The major focus of Project 1, Biology of Tumor-Stroma Interaction, will be on a novel soluble factor, beta 2- Vlicroglobulin (P2-M), discovered and characterized by our laboratory as a major growth factor and signaling molecule secreted by prostate cancer (PCa), bone stroma and inflammatory cells. p2-M was shown to promote osteomimicry, the ability of cancer cells to mimic their bone microenvironment, to induce growth and survival of PCa cells in culture and in vivo and accelerate not only PCa but also breast, lung and renal cancer bone colonization. The major objectives are:a) to define the function of p2-M in driving Epithelial to Mesenchymal Transition (EMT), the first step in cancer metastasis, and increased RANKL expression and bone turnover, critical for cancer colonization in bone;b) to mechanistically investigate how 32-M promotes anti-apoptosis and cancer cell survival;c) to test the anti-tumor effects of anti-p2-M antibody n mice;and d) to develop and validate new signaling pathway-related biomarkers for clinical translation. The overall hypotheses of this proposal are: 1) B2-M is a pleiotropic signaling molecule that promotes the growth and survival of PCa in bone bv increased bone turnover: 2) B2-M-mediated downstream signaling pathways are excellent therapeutic targets and predictive biomarkers for clinical translation.
Specific Aims are:
Aim 1 : To determine how P2-M enhances human PCa cell growth and metastasis to bone, with a focus on EMT and RANKL-mediated bone turnover.
Aim 2 : To dissect p2-M-activated survival mechanisms involving increased VEGF/neuropilin/Mcl-1 signaling and increased survivin expression..
Aim 3 : To develop strategies to target p2-M-mediated growth and survival mechanisms in clinically relevant PCa bone metastasis models.
Aim 4 : To determine the common molecular signatures of p2-M-mediated gene activation in cancer cells, """"""""reactive"""""""" prostate and bone stroma, and to assess their clinical utility as biomarkers.
These Aims will be accomplished with close inter-project and inter-core interaction, sharing reagents, cell lines, animal models and clinical materials and incorporating intellectual input from PO-1 investigators and trainees. Ultimately, progress in understanding the biology and targeting of PCa bone metastasis will improve the diagnosis, prognosis and treatment of PCa patients.
Prostate cancer bone metastasis is lethal and currently there is no effective therapy. The current Program Project comprised of experts with shared interests in elucidating the molecular mechanisms regulating prostate cancer bone metastasis and the development of effective therapeutic targeting of its lethal progression. The strategies described in this proposal could lead to reduced mortality and morbidity of patients with prostate cancer bone metastasis.
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