Cadherins in Human Prostate Carcinoma Progression

钙粘蛋白在人类前列腺癌进展中的作用

• 批准号: 6990129
• 负责人: Ronald L. Heimark
• 金额: $ 11.3万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-19 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6990129
• 关键词: SCID mouse; biological signal transduction; cadherins; cell adhesion; cell cell interaction; cell growth regulation; cell migration; epithelium; gene expression; genetically modified animals; in situ hybridization; integrins; laminin; ligands; male; molecular oncology; neoplasm /cancer invasiveness; neoplastic process; phenotype; phosphatidylinositol 3 kinase; prostate neoplasms; protein structure function; receptor expression; scanning electron microscopy; transfection

The focus in this application is on the switch in cadherin expression during prostate cancer progression to examine the intracellular signaling events that cause tumor cells to become metastatic. Important determinants for metastasis are not only the detachment of prostate carcinoma cells from the primary tumor by down regulation of E-cadherin, but also their ability to survive in different microenvironments. While the mechanisms by which stroma supports prostate cancer progression are unknown, one factor that may contribute to the enhancement of carcinoma cell survival by stromal cells maybe cell-cell adhesion. We have shown that the more invasive human prostate carcinoma cell lines have down-regulated E-cadherin and gained expression of N-cadherin. Carcinoma cells can form stable adherens junction complexes with N-cadherin on prostate-derived stromal fibroblasts. Our findings indicate that homophilic N-cadherin adhesion on adjacent prostate carcinoma cells is able to transduce an outside-in cell survival signal through activation of PI 3-kinase, and down-stream activation of serine/threonine kinase AKT/PKB, which can phosphorylate Bad and CREB. This proposal examines the hypothesis that expression of non-epithelial cadherin subtypes by prostate carcinomas contributes to the molecular events during invasion, which increase tumor cell survival and eventually lead to metastasis. To explore this hypothesis we will focus on the regulation of two critical cadherin subtypes, E-cadherin and N-cadherin, and their co-expression in the progression of prostate carcinomas. Specific aims are: Aim 1: Determine the mechanism of N-cadherin mediated adherens junctions signaling in prostate carcinoma cell survival pathways. Aim 2: Extend characterization of Bcl-2 regulation by the homophilic adhesion of N-cadherin. Aim 3: Investigate the molecular basis for N-cadherin mediated enhancement of the migratory phenotype of E-cadherin expressing prostate carcinomas. Aim 4: Determine the consequences of N-cadherin expression in epithelium of transgenic mice by prostate-directed over expression. Understanding the functional role of these changes in cadherin family of cell-cell adhesion molecules that lead to metastasis, would provide a potential prognostic indicator to identify individuals who are more likely to develop aggressive prostate cancer.

该应用的重点是前列腺癌期间钙粘蛋白表达的转换 进展以检查导致肿瘤细胞转移性的细胞内信号传导事件。转移的重要决定因素不仅是通过降低电子钙粘着蛋白的原发性肿瘤脱离前列腺癌细胞的脱离，而且是它们在不同微环境中生存的能力。尽管基质支持前列腺癌进展的机制尚不清楚，但可能有助于增强基质细胞癌细胞存活的因素可能是细胞细胞粘附。我们已经表明，更具侵入性的人类前列腺癌细胞系具有下调的E-钙粘着蛋白，并获得了N-钙粘着蛋白的表达。癌细胞可以在前列腺衍生的基质成纤维细胞上与N-钙粘着蛋白形成稳定的粘附连接络合物。我们的发现表明，相邻前列腺癌细胞上的同质N-钙粘着蛋白的粘附能够转导外部的细胞 生存信号通过激活PI 3-激酶，以及丝氨酸/苏氨酸激酶Akt/PKB的下游激活，这可以磷酸化和CREB磷酸化。该提案研究了以下假设：前列腺癌对非上皮钙粘蛋白亚型的表达有助于侵袭过程中的分子事件，从而增加了肿瘤细胞的存活并最终导致转移。为了探讨这一假设，我们将重点介绍对两个关键的钙粘蛋白亚型E-钙粘着蛋白和N-钙粘着蛋白的调节，以及它们在前列腺癌的进展中的共表达。具体目的是：目标1：确定前列腺癌细胞存活中N-钙粘蛋白介导的粘附连接的机理 途径。 AIM 2：通过N-钙粘着蛋白的均电粘附扩展BCL-2调节的表征。 AIM 3：研究表达前列腺癌的E-钙粘着蛋白的迁移表型的N-钙粘着蛋白介导的增强的分子基础。 AIM 4：通过前列腺在表达上定向，确定N-钙粘蛋白表达在转基因小鼠上皮的后果。了解这些变化在导致转移的细胞粘附分子家族中的功能作用将提供潜在的预后指标，以鉴定更有可能患上侵略性前列腺癌的个体。