Poster Sessions

CANCER-28

M. Zaidi

M.R. Zaidi, E. De Fabo, S. Davis, C. Graff-Cherry, T. Hawley, L. Feigenbaum, E. Fuchs, T. Hornyak, H. Arnheiter, G. Trinchieri, F. Noonan, P. Meltzer, G. Merlino

Ultraviolet Radiation-mediated Melanocyte Activation and Melanoma Susceptibility through Pro-inflammatory Microenvironmental Elements

Ultraviolet radiation (UV) is a major risk factor for melanomagenesis, but the underlying mechanisms are not well understood. We have generated a novel mouse model that expresses GFP in melanocytes specifically, allowing us to study melanocytes within their natural microenvironment. Using this model we have shown that neonatal UVB irradiation, but not UVA, induces melanocyte activation resulting in proliferation and migration towards epidermis. Microarray analysis of skin melanocytes isolated following UVB irradiation, but not UVA, showed upregulation of a distinct Interferon-induced gene expression signature. Antibody-mediated blockage of Interferon-gamma (Ifng) eliminated the UVB-induced melanocyte activation, but blockage of Type-I Interferons had no effect. The source of Ifng was a subset of macrophages that infiltrate the skin after UVB, but not UVA. These macrophages enhanced the growth of tumors when admixed with a mouse melanoma cell line and transplanted subcutaneously into syngeneic mice. The admixed tumors showed significantly less apoptosis than the control tumors, indicating activation of survival pathways in melanocytes. Finally, a human melanoma tissue microarray demonstrated the presence of Ifng-secreting macrophages in 70% of tumors. We conclude that Ifng is a critical signaling component of UVB-induced pro-tumorigenic inflammatory microenvironment of the skin, and defines melanocytic behavior by enhancing cellular survival.