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Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer

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Abstract

Increased bone marrow adiposity is a common feature of advanced age, obesity and associated metabolic pathologies. Augmented numbers of marrow adipocytes positively correlate with dysregulated bone remodeling, also a well-established complication of metastatic disease. We have shown previously that marrow adiposity accelerates prostate tumor progression in the skeleton and promotes extensive destruction of the bone; however, the factors behind adipocyte-driven osteolysis in the skeletal tumor microenvironment are not currently known. In this study, utilizing in vivo diet-induced models of bone marrow adiposity, we reveal evidence for positive correlation between increased marrow fat content, bone degradation by ARCaP(M) and PC3 prostate tumors, and augmented levels of host-derived CXCL1 and CXCL2, ligands of CXCR2 receptor. We show by in vitro osteoclastogenesis assays that media conditioned by bone marrow adipocytes is a significant source of CXCL1 and CXCL2 proteins. We also demonstrate that both the adipocyte-conditioned media and the recombinant CXCL1 and CXCL2 ligands efficiently accelerate osteoclast maturation, a process that can be blocked by neutralizing antibodies to each of the chemokines. We further confirm the contribution of CXCR2 signaling axis to adiposity-driven osteoclastogenesis by blocking fat cell-induced osteoclast differentiation with CXCR2 antagonist or neutralizing antibodies. Together, our results link CXCL1 and CXCL2 chemokines with bone marrow adiposity and implicate CXCR2 signaling in promoting effects of marrow fat on progression of skeletal tumors in bone.

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Acknowledgments

We gratefully acknowledge Dr. Halina Chkourko Gusky (WSU, Karmanos Cancer Institute) and Jonathan Diedrich (WSU, Karmanos Cancer Institute) for critical revisions to the manuscript. We also thank Dr. Karin List for access to her Zeiss Scope A.1 conventional light microscope, and Kamiar Moin, and the Microscopy, Imaging and Cytometry Resources Core (MICR) for assistance with animal imager analyses. Grant support was provided by: NIH/NCI 1 R01 CA181189-01, NIH/NCI 1F31CA165834-01A1, and MICR: P30 CA 22453.

Conflict of interest

The authors disclose no potential conflicts of interest.

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    Authors and Affiliations

    1. Department of Pharmacology, Wayne State University School of Medicine, 540 E. Canfield, Rm 6304, Detroit, MI, 48201, USA

      Aimalie L. Hardaway, Mackenzie K. Herroon, Erandi Rajagurubandara & Izabela Podgorski

    2. Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA

      Aimalie L. Hardaway & Izabela Podgorski

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    Correspondence to Izabela Podgorski.

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    Hardaway, A.L., Herroon, M.K., Rajagurubandara, E. et al. Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer. Clin Exp Metastasis 32, 353–368 (2015). https://doi.org/10.1007/s10585-015-9714-5

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