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Pain related behaviors and disease related outcomes in an immunocompetent mouse model of prostate cancer induced bone pain

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      The purpose of this study is to characterize a syngeneic mouse model of prostate cancer induced bone pain. We stably transfected a prostate cancer cell line (RM-1) with green fluorescent protein (GFP) or red fluorescent protein (RFP) and luciferase reporters in order to visualize tumor growth longitudinally in vivo and to assess the relationship between sensory neurons and tumor cells within the bone microenvironment. Following intra-femoral injection of the RM-1 prostate cancer cell line or Hank's buffered saline into male C57Bl6 mice, we observed a progressive increase in spontaneous guarding of the inoculated limb between 12-21 days post inoculation. Daily running wheel performance was assessed as a measure of functional impairment and movement evoked pain. We observed a progressive reduction in the distance traveled and percentage of time at an optimal velocity between 12-21 days post inoculation. We utilized histological, radiographic and μCT analysis to examine tumor induced bone remodeling and observed osteolytic lesions within the distal femur as well as extra-periosteal aberrant cortical bone formation in the tumor bearing femur similar to clinical findings in patients with mixed bone metastatic prostate cancer. Tumor bearing mice displayed significant increases in markers of central sensitization (pERK, pDyn), astrocyte activation (GFAP) but not microglial activation (IBA1) in the ipsilateral spinal cord compared to sham operated mice by three weeks post inoculation. We observed reorganization of blood vessels (endomucin) and alterations in nerve fibers (PGP 9.5) in the intramedullary space of the tumor bearing femur. This immunocompetent mouse model will be useful when combined with transgenic Cre/Flpo driver mice to examine tumor, immune cell and sensory neuron interactions in the bone microenvironment and their role in pain and disease progression associated with bone cancer. Supported by DOD grants W81XWH-17-1-0542 to CMP and W81XWH-17-1-0541 o YS.
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