ROLE OF STROMELYSIN 1 IN SQUAMOUS CELL CARCINOMA

该建议的重点是确定基质金属蛋白酶（MMP）基质溶解素-1在鳞状细胞癌进展中的功能作用。基质溶解素-1是一种主要的细胞外基质（ECM）降解蛋白酶，其参与多种正常和病理细胞过程，包括肿瘤细胞侵袭。人们集中注意力于定义个体MMP的特定作用，以便在临床环境中使用MMP抑制剂适当地调节它们的活性。不仅要了解单个MMP在肿瘤进展中的作用，而且还要了解宿主/基质和肿瘤MMP表达的不同作用，这是基质蛋白酶领域一个基本的未回答的问题。我们有证据表明，基质分解素-1的表达可以在肿瘤进展过程中发挥双重作用，这意味着在肿瘤进展的早期阶段基质分解素-1的表达是保护性的，而基质分解素-1的肿瘤表达密切参与鳞状细胞癌中的侵袭性表型的产生。目前的实验性癌症治疗模型包括使用MMP抑制剂。因此，我们需要明确基质溶解素-1在肿瘤进展的每个阶段的作用，以预测基质溶解素-1的缺失将如何影响肿瘤的发展和侵袭性。研究提案中概述的研究将为基质溶解素-1在肿瘤进展过程中的作用提供新的见解，并为在临床环境中测试MMP抑制剂提供体内模型。

The focus of this proposal is to define the functional role of the matrix metalloprotease (MMP) Stromelysin-1 in squamous cell carcinoma progression. Stromelysin-1 is a major extracellular matrix (ECM) degrading proteinases implicated in a variety of normal and pathological cellular processes including tumor cell invasion. There is focused attention on defining the particular roles of individual MMP in order to appropriately modulate their activity in a clinical setting with the use of MMP inhibitors. Understanding not only the role of individual MMPs in tumor progression, but additionally the distinct roles of host/stromal and tumor MMP expression is a fundamental unanswered question the matrix protease field. We have evidence that stromelysin-1 expression can play dual roles during tumor progression, meaning that expression of stromelysin-1 during early stages of tumor progression is protective whereas tumor expression of stromelysin-1 is intimately involved in generating an invasive phenotype in squamous cell carcinoma. Current experimental cancer therapy models include the use of MMP inhibitors. Thus, we need to well define the role of stromelysin-1 at each stage of tumor progression in order to predict how loss of stromelysin-1 will effect tumor development and invasiveness. The studies outlined in the research proposal will provide novel insight into the role of Stromelysin-1 during tumor progression and provide an in vivo model for testing of MMP inhibitors in a clinical setting.