ALPHA GAMMA INTEGRINS IN ORAL CANCER

口腔癌中的 ALPHA GAMMA 整合素

• 批准号: 6270367
• 负责人: ROBERT PYTELA
• 金额: $ 10.03万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6270367
• 关键词: cytokine; endopeptidases; extracellular matrix; gene expression; growth factor; histopathology; human tissue; immunologic assay /test; integrins; neoplastic growth; neoplastic process; oral mucosa; oral pharyngeal neoplasm; protein structure function; squamous cell carcinoma; tissue /cell culture; transfection

The invasive growth of carcinomas depends not only on soluble growth factors and activation of oncogenes. but also on altered interactions with the extracellular matrix that allow the tumor to spread. A family of cell surface receptors termed integrins, plays a central role in mediating cell responses to the extracellular matrix. Integrins interact with extracellular matrix proteins such as fibronectin, vitronectin, tenascin, collagen, and laminin and transmit signals that regulate gene expression, cell proliferation, survival. and morphology. In human oral cancer specimens, the expression of one major class of integrins, termed b 1 integrins, has been studied in some detail. The importance of another class of integrins termed av integrins, has only recently been recognized. Initial studies showed that at least three different av integrins are up-regulated in different cellular components of squamous cell carcinomas (scc) derived from the oral mucosa. The alpha-v-beta-6 integrin is neo-expressed in carcinoma cells, alphavbeta6 is strongly expressed in tumor-associated stromal cells, and alphavbeta3 is strongly expressed in blood vessels that support the growth and survival of the tumor. Thus, it is conceivable that inhibitors of av integrins could have potent effects on oral cancer growth and survival. It is proposed to extend the initial studies on integrin expression in oral carcinoma by analyzing a larger number of specimen from normal, hyperplastic and malignant oral mucosa, which will be processed and catalogued in conjunction with the oral cancer Tissue and Histopathology Core. The goal of this investigation is to confirm the correlation between oral cancer progression and av integrin expression and to evaluate the potential utility of av integrins as histopathological markers of oral cancer progression and prognosis. Furthermore, factors that regulate alpha-v-beta-6 expression in cultured SCC cells will be analyzed, and the hypothesis that alpha-v-beta-6 expression may be induced by stroma-derived signals will be tested. To assess the function of av integrins in oral carcinoma, we will test the effects of av-blocking antibodies on the growth and invasion of SCC cells in different in vitro models and compare the behavior of b6- negative SCC cell lines will be compared with that of their transfected counterparts overexpressing alpha-v-beta-6. Finally, the hypothesis that av integrins are involved in regulating the expression of proteases, growth factors, and cytokines in SCC cells will be tested. These studies will provide new insights into the role of cell matrix interactions in oral cancer, and will provide the basis for developing novel therapeutics that interfere with oral cancer growth and invasion by interfering with essential cell matrix interaction of SCC cells.

癌的侵袭性生长不仅依赖于可溶性生长 因子与癌基因的激活。但也包括改变后的互动 细胞外基质使肿瘤得以扩散。一个家庭 一种称为整合素的细胞表面受体，在 调节细胞对细胞外基质的反应。整合素相互作用 与细胞外基质蛋白，如纤维连接蛋白，玻璃体连接蛋白， Tenascin、胶原蛋白和层粘连蛋白，并传递调节基因的信号 表达，细胞增殖，存活。和形态。在人类口述中 癌症标本，一类主要整合素的表达，称为 对B1整合素进行了较为详细的研究。重要的是 另一类被称为av整合素的整合素，直到最近才被 被认可了。初步研究表明，至少有三种不同的av 整合素在鳞状细胞癌不同细胞成分中表达上调 源于口腔粘膜的细胞癌(SCC)。阿尔法-v-贝塔-6 整合素在癌细胞中新表达，αvbeta6强烈表达 在肿瘤相关的间质细胞中表达，并且αvbeta3强烈 在支持血管生长和生存的血管中表达 肿瘤。因此，可以想象av整合素的抑制剂可以 对口腔癌的生长和存活率有很大的影响。 建议将对整合素表达的初步研究扩展到 口腔癌通过分析来自正常人群的大量样本， 增生性和恶性口腔粘膜，将被加工和 与口腔癌组织和组织病理学联合编目 核心。这次调查的目的是确认两者之间的关联 口腔癌进展与av整合素表达之间的关系 评价av整合素作为组织病理学的潜在应用价值 口腔癌进展和预后的标志物。 此外，调节培养细胞中α-v-β-6表达的因素 将对鳞状细胞癌细胞进行分析，并假设α-v-β-6 可能由基质诱导表达的信号将被检测。至 评估av整合素在口腔癌中的作用，我们将测试 Av封闭抗体对鳞状细胞癌生长和侵袭的影响 细胞在不同的体外模型中，比较b6- 将阴性的SCC细胞系与其转染组进行比较 过度表达α-v-β-6的同龄人。最后，假设 Av整合素参与调节 将测试SCC细胞中的蛋白水解酶、生长因子和细胞因子。 这些研究将为细胞基质的作用提供新的见解 在口腔癌中的相互作用，并将为发展提供基础 干扰口腔癌生长和侵袭的新疗法 通过干扰鳞状细胞癌细胞的基本细胞基质相互作用。