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.