Targeting the SphK1/S1P/S1PR1 axis that links obesity, chronic inflammation and breast cancer metastasis

Although obesity with associated inflammation is now recognized as a risk factor for breast cancer and distant metastases, the functional basis for these connections remain poorly understood. Here we show that in breast cancer patients and in animal breast cancer models, obesity is a sufficient cause for increased expression of the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P) which mediates cancer pathogenesis. A high fat diet was sufficient to upregulate expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P, along with its receptor S1PR1 in syngeneic and spontaneous breast tumors. Targeting the SphK1/S1P/S1PR1 axis with FTY720/fingolimod attenuated key pro-inflammatory cytokines, macrophage infiltration and tumor progression induced by obesity. S1P produced in the lung pre-metastatic niche by tumor-induced SphK1 increased macrophage recruitment into the lung and induced IL-6 and signaling pathways important for lung metastatic colonization. Conversely, FTY720 suppressed IL-6, macrophage infiltration and S1P-mediated signaling pathways in the lung induced by a high fat diet, and it dramatically reduced formation of metastatic foci. In tumor-bearing mice, FTY720 similarly reduced obesity-related inflammation, S1P signaling and pulmonary metastasis, thereby prolonging survival. Taken together, our results establish a critical role for circulating S1P produced by tumors and the SphK1/S1P/S1PR1 axis in obesity-related inflammation, formation of lung metastatic niches and breast cancer metastasis, with potential implications for prevention and treatment.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2mW8o5Q