Role of Fibroblast-Derived MT1-MMP in Oral Cancer

描述（由申请人提供）：与许多上皮肿瘤一样，口腔鳞状细胞癌（OCSCC）不仅由癌细胞组成，还由含有细胞外基质、成纤维细胞、炎性细胞和内皮细胞的支持基质组成。从广义上讲，我们的实验室旨在了解肿瘤相关成纤维细胞促进肿瘤增殖和转移的机制。肿瘤侵袭部分由肿瘤微环境中蛋白酶的加工介导，所述蛋白酶切割周围的细胞外基质、趋化因子和其他生长促进分子。肿瘤相关的成纤维细胞在肿瘤增殖中的作用最近被认为是由定位的基质金属蛋白酶（MMPs）主要是周围的成纤维细胞在乳腺癌和口腔鳞状细胞癌肿瘤，而不是肿瘤细胞。膜1型MMP（MT 1-MMP）通过直接降解细胞外基质、激活其他MMP和改变肿瘤细胞粘附而参与促进肿瘤细胞侵袭。虽然在OCSCC中的肿瘤相关成纤维细胞中鉴定，但成纤维细胞衍生的MT 1-MMP在体内的功能作用尚未确定。我们推测成纤维细胞来源的MT 1-MMP促进了允许肿瘤细胞侵袭和转移的肿瘤微环境。为了检验这一假设，我们建议评估成纤维细胞在与1）MT 1-MMP缺陷型和野生型鼠成纤维细胞或2）MT 1-MMP载体或对照载体转染的成纤维细胞共培养期间促进体外和体内OCSCC肿瘤细胞系侵袭的潜力。

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.