Tumor Invasion and Metastasis Mediated by Cell Surface Proteolysis

描述（由申请人提供）：组织侵袭和转移是人类癌症获得的六种据称能力之一，占癌症死亡的90%以上，代表了一个研究不足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性和转移性表型。在未来五年，我们计划专注于肿瘤细胞表面的微环境，并测试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作为屏障的细胞外基质，而且还通过释放潜在的生长因子或切割各种受体及其配体以激活和失活来调节控制细胞生长、迁移和凋亡的途径，从而促进肿瘤的侵袭和转移。然而，迄今为止，针对肿瘤蛋白酶特别是MMPs的努力尚未取得任何临床成功。最近发表了几篇杰出的综述，以解决MMP领域“科学成功与临床失败”之间的明显差距。我们认为，一个被忽视的领域是肿瘤细胞表面的蛋白水解。我们的证据在体外和体内表明，相同的蛋白酶的行为不同，当它被拴在细胞表面或分泌。我们推测，膜结合的MMPs比可溶性的MMPs更有效地进行蛋白水解，更难抑制，因此，使肿瘤的侵袭和转移。为了验证这一想法，我们设计了三个具体的目标：1）在体外和体内表征由在肿瘤细胞表面表达的MT 1-MMP赋予的侵袭和转移表型：2）确定MT 1-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）研究肿瘤细胞表面微环境对MT 1-MMP介导侵袭和转移的影响。这些目标的实现可能使新一代MMP抑制剂靶向肿瘤细胞表面的设计，并提供模型系统，以测试这些潜在的治疗效果。

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.