AWARD NUMBER: W81XWH-12-1-0348 TITLE: Activation of Myeloid-Derived Suppressor Cells in Bone Marrow PRINCIPAL INVESTIGATOR:

In the tumor microenvironment, CD11bþGr1þ bone marrow–derived cells are a predominant source of protumorigenic factors such as matrix metalloproteinases (MMP), but how distal tumors regulate these cells in the bone marrow is unclear. Here we addressed the hypothesis that the parathyroid hormone–related protein (PTHrP) potentiates CD11bþGr1þ cells in the bone marrow of prostate tumor hosts. In two xenograft models of prostate cancer, levels of tumor-derived PTHrP correlated with CD11bþGr1þ cell recruitment and microvessel density in the tumor tissue, with evidence for mediation of CD11bþGr1þ cell–derived MMP-9 but not tumorderived VEGF-A. CD11bþGr1þ cells isolated from mice with PTHrP-overexpressing tumors exhibited relatively increased proangiogenic potential, suggesting that prostate tumor–derived PTHrP potentiates this activity of CD11bþGr1þ cells. Administration of neutralizing PTHrP monoclonal antibody reduced CD11bþGr1þ cells and MMP-9 in the tumors. Mechanistic investigations in vivo revealed that PTHrP elevated Y418 phosphorylation levels in Src family kinases in CD11bþGr1þ cells via osteoblast-derived interleukin-6 and VEGF-A, thereby upregulating MMP-9. Taken together, our results showed that prostate cancer–derived PTHrP acts in the bone marrow to potentiate CD11bþGr1þ cells, which are recruited to tumor tissue where they contribute to tumor angiogenesis and growth. Cancer Res; 73(22); 6574–83. 2013 AACR.