Prostate tumor cell-derived IL-1β induces an inflammatory phenotype in bone marrow adipocytes and reduces sensitivity to docetaxel via lipolysis-dependent mechanisms

Adipocyte-tumor cell crosstalk is one of the critical mediators of tumor progression and an emerging facilitator of therapy evasion. Tumor cells that metastasize to adipocyte-rich bone marrow take advantage of the interplay between metabolic and inflammatory pathways to activate pro-survival mechanisms that allow them to thrive and escape therapy. Using in vitro and in vivo models of marrow adiposity, we demonstrate that metastatic prostate carcinoma (PCa) cells engage bone marrow adipocytes in a functional crosstalk that promotes IL-1β expression in tumor cells. Tumor-supplied IL-1β contributes to adipocyte lipolysis and regulates a pro-inflammatory phenotype in adipocytes via upregulation of COX-2 and MCP-1. We further show that the enhanced activity of the IL-1β/COX-2/MCP-1 axis and a resulting increase in PGE2 production by adipocytes coincide with augmented hypoxia signaling and activation of pro-survival pathways in tumor cells, revealing a potential mechanism of chemoresistance. The major consequence of this interplay is the reduced response of PCa cells to docetaxel, a phenomenon sensitive to the inhibition of lipolysis. Implications: Studies presented herein highlight adipocyte lipolysis as a tumor-regulated metabolic event that engages pro-inflammatory crosstalk in the microenvironment to promote PCa progression in bone. Understanding the impact of bone marrow adipose tissue on tumor adaptation, survival and chemotherapy response is fundamentally important, as current treatment options for metastatic PCa are palliative.