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Supplementary Figures 1-6 from Prostate Tumor Cell–Derived IL1β Induces an Inflammatory Phenotype in Bone Marrow Adipocytes and Reduces Sensitivity to Docetaxel via Lipolysis-Dependent Mechanisms

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posted on 2023-04-03, 16:44 authored by Mackenzie K. Herroon, Jonathan D. Diedrich, Erandi Rajagurubandara, Carly Martin, Krishna R. Maddipati, Seongho Kim, Elisabeth I. Heath, James Granneman, Izabela Podgorski

Figure S1: Production of eicosanoid species in tumor cell-adipocyte Transwell co-cultures and experimental bone tumors Figure S2. Bone marrow adipocyte numbers are increased in mice treated with Rosiglitazone (ROSI) and in genetically obese ob/ob mice. Figure S3. MCP-1 expression is induced in bone marrow adipocytes interacting with prostate tumor cells in vivo and in vitro. Figure S4. HFD and Rosiglitazone do not have significant effect on COX-2, mPGES and MCP-1 levels in subcutaneous tumors. Figure S5. IL-1b expression in experimental ARCaP(M) tumors and bone metastasis tissues from PCa patients. Figure S6. Tumor-induced adipocyte expression of mPGES and MCP-1 is sensitive to inhibition by IL-1RA.

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ARTICLE ABSTRACT

Adipocyte–tumor cell cross-talk 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 prosurvival 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 cells engage bone marrow adipocytes in a functional cross-talk that promotes IL1β expression in tumor cells. Tumor-supplied IL1β contributes to adipocyte lipolysis and regulates a proinflammatory phenotype in adipocytes via upregulation of COX-2 and MCP-1. We further show that the enhanced activity of the IL1β/COX-2/MCP-1 axis and a resulting increase in PGE2 production by adipocytes coincide with augmented hypoxia signaling and activation of prosurvival pathways in tumor cells, revealing a potential mechanism of chemoresistance. The major consequence of this interplay is the reduced response of prostate cancer cells to docetaxel, a phenomenon sensitive to the inhibition of lipolysis. Studies presented herein highlight adipocyte lipolysis as a tumor-regulated metabolic event that engages proinflammatory cross-talk in the microenvironment to promote prostate cancer 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 prostate cancer are palliative.

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    Molecular Cancer Research

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    Drug ResistanceGenitourinary CancersProstate cancerTumor MicroenvironmentHost-tumor interactions

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