Mechanisms of Metastasis in Experimental Prostate Cancer

描述（由申请人提供）：Caveolin-1 （cav-1）是一种重要的结构/调节分子，参与分子运输和细胞信号传导的许多方面。Cav-1的活性依赖于蛋白水平和细胞环境，但对恶性细胞中Cav-1不适当表达的生物学后果的机制理解尚不明确。我们之前已经表明，cav-1上调与转移性雄激素不敏感的前列腺癌有关。在该基金资助的研究中，我们确定了前列腺癌细胞在进展过程中选择cav-1过表达的潜在机制。我们发现cav-1结合并抑制PP1/PP2A丝氨酸/苏氨酸磷酸酶的活性，通过去磷酸化阻止Akt的失活，从而维持磷酸化Akt的水平及其致癌活性。最近我们发现，cav-1过表达导致c-myc蛋白水平升高，VEGF、FGF2和TGF- 1的上调和分泌。重要的是，我们还发现cav-1本身是由前列腺癌细胞特异性分泌的，并被前列腺癌细胞和内皮细胞（EC）吸收。总的来说，我们的数据表明，表达cav-1的细胞可以通过分泌cav-1和cav-1刺激的生长因子(GF)/血管生成细胞因子（AC），成为局部和潜在远处前列腺癌细胞和肿瘤相关EC的“喂食细胞”。为了支持这一概念，我们已经证明，实验诱导的转移在过表达cav-1的宿主转基因小鼠中得到增强，而在宿主cav-1-/-小鼠中受到抑制。根据这一新的信息，我们假设通过特定的促生存/促血管生成分子途径，细胞内和分泌的cav-1促进前列腺癌的进展。我们将通过以下具体目标来验证这一假设：1)识别和表征前列腺癌中新的cav-1刺激的促生存/血管生成途径；2)研究cav-1在前列腺癌细胞和EC中的摄取，以及cav-1对前列腺癌细胞和EC中GF/AC活性的调节作用；3)明确并表征cav-1在前列腺癌转移中的全身作用机制；4)分析新型转基因小鼠前列腺重构模型中cav-1在良、恶性前列腺上皮细胞生长及其相关血管生成中的作用。

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.