Mechanisms of Metastasis in Experimental Prostate Cancer

小窝蛋白-1(Cav-1)是一种重要的结构/调节分子，参与分子转运和细胞周期调控的多个方面。 细胞信号。CAV-1的活性依赖于蛋白质水平和细胞环境，但对 在恶性细胞中不适当表达Cav-1的生物学后果一直难以捉摸。我们已经展示了 以前，Cav-1的上调与转移性、雄激素不敏感的前列腺癌有关。在研究中 在这笔资金的资助下，我们确定了前列腺癌中Cav-1过度表达的潜在机制。 进展过程中的细胞。我们发现CaV-1结合并抑制PP1/PP2A丝氨酸/苏氨酸的活性 磷酸酶，通过去磷酸化防止Akt失活，从而维持磷酸化Akt和 其致癌活性。最近我们发现Cav-1的过度表达会导致c-myc蛋白水平的升高。 上调血管内皮生长因子、成纤维细胞生长因子2、转化生长因子-D_1的表达和分泌。重要的是，我们还发现Cav-1本身就是 由前列腺癌细胞特异性分泌，并由前列腺癌细胞和内皮细胞(EC)摄取。总括 我们的数据表明，表达Cav-1的细胞可以作为局部和潜在远处前列腺的“饲养细胞”。 肿瘤细胞和肿瘤相关EC通过分泌Cav-1和Cav-1刺激生长因子(GF)/血管生成 细胞因子(AC)。为了支持这一概念，我们已经证明了实验诱导的转移在宿主中得到了增强。 过表达Cav-1并在宿主Cav-1-/-小鼠中被抑制的转基因小鼠。受这一新信息的影响，我们 假设通过特定的生存/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。我们将通过特定的目标来检验这一假设：1)识别和 描述前列腺癌中Cav-1刺激的促生存/血管生成途径；2)表征前列腺癌对Cav-1的摄取 前列腺癌和EC及Cav-1对前列腺癌和EC中GF/AC活性的调节作用 确定和表征Cav-1在前列腺癌转移中的全身作用的机制；以及 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.