Role for CXC Cytokine Receptors in Metastases

dandelionTwo recent reports in the British Journal of Cancer highlight the importance of chemokines in the spread and progression of cancer.

Using a mouse xenograft model, researchers from the University of Nebraska Medical Center showed that CXCR1 and CXCR2 receptors are important in the progression of melanoma, the most aggressive form of skin cancer. The study, which is published in the May 12th issue of the journal, investigated the effect of overexpression of CXCR1 or CXCR2 in two different human melanoma cell lines – one non-tumourigenic and the other with low tumourigenicity. Both cell lines showed low endogenous expression of the receptors. Both CXCR1- or CXCR2-overexpressing melanoma cells showed enhanced proliferation, chemotaxis and invasiveness in vitro. In vivo, overexpression induced tumourigenicity in the non- tumourigenic cell line and significantly enhanced tumour growth in the low-tumourigenic cell line. Tumours generated from CXCR1- or CXCR2-overexpressing melanoma cells showed significantly increased tumour cell proliferation and microvessel density as well as reduced apoptosis, indicating an essential role for the receptors in growth, survival, motility and invasion of human melanoma.

AMG487 structureThe second study, published in the 12th May advance online edition of the journal, investigated the effect of CXCR3 receptors on the metastasis of colorectal cancer (CRC). Liver and lung metastases are the main cause of death from colorectal cancer and the study looked at the ability of CXCR3-expressing CRC cell lines from humans or mice to induce metastases in immunodeficient and immunocompetent mice, respectively. In vitro, activation of CXCR3 on both human and mouse CRC cells by its cognate ligands induced migratory and growth responses which could be blocked by the CXCR3 receptor antagonist, AMG487. In vivo, preventative or curative treatment with AMG487 markedly inhibited implantation and growth of both human and mouse CRC cells in the lung, but had no effect on metastases affecting the liver.