Role of Fibroblast-Derived MT1-MMP in Oral Cancer

描述(申请人提供)：口腔鳞状细胞癌(OCSCC)，像许多上皮性肿瘤一样，不仅由癌细胞组成，而且由含有细胞外基质、成纤维细胞、炎症细胞和内皮细胞的支持基质组成。总的来说，我们的实验室试图了解肿瘤相关成纤维细胞促进肿瘤增殖和转移的机制。肿瘤侵袭的部分原因是肿瘤微环境中的蛋白水解酶分解细胞外基质、趋化因子和其他促进生长的分子。最近，基质金属蛋白酶(MMPs)主要定位于乳腺和口腔鳞癌肿瘤周围的成纤维细胞，而不是肿瘤细胞，表明了肿瘤相关成纤维细胞在肿瘤增殖中的作用。膜型基质金属蛋白酶(MT1-MMPs)通过直接降解细胞外基质、激活其他MMPs和改变肿瘤细胞的黏附而促进肿瘤细胞的侵袭。尽管在口腔鳞状细胞癌的肿瘤相关成纤维细胞中已被证实，但成纤维细胞来源的MT1-基质金属蛋白酶在体内的功能作用尚未确定。我们假设成纤维细胞来源的MT1-MMPs促进肿瘤微环境，允许肿瘤细胞侵袭和转移。为了验证这一假说，我们建议评估成纤维细胞在体外和体内促进OCSCC肿瘤细胞侵袭的潜力，在1)MT1-MMP缺陷的小鼠成纤维细胞和野生型小鼠成纤维细胞，或2)MT1-MMP载体或对照载体转染的成纤维细胞。

DESCRIPTION (provided by applicant): Oral cavity squamous cell carcinoma (OCSCC), like many epithelial tumors, is composed of not only carcinoma cells but supporting stroma containing extracellular matrix, fibroblasts, inflammatory cells, and endothelial cells. Broadly, our lab seeks to understand mechanisms by which tumor-associated fibroblasts promote tumor proliferation and metastasis. Tumor invasion is in part mediated by the elaboration of proteinases in the tumor microenvironment that cleave surrounding extracellular matrix, chemokines, and other growth promoting molecules. The role for tumor-associated fibroblasts in tumor proliferation was recently suggested by localization of matrix metalloproteases (MMPs) primarily to surrounding fibroblasts in breast and OCSCC tumors, rather than the tumor cells. Membrane type-1 MMP (MT1-MMP) has been implicated in promoting tumor cell invasion by direct extracellular matrix degradation, activation of other MMPs, and altering tumor cell adhesion. Although identified in tumor-associated fibroblasts in OCSCC, the functional role of fibroblast-derived MT1-MMP in vivo has not been determined. We hypothesize that fibroblast-derived MT1-MMP promotes a tumor microenvironment permissive to tumor cell invasion and metastasis. To test this hypothesis we propose to assess the potential of fibroblasts to promote in vitro and in vivo OCSCC tumor cell line invasion during co-culture with 1) MT1-MMP deficient and wild-type murine fibroblasts, or 2) MT1-MMP vector or control vector transfected fibroblasts.