Prostate Tumor Cell-Derived IL1β Induces an Inflammatory Phenotype in Bone Marrow Adipocytes and Reduces Sensitivity to Docetaxel via Lipolysis-Dependent Mechanisms
| Autor: | Mackenzie K. Herroon, Izabela Podgorski, Erandi Rajagurubandara, Jonathan Diedrich, James G. Granneman, Seongho Kim, Carly E. Martin, Krishnarao Maddipati, Elisabeth I. Heath |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Cancer Research Biopsy Lipolysis Cell Interleukin-1beta Adipose tissue Bone Marrow Cells Docetaxel Dinoprostone Article Proinflammatory cytokine 03 medical and health sciences Prostate cancer chemistry.chemical_compound Mice 0302 clinical medicine Downregulation and upregulation Adipocyte medicine Adipocytes Tumor Microenvironment Animals Humans Molecular Biology Chemokine CCL2 Inflammation business.industry Prostate Prostatic Neoplasms medicine.disease 030104 developmental biology medicine.anatomical_structure Oncology chemistry Tumor progression Cyclooxygenase 2 Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Bone marrow business Signal Transduction |
| Zdroj: | Mol Cancer Res |
| ISSN: | 1557-3125 |
| Popis: | 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. Implications: 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. |
| Databáze: | OpenAIRE |
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