Chemokines and their receptors play important roles in the development of hepatocellular carcinoma

Table 1 Chemokines and chemokine receptors in hepatocellular carcinoma

Chemokines	Other names	Chemokine receptors	Subclass	Ref.
CXCL1	GROα	CXCR2	CXC	[20,21,83]
CXCL2	GROβ	CXCR2	CXC	[21,83]
CXCL5	ENA78	CXCR2	CXC	[21,22]
CXCL8	IL-8	CXCR1, CXCR2	CXC	[16,17,21]
CXCL9	MIG	CXCR3	CXC	[17,18,70]
CXCL10	IP-10	CXCR3	CXC	[17,29,51,70]
CXCL11	I-TAC	CXCR3, CXCR7	CXC	[14,50]
CXCL12	SDF-1	CXCR4, CXCR7	CXC	[12,13,15,86,89,92]
CXCL14	BRAK	Unknown	CXC	[23]
CXCL16	SR-PSOX	CXCR6	CXC	[49,106]
CCL2	MCP-1	CCR2	CC	[17,56,81,116]
CCL3	MIP-1α	CCR1, CCR5	CC	[27,28,81,122]
CCL4	MIP-1β	CCR5	CC	[29,48]
CCL5	RANTES	CCR1, CCR3, CCR5	CC	[27,29,100]
CCL15	HCC-2, leukotactin-1	CCR1, CCR3	CC	[33,100]
CCL17	TARC	CCR4	CC	[34,66]
CCL19	ELC, MIP-3β	CCR7	CC	[37,117-119]
CCL20	MIP-3α	CCR6	CC	[30-32]
CCL21	SLC	CCR7	CC	[37,117-119]
CCL22	MDC	CCR4	CC	[35,66]
CCL26	Eotaxin-3	CCR3, CX3CR1	CC	[110]
CCL27	CTACK, ILC	CCR10	CC	[36]
CX3CL1	Fractalkine	CX3CR1	CX3C	[39,40]

GRO: Growth regulated oncogene; ENA78: Epithelial neutrophil-activating protein 78; IL-8: Interleukin 8; MIG: Monokine induced by IFN-γ; IP-10: IFN-γ-induced protein 10; I-TAC: IFN-inducible T cell alpha chemoattractant; SDF-1: Stromal cell-derived factor 1; BRAK: Breast and kidney expressed chemokine; SR-PSOX: Scavenger receptor that binds phosphatidylserine and oxidized lipoprotein; MCP-1: Monocyte chemotactic protein 1; MIP-1α: Macrophage inflammatory protein-1α; HCC: Hepatocellular carcinoma; TARC: Thymus activation-regulated chemokine; ELC: Epstein-Barr virus-induced molecule 1 ligand CC chemokine; SLC: Secondary lymphoid tissue chemokine; MDC: Macrophage-derived chemokine; CTACK: Cutaneous T-cell-attracting chemokine; ILC: Interleukin-11 receptor α-locus chemokine; IFN: Interferon.

Table 2 Pleiotropic functions of chemokines in hepatocellular carcinoma

Categories	Chemokines	Chemokine origins	Receptors participated	Functions
Inflammation	CXCL8	HCC cells	Not clarified	Increasing inflammatory cytokines
	CXCL16	HCC cells	CXCR6	(IL-6, IL-8, etc.) and recruiting leukocytes
	CCL3	HCC cells and HSC	CCR3	(macrophages, neutrophils, etc.)
	CCL5	HCC cells and HSC	CCR5
Influences on immune cells	CXCL5	HCC cells	Not clarified	Chemotaxis of neutrophils
	CXCL9	HCC cells and endothelial cells	CXCR3	Chemotaxis of T cells
	CXCL10	HCC cells, macrophages and TILs	CXCR3	Chemotaxis of T cells and NK cells
	CXCL16	HCC cells	CXCR6	Chemotaxis of neutrophils
	CCL2	HCC cells, macrophages and TILs	CCR2	Chemotaxis of HSC, macrophages, MDSC, and T cells
	CCL5	HCC cells, macrophages and TILs	CCR5	Chemotaxis of T cells and NK cells
	CCL20	HCC cells	CCR6	Chemotaxis of Th17 cells and Tregs
	CCL22	HCC cells and DCs	CCR4	Chemotaxis of Tregs
Angiogenesis	CXCL3, CXCL5	HCC cells	Not clarified	Promoting angiogenesis via mechanisms not clarified
	CXCL8	CSCs	Not clarified	Promoting endothelial cell tube formation
	CXCL9	Not clarified	CXCR3	Inhibiting angiogenesis by abrogation of VEGF effects
	CXCL12	Endothelia cells	CXCR4, CXCR7	Enhancing angiogenesis through VEGF
	CXCL16	HCC cells	CXCR6	Promoting angiogenesis via mechanisms not clarified
	CCL2	HCC cells and endothelial cells	CCR2	Enhancing the proliferation of endothelial cells
	CCL3	HCC cells and endothelial cells	CCR1, CCR5	Enhancing the proliferation of endothelial cells
Direct effects on HCC cells	CXCL1, CXCL2, CXCL16	Not clarified	Not clarified	Enhancing the growth of HCC cells
	CXCL5	HCC cells	Not clarified	Enhancing the migration, invasion, and growth of HCC cells
	CXCL8	Not clarified	CXCR2	Enhancing the migration of HCC cells
	CXCL10	hepatocytes	Not clarified	Enhancing the survival of hepatocytes
	CXCL12	HCC cells, HSC	CXCR4, CXCR7	Enhancing the migration, invasion, growth and survival of HCC cells
	CCL2	WAT, CAF	CCR2	Enhancing the migration, invasion, and growth of HCC cells
	CCL3, CCL5	Not clarified	CCR1	Enhancing the migration and invasion of HCC cells
	CCL15	HCC cells	Not clarified
	CCL20	HCC cells	CCR6	Enhancing the migration, invasion, and growth of HCC cells

HSC: Hepatic stellate cells; TILs: Tumor-infiltrating leucocytes; MDSC: Myeloid derived suppressor cells; Tregs: Regulatory T cells; DCs: Dendritic cells; VEGF: Vascular endothelial growth factor; CSCs: Cancer stem cells; WAT: White adipose tissue; CAF: Cancer-associated fibroblast; HCC: Hepatocellular carcinoma.