CONICET | Buscador de Institutos y Recursos Humanos

The observation that leukocytes infiltrate tumors led Virchow in 1863 to propose the existence of a link between chronic inflammation and cancer. The tumor microenvironment is populated by different cell types that can interact by direct cell-cell contact or may communicate through soluble factors. This bidirectional communication critically influences tumor progression and recent insights suggest that has a crucial role in the resistance to chemotherapy observed in many cancer types. In that regard, increasing evidences in the last few years demonstrate that sphingosine-1-phosphate (S1P), a bioactive sphingolipid with many functions in cancer and inflammation, displays important roles in the tumor microenvironment. Indeed, numerous studies show that augmented tissue levels of this sphingolipid metabolite affect survival, proliferation, angiogenesis and metastatic spread of many cancers. We and others have shown that S1P recruit monocytes toward the tumor tissue and induces their differentiation to M2-like tumor associated macrophages (TAM). Moreover, our results uncovered that S1P is involved in the activation of NF-B, a transcription factor that has been pointed as critical for inflammation and tumorigenesis. In turn, activation of NF-B reduces apoptosis while induces cytokine and chemokine release that may enhance tumor growth. In addition, our preliminary results indicate that S1P modulates the viability of murine melanoma cells and enhances the migratory ability of human BRAFV600E melanoma cells in hypoxia, a main hallmark of the tumor microenvironment. Altogether, these results highlight the many functions of this sphingolipid in cancer progression through modulation of distinct and important features of the disease, including phenotypic plasticity of immune cells, survival and metastatic potential of tumor cells and hypoxic response.