The study of the molecular alterations that contribute to prostate cancer progression is nowadays the subject of numerous investigations. Abnormal migration, proliferation and survival of prostate cells contribute to prostate cancer progress; however, the molecular requirements and the signaling pathways involved, are poorly understood. Adhesive interactions between cells and extracellular matrix are mediated by Integrins, adhesion receptors that trigger a cascade of intracellular signaling events regulating cell motility, survival and proliferation. The applicant has demonstrated that the (alpha)v(beta)3 integrin is undetectable in normal or benign prostatic epithelium and is upregulated in prostatic carcinoma; its expression is found in primary tumors as well as in metastatic lesions. (Alpha)v(beta)3 expression confers prostate cancer cells a migratory phenotype on substrates found in bone, where prostate cancer cells preferentially metastasize, and activates signaling pathways that contribute to cell migration. To investigate the downstream pathways activated by (alpha)v(beta)3 engagement by vitronectin or osteopontin, the applicant will characterize the role of PI 3-kinase and Src, and of FAK/PI 3-kinase or FAK/Src association in modulating migration of LNCaP, PC3 and primary prostate cancer cells. The in vivo role for (alpha)v(beta)3 in establishment of metastases will be evaluated using orthotopical injection in SCID mice and a human bone/scid mouse model system. (Alpha)v(beta)3 structural requirements for activation of AKT and migration of prostate cancer cells will also be studied. A role for AKT in supporting primary prostate cancer cell migration will be analyzed using a similar approach. Finally, the role of (alpha)v(beta)3 and FAK and PI 3-kinase/AKT in increasing cell survival and proliferation of prostate cancer cells will be investigated. Whether either proliferation or survival will be increased by either (alpha)v(beta)3 expression or engagement, activation of downstream pathways will be analyzed using FAK and PI 3-kinase/AKT active or dominant negative variants. Finally, immunohistochemical analysis of prostate cancer tissue specimens will be performed to correlate (alpha)v(beta)3 expression in metastatic sites with apoptosis and proliferation markers. As examined by the NCI Prostate Cancer Review group this area of research """"""""on the molecular, cellular events that lead to uncontrolled growth and metastases"""""""" is under explored and is likely to provide important advances in the status of treatment of prostate cancer.
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