ALPHA GAMMA INTEGRINS IN ORAL CANCER

口腔癌中的 ALPHA GAMMA 整合素

• 批准号: 6471771
• 负责人: ROBERT PYTELA
• 金额: $ 10.37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6471771
• 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， 致癌因子和致癌基因的激活。也会影响到 与细胞外基质结合，使肿瘤得以扩散一个家庭 被称为整合素的细胞表面受体的一部分，在 介导细胞对细胞外基质的应答。整合素相互作用 与细胞外基质蛋白如纤连蛋白，玻连蛋白， 腱生蛋白、胶原蛋白和层粘连蛋白，并传递调节基因信号 表达、细胞增殖、存活。和形态学。人口腔 在癌症标本中，一种主要类型的整合素表达，称为 B 1整联蛋白已被详细研究。的重要性 另一类称为AV整联蛋白的整联蛋白， 认可.最初的研究表明，至少有三种不同的av 整联蛋白在鳞状细胞癌的不同细胞成分中上调， 来源于口腔粘膜的细胞癌（SCC）。阿尔法v β 6 整联蛋白在癌细胞中新表达，α v β 6在癌细胞中强烈表达。 在肿瘤相关的基质细胞中表达，而α v β 3在肿瘤相关的基质细胞中强烈表达。 在血管中表达，支持生长和生存的 肿瘤因此，可以想象，α v整联蛋白的抑制剂可以 对口腔癌的生长和生存有很大的影响。 建议扩展整合素表达的初步研究， 口腔癌通过分析大量的正常标本， 增生和恶性口腔粘膜，将被处理， 与口腔癌组织和组织病理学 核心本研究的目的是确认 口腔癌进展与av整合素表达之间的关系， 评价AV整联蛋白作为组织病理学指标的潜在效用 口腔癌进展和预后的标志物。 此外，在培养的细胞中调节α-v-β-6表达的因子 将分析SCC细胞，并且假设α-v-β-6 将测试基质来源的信号可能诱导的表达。 到 为了评估av整合素在口腔癌中的作用，我们将检测av整合素在口腔癌中的表达， 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，并比较b6- 将阴性SCC细胞系与其转染的SCC细胞系进行比较， 过表达α-v-β-6的对应物。 最后，假设 AV整合素参与调节 将测试SCC细胞中的蛋白酶、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 口腔癌的相互作用，并将提供基础， 干扰口腔癌生长和侵袭的新疗法 通过干扰SCC细胞的基本细胞基质相互作用。