Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonism

Abstract

e14619 Background: Liver and lung metastases are the predominant cause of colorectal cancer (CRC) related mortality. Recent research has indicated that CXCR3/chemokines interactions that orchestrate hematopoetic cell movement are implicated in the metastatic process of malignant tumors, 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. Methods: 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. Results: 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 metastasis of human and mouse CRC cells to the lung without affecting that to the liver. Also, we measured increased levels of CXCR3 and ligands expression within lung nodules compared to liver tumors. Conclusions: Altogether, our findings indicate that CXCR3 is a key mediator for lung metastasis of colon carcinoma and identify CXCR3-blocking approaches as promising strategies against established lung metastases. No significant financial relationships to disclose.