Mechanisms of Metastasis in Experimental Prostate Cancer

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DESCRIPTION (provided by applicant): Caveolin-1 (cav-1) is an important structural/regulatory molecule involved in many aspects of molecular transport and cell signaling. Cav-1 activities are dependent on protein levels and cell context, yet a mechanistic understanding of the biological consequences of inappropriate cav-1 expression in malignant cells has been elusive. We have shown previously that cav-1 up-regulation is associated with metastatic, androgen-insensitive prostate cancer. In studies funded by this grant we identified an underlying mechanism for the selection of cav-1 overexpression in prostate cancer cells during progression. We found that cav-1 binds to and inhibits the activities of PP1/PP2A serine/threonine phosphatases, preventing inactivation of Akt through dephosphorylation and thus sustaining levels of phospho-Akt and its oncogenic activities. Recently we demonstrated that cav-1 overexpression leads to increased levels of c-myc protein and up-regulation and secretion of VEGF, FGF2 and TGF-?1. Importantly, we have also discovered that cav-1 itself is specifically secreted by prostate cancer cells and taken up by prostate cancer cells and endothelial cells (EC). Overall our data suggest that cells expressing cav-1 can function as "feeder cells" for local and potentially distant prostate cancer cells and tumor-associated EC through secretion of cav-1 and cav-1 stimulated growth factors (GF)/angiogenic cytokines (AC). In support of this concept we have shown that experimentally induced metastasis is potentiated in host transgenic mice that overexpress cav-1 and is suppressed in host cav-1-/- mice. Informed by this new information we hypothesize that through specific prosurvival/proangiogenic molecular pathways, intracellular and secreted cav-1 promote prostate cancer progression. We will test this hypothesis through specific aims to: 1) identify and characterize novel cav-1 stimulated pro-survival/angiogenic pathways in prostate cancer; 2) characterize cav-1 uptake in prostate cancer cells and EC and the modulatory effects of cav-1 on GF/AC activities in prostate cancer cells and EC; 3) identify and characterize the mechanisms that underlie the systemic effects of cav-1 on prostate cancer metastasis; and 4) analyze the role of cav-1 in benign and malignant prostate epithelial cell growth and its associated angiogenesis in novel transgenic mouse prostate reconstitution models.