNK and p-ERK	Down-regulating VEGF and inhibiting MAPK (JNK/ERK) signaling	Without renal or hepatic toxicity	In vitro In vivo	[14]
		LOVO	Inhibiting VEGF-induced proliferation, migration, invasion, capillary tube formation of HUVECs and LOVO proliferation; inhibiting tumor angiogenesis and tumor growth in vivo; inhibiting VEGFR2/MEK/ERK pathway	Blocking VEGFR2/MEK/ERK			[86]
Anti-VM	Gallbladder cancer	GBC-SD	Inhibiting proliferation, invasion, migration, VM formation in vitro and in vivo; downregulating EphA2, FAK and Paxillin	Blocking the EphA2/FAK/Paxillin signaling pathway	Prolonging xenograft mice survival	In vitro In vivo	[13]
		GBC-SD	Inhibiting proliferation, growth, invasion, migration and VM formation in vitro and in vivo; downregulating MMP-2, MT1-MMP, PI3-K, Ln-5γ2	Suppression of the PI3-K/MMPs/Ln-5γ2 signaling pathway			[91]
		GBC-SD	MMP‑2, MT1‑MMP relating tumor VM In vitro; a poor survival in VM+ patients with high MMP‑2, MT1‑MMP expression; inhibiting tumor growth, VM formation, VM hemodynamic in vivo; inhibiting proliferation, invasion, migration and VM‑like networks in vitro; downregulating MMP‑2 and MT1‑MMP in vivo and in vitro; thus, enhancing TIMP‑2 antitumor and anti‑VM activities	Enhancing TIMP-2 anti-VM via downregulating MMP-2 and MT1-MMP	With TIMP-2 synergistic effect; prolonging xenograft mice survival		[92]
	Melanoma	A375		Suppressing MMP-2 expression		In vitro In vivo	[83]
Anti-lymphangiogenesis	HLEC	HDLECs	Inhibiting proliferation, migration, invasion, lymphatic tube formation (lymphangiogenesis), inducing apoptosis; downregulating VEGF-C, VEGF-D and VEGFR-3 expression	Blocking VEGF-C,-D, VEGFR-3		In vitro	[98]
		HDLECs	Inhibiting growth, lymphatic tube formation; inducing apoptosis; downregulating VEGF-C and VEGF-D expression	Downregulating the expression of VEGF-C and VEGF-D			[99]
	Colorectal cancer	HT-29	S-phase cell-cycle arrest; Inhibiting proliferation, migration, invasion, lymphatic tube formation in vitro and tumor growth and lymphangiogenesis in vivo; downregulating Ki-67, Bcl-2, LYVE-1, D2-40, CK20 and their LMVD, and VEGF-A, VEGF-C, VEGF-D, VEGFR-2 and VEGFR-3 in vitro and in vivo	Blocking the VEGF-A,-C,-D, VEGFR-2, -3 “multi-points priming” mechanisms	With mF4-31C1 or Sorafenib synergistic effect	In vitro In vivo	[100]
	AML	TSC-null cell 21-101	Inhibiting proliferation of TSC2−, TSC2+ cells with rapamycin		An additive effect between rapamycin and NCTD in inhibiting lymphangiogenesis	In vitro	[171]