Contributions of the Bone Marrow Microenvironment to Bone and Skeletal Metastasis.

The skeleton, a favored organ for prostate cancer is organized by a mineralized connective tissue, and a rich marrow where hematopoiesis replenishes a variety of blood cells and gives rise to many cell populations. Thus, when tumors metastasize to bones they encounter many cells, once considered bystanders such as hematopoietic stem cells and macrophages, which play key roles in tumor growth progression and metastasis. Macrophages are implicated in both skeletal homeostasis and tumorigenesis; yet their role in skeletal metastasis is unclear. Macrophage phagocytosis of apoptotic cells is referred to as efferocytosis, and is an integral process by which harmful by-products of dead and dying cells are removed to create a pro-resolving environment. The purpose of this study was to determine the role of macrophages and efferocytosis in prostate cancer skeletal metastasis. In vivo experimental approaches resulting in macrophage ablation showed significant reduction in tumor growth in tibiae after intratibial tumor inoculations. Efferocytosis of apoptotic tumor cells increased MFG-E8 expression and promoted macrophage polarization into the M2 macrophage phenotype. Conversely, efferocytosis inhibition with neutralizing MFG-E8 antibody resulted in reduced M2 polarization, suggesting that efferocytosis is important for macrophage polarization into tumor promoting M2 cells. The involvement of the STAT3/SOCS3 activation pathway in macrophage polarization was observed. Increased MFG-E8 levels when bone marrow macrophages were co-cultured with apoptotic cells was accompanied by SOCS3 downregulation. Inhibition of STAT3 phosphorylation resulted in decreased efferocytosis and M2 macrophage polarization with an associated increase in SOCS3 protein expression. This suggests that SOCS3 and phospho-STAT3 act in an inversely dependent manner when stimulated by MFG-E8 and efferocytosis. Therefore we report a novel mechanism by which MFG-E8, by mediating efferocytosis of prostate cancer cells, can support tumor growth through facilitation of M2 macrophage polarization and regulation of SOCS3/STAT3 activation. In conclusion, the bone microenvironment provides a dynamic and rich soil for tumors to thrive. Continued investigation on the role of bone marrow cells will provide a better understanding of the metastatic bone environment and aid in the advancement of new targets for the treatment and prevention of skeletal metastasis.PhDOral Health SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111335/1/fabisoki_1.pd