Abstract 1572: The role of MIF signaling in melanoma progression

Abstract

Abstract Melanoma is the most life-threatening form of skin cancer and although highly curable at the early stages, metastatic melanoma is incurable. One of the early events in melanoma progression is the activation of ERK and Akt signalling pathways, involved in proliferation, migration and survival. The causes of such kinase activation include mutations in BRAF, N-RAS and PTEN. Besides gene mutation, it has been shown that autocrine production of growth factors can also contribute to ERK and Akt activation in melanoma. As both pathways are believed to contribute to the chemotherapeutic resistance of melanoma cells, an effective treatment should target both ERK and Akt cascades. One potentially attractive target is the cytokine MIF (migration inhibition factor), since MIF can activate both the ERK and the Akt pathways. Targeting of MIF signalling in tumours producing autocrine MIF is already showing promise in prostate, breast and bladder cancers and although limited, some in vitro evidence suggests that MIF is an autocrine factor involved in the growth and invasion of melanoma cells. We have now extended these findings in an immunohistological study showing the universal in vivo expression of MIF in melanoma with increasing expression levels associated with metastatic tumours. MIF signalling can act through both CXCR4 and CD74/CD44 receptors, the latter molecule acting as a co-receptor. Examination of a panel of 20 melanoma cell lines showed 20/20 to express MIF and CD44 with 7/20 also co-expressing CD74. Only 6/20 cell lines showed heterogenous expression of CXCR4. Inhibition of MIF expression using siRNA-mediated gene knockdown decreased the proliferation and cell migration in a number of melanoma cell lines, an effect attributed to effects on cell cycle with a reduction of the number of cells entering S phase. Conversely, addition of exogenous MIF was shown to increase ERK phosphorylation. Taken together, these results suggest a role for MIF in melanoma progression. Future work will aim to determining the molecular nature of the receptors driving MIF signalling in melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1572.