Both cell-autonomous and non-cell-autonomous factors contribute to
tumor growth and
metastasis of
melanoma. The function of
caveolin-1 (Cav1), a multifunctional scaffold
protein known to modulate several biologic processes in both normal tissue and
cancer, has been recently investigated in
melanoma cancer cells, but its role in the
melanoma microenvironment remains largely unexplored. Here, we show that orthotopic implantation of B16F10
melanoma cells in the skin of Cav1KO mice increases
tumor growth, and co-injection of Cav1-deficient dermal fibroblasts with
melanoma cells is sufficient to recapitulate the
tumor phenotype observed in Cav1KO mice. Using indirect coculture experiments with fibroblasts and
melanoma cells combined with
cytokine analysis, we found that Cav1-deficient fibroblasts promoted the growth of
melanoma cells via enhanced paracrine
cytokine signaling. Specifically, Cav1-deficient fibroblasts displayed increased ShhN expression, which heterotypically enhanced the Shh signaling pathway in
melanoma cells. In contrast to primary
tumor growth, the ability of B16F10
melanoma cells to form lung
metastases was significantly reduced in Cav1KO mice. This phenotype was associated mechanistically with the inability of
melanoma cells to adhere to and to transmigrate through a monolayer of endothelial cells lacking Cav1. Together, our findings show that Cav1 may regulate different mechanisms during primary
melanoma tumor growth and metastatic dissemination.