The role of the CXCR4-CXCL12 chemokine axis in melanoma metastasis to the normal and fibrotic liver

Abstract

Malignant melanoma represents the most aggressive form of skin cancer. Although early stage disease is treatable through surgical excision alone, late stage tumours frequently metastasise to the liver, at which point treatment options remain limited. Migration of melanoma towards metastatic sites has been shown to be associated with the CXCR4-CXCL12 chemokine axis. The chemokine receptor CXCR4 is expressed by melanoma cells and the chemokine CXCL12 is secreted by the liver. Expression of CXCL12 has been shown to be increased in liver fibrosis and therefore it was hypothesized that cells involved in liver damage may promote melanoma metastasis to this organ. CXCR4 and CXCL12 expression in melanoma and liver cells in vitro and in vivo was examined by RT-PCR, Western blotting and immunohistochemical staining. Chemotaxis assays were performed to test the ability of AMD11070 to inhibit migration of melanoma cells. Quantitative RT-PCR and Western blotting determined the influence of different fibrosis models (Carbon tetrachloride (CCl4), Bile Duct Ligation (BDL) and Methapyrilene (MP)) on CXCL12 expression. Furthermore, the migration of melanoma was examined in animal models of liver injury. Results showed that melanoma cells and different liver cell types (myofibroblasts and biliary epithelial cells) express both CXCR4 and CXCL12. CXCR4 expression in melanoma promoted migration of tumour cells towards CXCL12 secreting liver cells and AMD11070 inhibited this. CXCR4 and CXCL12 proteins of varying sizes were observed in vivo suggesting that post translational modifications of these proteins may occur. CXCL12 expression increased in three models of chronic liver injury; CCl₄, BDL and MP. In an animal model, murine melanoma cells metastasized to the lungs and to both the fibrotic and normal liver. These findings suggest that the reduction of liver cells secreting CXCL12 may help to reduce melanoma metastasis to this organ.