Tumor Invasion and Metastasis Mediated by Cell Surface Proteolysis

细胞表面蛋白水解介导的肿瘤侵袭和转移

• 批准号: 7213697
• 负责人: DUANQING PEI
• 金额: $ 23.48万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-21 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7213697
• 关键词: cell membrane; metastasis; neoplasm /cancer; proteolysis

DESCRIPTION (provided by applicant): Tissue invasion and metastasis, one of the six purported capabilities acquired by human cancers, accounts for more than 90% of cancer deaths and represents an understudied but promising area for future therapeutic developments. The long-term goal of our program is to understand how malignant tumor cells acquire the invasive and metastatic phenotype. In the next five years, we plan to focus on the microenvironment of tumor cell surface and test the hypothesis that cell surface proteolysis regulates the invasive and metastatic properties of malignant tumors. Current evidence suggest that proteinases contribute to tumor invasion and metastasis by not only degrading the extracellular matrix as a barrier, but also functioning to regulate pathways controlling cell growth, migration and apoptosis through releasing latent growth factors or cleaving various receptors and their ligands for both activation and inactivation. Yet, efforts targeting tumor proteinases especially the MMPs have not achieved any clinical success so far. Several outstanding reviews have recently been published to address this apparent gap between "scientific success and clinical failure" for the MMP field. We would like to argue that one neglected area is proteolvsis on tumor cell surface. Our evidence both in vitro and in vivo suggests that the same proteinase behaves differently when it is tethered on cell surface or secreted. We hypothesize that the membrane-bound MMPs are more efficient for proteolysis and harder to inhibit than soluble ones, thus, enabling tumor invasion and metastasis. To test this idea, we designed three specific aims: 1) Characterize the invasive and metastatic phenotype conferred by MT1-MMP expressed on tumor cell surface both in vitro and in vivo; 2) Determine the contributions of the hemopexin- and catalytic- domains of MT1-MMP towards the invasive and metastatic phenotype; and 3) Characterize the microenvironment on tumor cell surface that enables MT1-MMP to mediate invasion and metastasis. Accomplishment of these aims may empower the design of a new generation of MMP inhibitors targeting the tumor cell surface and provide model systems to test the efficacies of these potential therapeutics.

描述（由申请人提供）：组织侵袭和转移是人类癌症据称具有的六种能力之一，占癌症死亡的 90% 以上，是一个尚未得到充分研究但有前途的未来治疗发展领域。我们项目的长期目标是了解恶性肿瘤细胞如何获得侵袭和转移表型。未来五年，我们计划重点研究肿瘤细胞表面的微环境，检验细胞表面蛋白水解调节恶性肿瘤侵袭和转移特性的假设。目前的证据表明，蛋白酶不仅通过降解细胞外基质作为屏障，还通过释放潜在生长因子或裂解各种受体及其配体来调节控制细胞生长、迁移和凋亡的途径，从而促进肿瘤侵袭和转移。和失活。然而，针对肿瘤蛋白酶尤其是基质金属蛋白酶的努力迄今为止尚未取得任何临床成功。最近发表了几篇杰出的评论来解决 MMP 领域“科学成功与临床失败”之间的明显差距。我们想说，一个被忽视的领域是肿瘤细胞表面的蛋白水解作用。我们的体外和体内证据表明，相同的蛋白酶在被束缚在细胞表面或分泌时表现不同。我们假设膜结合的 MMP 比可溶性 MMP 的蛋白水解效率更高，并且更难抑制，从而促进肿瘤侵袭和转移。为了检验这个想法，我们设计了三个具体目标：1）在体外和体内表征肿瘤细胞表面表达的 MT1-MMP 赋予的侵袭和转移表型； 2) 确定MT1-MMP的血红素结合蛋白和催化结构域对侵袭和转移表型的贡献； 3) 表征肿瘤细胞表面使 MT1-MMP 介导侵袭和转移的微环境。这些目标的实现可能有助于设计针对肿瘤细胞表面的新一代 MMP 抑制剂，并提供模型系统来测试这些潜在疗法的功效。