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，占癌症死亡人数的90%以上，是未来治疗发展的一个未被充分研究但很有前途的领域。我们计划的长期目标是了解恶性肿瘤细胞是如何获得侵袭和转移表型的。在接下来的五年里，我们计划将重点放在肿瘤细胞表面的微环境上，并测试细胞表面蛋白分解调节恶性肿瘤侵袭和转移特性的假设。目前的证据表明，蛋白酶不仅作为屏障降解细胞外基质，而且通过释放潜在的生长因子或裂解各种受体及其配体以激活和失活，调节控制细胞生长、迁移和凋亡的通路，从而参与肿瘤的侵袭和转移。然而，到目前为止，针对肿瘤蛋白，特别是MMPs的研究还没有取得任何临床成功。最近发表了几篇杰出的综述，以解决基质金属蛋白酶领域“科学成功和临床失败”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溶解。我们在体外和体内的证据表明，当同一种蛋白酶被拴在细胞表面或被分泌时，其表现不同。我们推测，膜结合的MMPs比可溶性的MMPs更有效地降解蛋白质，并且更难抑制，从而促进肿瘤的侵袭和转移。为了验证这一想法，我们设计了三个特定的目标：1)表征MT1-MMP在体外和体内表达的肿瘤细胞表面的侵袭和转移表型；2)确定MT1-MMP的血凝蛋白和催化结构域对侵袭和转移表型的贡献；以及3)表征使MT1-MMP能够介导侵袭和转移的肿瘤细胞表面的微环境。这些目标的实现可能会使新一代靶向肿瘤细胞表面的基质金属蛋白酶抑制剂的设计成为可能，并提供模型系统来测试这些潜在疗法的有效性。

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.