Mechanisms of Metastasis in Experimental Prostate Cancer

小窝蛋白-1（Caveolin-1，cav-1）是一种重要的结构/调节分子，参与分子转运的许多方面， 细胞信号Cav-1活性依赖于蛋白水平和细胞环境，但对Cav-1活性的机制理解还不清楚。 在恶性细胞中不适当的CAV-1表达的生物学后果是难以捉摸的。我们已经表明 以前认为CAV-1上调与转移性雄激素不敏感的前列腺癌有关。研究中 在该基金的资助下，我们确定了前列腺癌中选择cav-1过表达的潜在机制。 细胞在发展过程中我们发现cav-1与PP 1/PP 2A丝氨酸/苏氨酸结合并抑制其活性 磷酸酶，通过去磷酸化防止Akt失活，从而维持磷酸化Akt的水平， 其致癌活性。最近我们证实cav-1过表达导致c-myc蛋白水平的增加 以及VEGF、FGF 2和TGF-D1的上调和分泌。重要的是，我们还发现cav-1本身 由前列腺癌细胞特异性分泌并被前列腺癌细胞和内皮细胞（EC）摄取。整体 我们的数据表明表达cav-1的细胞可以作为局部和潜在的远处前列腺的“饲养细胞”发挥作用。 通过分泌cav-1和cav-1刺激的生长因子（GF）/血管生成抑制癌细胞和肿瘤相关EC 细胞因子（AC）。为了支持这一概念，我们已经表明，实验诱导的转移在宿主中是增强的。 过表达CAV-1并在宿主CAV-1-/-小鼠中被抑制的转基因小鼠。根据这些新信息，我们 假设通过特定的促存活/促血管生成分子途径，细胞内和分泌的cay-1 促进前列腺癌进展。我们将通过具体的目标来检验这一假设：1）识别和 表征前列腺癌中新的cav-1刺激的促存活/血管生成途径; 2）表征前列腺癌中cav-1摄取 cav-1对前列腺癌细胞和EC中GF/AC活性的调节作用; 鉴定和表征cav-1对前列腺癌转移的全身作用的机制;和 4)分析cav-1在良性和恶性前列腺上皮细胞生长及其相关血管生成中的作用， 新型转基因小鼠前列腺重建模型。

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-D1. 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 cay-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.