Invasion and metastasis in prostate cancer

描述(申请人提供)：分泌的和细胞表面的蛋白水解酶对细胞-细胞和细胞-基质黏附的干扰在上皮性肿瘤的扩散中起重要作用。最近的多项DNA微阵列研究证实，细胞表面丝氨酸蛋白酶Hepsin是一种转录本，在转移性前列腺癌中显著过度表达。我们假设，肝素的过度表达会破坏前列腺上皮细胞的细胞-细胞和细胞-基质黏附，从而促进前列腺癌的发展。为了分析体内前列腺癌中肝素过度表达的功能意义，我们已经建立并正在分析在前列腺上皮细胞中表达肝素的转基因小鼠。由于前列腺癌的发生可能需要多个基因修饰，我们将研究肝素和其他癌基因之间的潜在合作。为了确定肝素在前列腺癌进展的不同时间点的潜在作用，我们将用前列腺癌前病变或非转移性前列腺癌的小鼠模型培育我们的肝素转基因小鼠。我们推测，如果肝素与前列腺癌的进展密切相关，则前列腺癌前病变中肝素的过度表达将导致前列腺癌的发生。如果肝素参与了肿瘤的扩散，非转移性前列腺癌中肝素的过度表达将导致非转移性前列腺癌向转移性前列腺癌的转变。为了确定肝素功能的分子机制，我们将分析过表达该蛋白的原代前列腺上皮细胞系。总体而言，该项目的研究将有助于确定前列腺癌中肝素过度表达的功能意义和分子后果。

DESCRIPTION (provided by applicant): Perturbation of cell-cell and cell-substratum adhesion by secreted and cell-surface proteases plays an important role in dissemination of epithelial tumors. Multiple recent DNA microarray studies identified cell-surface serine protease hepsin as a transcript that is drastically overexpressed in metastatic prostate carcinomas. We hypothesize that overexpression of hepsin causes disruption of cell-cell and cell-substratum adhesion in prostate epithelial cells and, therefore, contributes to prostate cancer progression. To analyze the functional significance of hepsin overexpression in the context of a prostate gland in vivo, we have generated and are now analyzing transgenic mice expressing hepsin in prostate epithelia. Since development of prostate carcinoma may require multiple genetic modifications, we will investigate potential cooperation between hepsin and other oncogenes. To determine potential role for hepsin at different time points of prostate cancer progression, we will breed our hepsin transgenic mice with mouse models of prostate cancer that develop precancerous prostate lesions, or nonmetastatic prostate cancer. We reason that if hepsin is positively involved in prostate cancer progression, overexpression of hepsin in the precancerous prostate lesions will lead to the development of prostate carcinoma. If hepsin is involved in cancer dissemination, overexpression of hepsin in the nonmetastatic prostate tumors will lead to a transition from nonmetastatic to metastatic cancer. To determine the molecular mechanisms responsible for hepsin function, we will analyze the primary prostate epithelial cell lines overexpressing this protein. Overall, the studies in this project will help to determine the functional significance and molecular consequences of hepsin overexpression in prostate cancer.