Title: Reciprocal Tumor Host Interactions in the Bone Metastatic Prostate Cancer Microenvironment
Bone metastatic prostate cancer is common in men with advanced disease. In bone, prostate cancer promotes the formation of lesions composed of areas of extensive bone formation and destruction driven by mesenchymal stromal cell (MSC) derived osteoblasts and myeloid derived osteoclasts respectively. Our studies show that prostate cancer cells drive this process via parathyroid hormone related peptide (PTHrP) and post-translational modification of PTHrP by matrix metalloproteinases (MMPs). Reciprocally, we have found that bone marrow MSCs can drive the evolution of apoptosis resistant prostate cancer cells via the secretion of interleukin-28 (IL-28). Chronic exposure to IL-28 results in a rewiring of the prostate cancer cell circuitry with heightened phosphorylated STAT3 noted in the resistant cancer cell sub-populations. STAT3 activity has been noted in the majority of bone metastatic prostate cancers and may offer an opportunity for therapeutic intervention to treat this disease.