Antagonising the CXCL12 pathway with AMD3100 inhibits skin cancer

Abstract

One way sunlight causes skin cancer is by suppressing the anti-tumor immune response. A major mechanism involves altering mast cell migration via the C-X-C motif chemokine receptor 4-C-X-C motif chemokine ligand 12 (CXCR4-CXCL12) chemokine pathway. I have discovered that pharmacologically blocking this pathway with the CXCR4 antagonist AMD3100 prevents both UV radiation-induced immune suppression and skin cancer. The majority of control mice receiving UV-alone developed histopathologically confirmed squamous cell carcinomas. In contrast, skin tumor incidence and burden was significantly lower in AMD3100-treated mice. Perhaps most striking was that AMD3100 completely prevented the outgrowth of latent tumors that occurred once UV irradiation ceased. AMD3100 protection from UV immunosuppression and skin cancer was associated with reduced mast cell infiltration into the skin, draining lymph nodes, and the tumor itself. Thus a major target of CXCR4 antagonism was the mast cell. The results presented in this thesis provide important evidence that the CXCR4-CXCL12 chemokine axis plays multiple roles in the development of UV-induced skin cancer. It makes a significant and unique contribution to our understanding of the effects of antagonising CXCR4 in chronic UV-induced skin damage, mast cell migration, UV- immune suppression and melanin production. These studies provide important pre-clinical proof of principle evidence that antagonising CXCR4 will be of therapeutic benefit to high risk, chronically sun-damaged patients.