Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonism

• Published in: British journal of cancer Vol. 100; no. 11; pp. 1755 - 1764
• Main Authors: Cambien, B, Karimdjee, B F, Richard-Fiardo, P, Bziouech, H, Barthel, R, Millet, M A, Martini, V, Birnbaum, D, Scoazec, J Y, Abello, J, Saati, T Al, Johnson, M G, Sullivan, T J, Medina, J C, Collins, T L, Schmid-Alliana, A, Schmid-Antomarchi, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.06.2009; Nature Publishing Group; Cancer Research UK
• Subjects: Animals; Antibodies; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer; Cancer Research; Cell Line, Tumor; Cell Movement; Chemokines; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Drug Resistance; Epidemiology; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Immunocompetence; Laboratory animals; Life Sciences; Ligands; Liver; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Lymphatic system; Medical research; Medical sciences; Melanoma; Metastasis; Mice; Molecular Medicine; Neoplasm Transplantation; Oncology; Organ Specificity; Receptors, CXCR3 - antagonists & inhibitors; Receptors, CXCR3 - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Survival Rate; Translational Therapeutics; Tumors; France; United States > US; anti-tumour strategy; animal model; metastasis; colon cancer; chemokine receptor; Antineoplastic agent; Animal model; Chemokine receptor; Malignant tumor; Metastasis; Colonic disease; Antagonism; Colon cancer; Cancerology; Digestive diseases; Intestinal disease; Advanced stage; Inhibitor; Colon carcinoma; Cancer; Organ; CXCR3 chemokine receptor
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605078

Liver and lung metastases are the predominant cause of colorectal cancer (CRC)-related mortality. Recent research has indicated that CXCR3/chemokines interactions that orchestrate haematopoetic cell movement are implicated in the metastatic process of malignant tumours, including that of CRC cells to lymph nodes. To date, however, the contribution of CXCR3 to liver and lung metastasis in CRC has not been addressed. To determine whether CXCR3 receptors regulate malignancy-related properties of CRC cells, we have used CXCR3-expressing CRC cell lines of human (HT29 cells) and murine (C26 cells) origins that enable the development of liver and lung metastases when injected into immunodeficient and immunocompetent mice, respectively, and assessed the effect of CXCR3 blockade using AMG487, a small molecular weight antagonist. In vitro , activation of CXCR3 on human and mouse CRC cells by its cognate ligands induced migratory and growth responses, both activities being abrogated by AMG487. In vivo , systemic CXCR3 antagonism by preventive or curative treatments with AMG487 markedly inhibited the implantation and the growth of human and mouse CRC cells within lung without affecting that in the liver. In addition, we measured increased levels of CXCR3 and ligands expression within lung nodules compared with liver tumours. Altogether, our findings indicate that activation of CXCR3 receptors by its cognate ligands facilitates the implantation and the progression of CRC cells within lung tissues and that inhibition of this axis decreases pulmonary metastasis of CRC in two murine tumour models.