Role of Fibroblast-Derived MT1-MMP in Oral Cancer

成纤维细胞衍生的 MT1-MMP 在口腔癌中的作用

• 批准号: 7046085
• 负责人: EBEN L. ROSENTHAL
• 金额: $ 7.1万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046085
• 关键词: cell growth regulation; cell line; cell migration; disease /disorder model; enzyme mechanism; extracellular matrix; fibroblasts; gene expression; human tissue; laboratory mouse; metalloendopeptidases; metastasis; mixed tissue /cell culture; mouth neoplasms; neoplastic growth; protease inhibitor; protein localization; small interfering RNA; squamous cell carcinoma; transfection /expression vector; xenotransplantation

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.

描述（由申请人提供）：像许多上皮肿瘤一样，口腔鳞状细胞癌（OCSCC）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基质组成。从广义上讲，我们的实验室试图理解与肿瘤相关的成纤维细胞促进肿瘤增殖和转移的机制。肿瘤浸润部分是由蛋白酶在肿瘤微环境中阐述的部分介导的，这些蛋白酶围绕细胞外基质，趋化因子和其他促进分子的生长。最近，通过将基质金属蛋白酶（MMP）定位在乳腺癌和OCSCC肿瘤周围的成纤维细胞而不是肿瘤细胞中，而不是肿瘤细胞。膜型1MMP（MT1-MMP）与直接细胞外基质降解，其他MMP的激活和改变肿瘤细胞粘附的直接促进肿瘤细胞浸润有关。尽管在OCSCC中与肿瘤相关的成纤维细胞中鉴定，但尚未确定成纤维细胞衍生的MT1-MMP体内的功能作用。我们假设成纤维细胞衍生的MT1-MMP促进了允许肿瘤微环境对肿瘤细胞侵袭和转移的允许。为了检验这一假设，我们建议评估成纤维细胞在共培养过程中促进体外和体内OCSCC肿瘤细胞系侵袭的潜力，1）MT1-MMP缺乏和野生型鼠鼠成纤维细胞，或2）MT1-MMP载体或MT1-MMP载体或对照载体转录的纤维纤维转载纤维转染。