Oral communication, CS18 / C85

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

Edn3 promotes metastasis and alters tumor heterogeneity in a mouse model of melanoma

Melanoma is highly metastatic and resistant to current therapies. Accumulating evidence suggests that particular populations of tumor cells with a more undifferentiated phenotype may be responsible for these characteristics. Melanoma progression and metastasis is not only a result of these cells’ intrinsic properties but is also determined by a number of complex tumor-host interactions. Cytokines released by cells in the tumor and in the microenvironment alter a variety of processes that result in tumor progression and malignancy. Tumor cells with a more undifferentiated phenotype may be more sensitive to the effects of these secreted factors and acquire a highly metastatic potential. The cytokine Endothelin 3 (Edn3) has been implicated in melanoma progression based on in vitro data showing that Edn3 alters the expression of cell adhesion proteins and metalloproteinases in melanoma cell lines. In this study we investigated the effects of Edn3 over-expression in melanoma progression and heterogeneity in vivo. We crossed Dct-Grm1 mice whose expression of the metabotropic glutamate receptor 1(Grm1) under the Dopachrome tautomerase (Dct) promoter produce spontaneous melanocytic lesions in the ears and tails that do not metastasize, with transgenic mice that over express Edn3 under the keratin 5 promoter (K5-Edn3). Tumors appeared 2 to 3 months earlier and grew at a rate 3-4 times faster in Dct-Grm1/K5-Edn3 mice when compared to the Dct-Grm1 control mice. Ninety-five percent of Dct-Grm1/ K5-Edn3 mice had pigmented lesions in distant organs such as the lung, spleen and salivary glands. These results indicate that Edn3 paracrine signaling alters the kinetics of melanocytic tumors’ progression and can lead them to a fully malignant state. Dct-Grm1 tail tumors present heterogeneity with cells at different levels of differentiation as shown by non-overlapping populations of cells expressing the stem cell marker Nestin and the melanocyte-specific marker Tyrosinase related protein 1 (Trp1). There was a dramatic increase in the number of Nestin positive cells in the tail tumors of Dct-Grm1/ K5-Edn3 when compared to Dct-Grm1control tumors indicating that Edn3 affects the size of the undifferentiated cell population. Together these results suggest that Edn3 may promote metastasis by regulating tumor cellular heterogeneity.

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