Chemokines, chemokine receptors and the gastrointestinal system

Table 1 Ligand specificity of chemokine receptors implicated in gastrointestinal disease

CC-chemokines		CXC-chemokines		CX3C-chemokine
Ligands	Receptors	Ligands	Receptors	Ligands	Receptors
CCL2	CCR2	CXCL1	CXCR2/CXCR1	CX3CL1	CX3CR1
CCL3	CCR1/CCR5	CXCL2	CXCR2
CCL4	CCR5	CXCL4L1	CXCR3
CCL5	CCR1/CCR3/CCR5	CXCL5	CXCR2
CCL7	CCR1/CCR2/CCR3	CXCL7	CXCR2
CCL8	CCR3/CCR5	CXCL8	CXCR1
CCL13	CCR2/CCR3	CXCL9	CXCR3
CCL19	CCR7	CXCL10	CXCR3
CCL20	CCR6	CXCL11	CXCR3
CCL21	CCR7	CXCL12	CXCR4/R7
CCL25	CCR9	CXCL14	Unknown
CCL27	CCR10	CXCL17	Unknown

CXCL: CXC chemokine ligand; CXCR: CXC-chemokine receptor; CCR: CC-receptor; CX₃CR: CX₃C-receptor.

Table 2 Chemokines/chemokine receptors in this table appear sequentially according to their description in this review

Organ	Chemokines and receptors	Possible role/observed phenomenon
Oral cavity	CXCL1	Angiogenic activity[103]
	CXCL8	Proliferation, metastasis, tumor development and the induction of inflammation in periodontal disease[60,104-106]
	CXCL5	Proliferation, cell motility and invasion[107]
	CXCR4	Enhancement of invasiveness[108]
	CXCL12	Upregulation in metastasis[109]
	CCR6, CCR7	Involvement in metastatic activity[110]
	CCR7	Enhancement of invasion[111]
	CCL20	Upregulated with bacterial infection in OSCC cell lines[152]
Esophagus	CXCL8	Possible index of inflammation, upregulation in cancer-related cachexia[113,114]
	CXCR4	Positive regulator of HER[116]
Stomach	CXCL12, CXCR4	Metastasis through activation of AKT-mTOR pathway and MMPs, upregulation in lymph node metastasis, strong correlation with tumor development[117,118,124]
	CXCR4	Enhancement of metastasis through p38 signaling pathway[119]
	CXCL12	Acquisition of invasive/metastatic phenotype, enhancement of proliferation when coexpressed with other molecules[120,123]
	CXCL1	Activation of lymphangiogenesis by stimulating LECs[126]
	CXCR2	Strong correlation with TNM staging and lymphatic vessel density[127-130]
	CXCL8	Enhancement of tumor development factors, and a possible risk factor as mutant, association with angiogenesis, development of gastric adenocarcinoma[132-134,183]
	CXCL5	Marker for late stage gastric cancer[137]
	Other candidates	CC-chemokines (CCL2, 3, 5, 21, 25)/CXC-chemokines (1, 7, 8, 12, 14)/CCR6[139]
Liver	CXCR4	Metastasis, upregulation in PVTT[142-143]
	CXCR2	Upregulation in HCC, especially in late stage[128]
	CCL2	Application to prevent metastasis, application to prevent HCC by deactivating AKT pathway[144-147]
	CXCR7	Upregulation in HCC, functional in tumor development and angiogenesis but not in metastasis[148-149]
	CXCL12, CXCR4	Enhancement of tumor cell extravasation through upregulation of Rho/Rac/Cdc42[150]
	CCR6	Upregulation in metastasis[153]
	CCL20	Enhanced expression in HCC[155]
	D6 receptor	Prevention of liver injury[171]
Pancreas	CCL20	Associated with tumor staging[154]
	CCR6	Upregulated in chronic pancreatitis, pancreatic cystadenoma and pancreatic carcinoma[154]
	CXCL5, CXCL8	Upregulation in metastatic pancreatic carcinoma[140]
	CXCL5	Correlated with poorer tumor differentiation, advanced clinical stage, and shorter patient survival, and ERK, AKT and STAT mediated angiogenesis[156]
	CXCL8, CXCR1/2	Upregulation in adenocarcinomas and neuroendocrine tumors[157]
	CXCL12, CXCR4	Downregulation of CXCL12 and upregulation of CXCR4 in tumors. CXCL12 correlated with MVD but not with MLVD, while CXCR4 showed opposite pattern[158]
	CXCR4, CXCR7	CXCR7 associated with tumor grade, inversely associated with tumor size, and possibly associated with tumor progression and differentiation but not with CXCR4[159]
	CX3CL1,CX3CR1	Perineural invasion and dissemination of neoplastic cells along intra- and extra-pancreatic nerves[163,164]
	CXCL17 (+ ICAM2)	Diagnostic molecular marker[167]
	CXCL7 (+ CA19-9)	Diagnostic molecular marker[168]
Colon	CXCL4L1	Upregulation in colorectal cancer[115]
	CCL2	upregulation in mucosa of IBD[169]
	D6 receptor	Plays role of sequestering several chemokines (in mouse colitis model experiment), plays suppressive role in the development and growth of vascular tumors[170,172]
	CCL2, CCR2	important mediator in colon tumor development[173]
	CXCL8	Upregulation along with the development of Crohn's disease, affecting biological responses of human intestinal microvascular endothelial cells in colitis model, positvely correlated with earlier disease stage and improved relapse-free survival[164,175,180]
	CXCL10, CXCL41	Synergistic upregulation with CXCL8 by diverse stimuli, induction by ERK2 and PI-3K/AKT pathway via PAR2[175,178]
	CCL20, CXCL1/2, CXCL8	Remains high even after the treatment with anti-TNF antibody[179]
	CXCL1, CXCR1/2	Upregulation in stage II and III CRC, upregulation in stage II and III CRC[180]
	CXCR3 pathway	CXCL9-pediatric Crohn’s disease, CXCL11-UC in all age groups[181]
	Other chemokines	IL-17 affects CXCL8, CXCL1, CCL20, CXCL10, CXCL11 and CCR5 in colon cancer cells[182]

CXCL: CXC chemokine ligand; CXCR: CXC-chemokine receptor; CCR: CC-receptor; CX₃CR: CX₃C-receptor; CA19-9: Carbohydrate antigen 19-9; OSCC: Oral squamous cell carcinoma; HER: Human epidermal growth factor receptor; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; MMPs: Matrix metalloproteinases; LECs: Lymphatic endothelial cells; TNM: Tumor, node, and metastasis; PVTT: Portal vein tumor thrombus; HCC: Hepatocellular carcinoma; STAT: Signal transducer and activator of transcription; ERK: Extracellular signal-regulated kinase; MVD: Microvessel density; MLVD: Microlymphatic vessel density; IBD: Inflammatory bowel disease; PI-3K: Phosphatidyl inositide-3-OH kinase; PAR2: Protease-activated receptor-2; CRC: Colorectal cancer; IL: Interleukin; TNF-α: Tumor necrosis factor-α.