Invasion and metastasis in prostate cancer

描述（由申请人提供）：分泌和细胞表面蛋白酶对细胞-细胞和细胞-基质粘附的扰动在上皮性肿瘤的传播中起重要作用。最近的多个DNA微阵列研究发现，细胞表面丝氨酸蛋白酶hepsin是转移性前列腺癌中急剧过表达的转录物。我们假设hepsin的过度表达会导致前列腺上皮细胞细胞间和细胞基质粘附的破坏，从而导致前列腺癌的进展。为了分析体内前列腺中hepsin过表达的功能意义，我们已经产生并正在分析在前列腺上皮中表达hepsin的转基因小鼠。由于前列腺癌的发展可能需要多种基因修饰，我们将研究hepsin与其他癌基因之间的潜在合作关系。为了确定hepsin在前列腺癌进展的不同时间点的潜在作用，我们将用hepsin转基因小鼠与发生癌前前列腺病变或非转移性前列腺癌的前列腺癌小鼠模型进行繁殖。我们推断，如果hepsin在前列腺癌的进展中起着积极的作用，那么在前列腺癌前病变中，hepsin的过度表达将导致前列腺癌的发展。如果hepsin参与了癌症的传播，那么在非转移性前列腺肿瘤中，hepsin的过表达将导致从非转移性癌症向转移性癌症的转变。为了确定hepsin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。总之，本项目的研究将有助于确定前列腺癌中hepsin过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.