Invasion and metastasis in prostate cancer

前列腺癌的侵袭和转移

• 批准号: 6778884
• 负责人: VALERI VASIOUKHIN
• 金额: $ 31.51万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6778884
• 关键词: affinity chromatography; cell adhesion; cell cell interaction; endopeptidases; epithelium; gene expression; genetically modified animals; immunofluorescence technique; laboratory mouse; membrane proteins; metastasis; neoplastic process; northern blottings; posttranslational modifications; prostate neoplasms; prostate preneoplastic state; protein quantitation /detection; protein structure function; serine proteinases; terminal nick end labeling; tissue /cell culture; western blottings

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.

描述（由申请人提供）：分泌的和细胞表面蛋白酶对细胞细胞和细胞 - 丝状粘附的扰动在传播上皮肿瘤中起重要作用。最近的多项DNA微阵列研究将细胞表面丝氨酸蛋白酶肝蛋白hepsin鉴定为在转移性前列腺癌中急剧过表达的转录本。我们假设Hepsin的过表达会导致前列腺上皮细胞中细胞细胞和细胞肌间粘附的破坏，因此有助于前列腺癌的进展。为了分析在体内前列腺腺体中赫布斯蛋白过表达的功能意义，我们已经生成并正在分析在前列腺上皮中表达肝素的转基因小鼠。由于前列腺癌的发展可能需要进行多种遗传修饰，因此我们将研究Hepsin和其他肿瘤基因之间的潜在合作。为了确定前列腺癌进展的不同时间点的肝素的潜在作用，我们将使用前列腺癌的小鼠模型来繁殖Hepsin转基因小鼠，这些小鼠的前列腺癌模型会产生前列腺癌前列腺损伤或非转移性前列腺癌。我们认为，如果Hepsin积极参与前列腺癌的进展，则在前列腺癌病变中赫普蛋白的过表达将导致前列腺癌的发展。如果肝素参与癌症的传播，则非转移性前列腺肿瘤中肝素的过表达将导致从非转移性转移性癌症过渡。为了确定负责肝蛋白功能的分子机制，我们将分析过表达该蛋白质的主要前列腺上皮细胞系。总体而言，该项目的研究将有助于确定前列腺癌中Hepsin过表达的功能意义和分子后果。