PATHWAYS AND MECHANISMS CONTROLLING EARLY ORAL NEOPLASIA

控制早期口腔肿瘤的途径和机制

• 批准号: 6516475
• 负责人: JONATHAN A GARLICK
• 金额: $ 24.41万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6516475
• 关键词: Adenoviridae; athymic mouse; biological signal transduction; cadherins; cell adhesion; cell cell interaction; cell growth regulation; disease /disorder model; epithelioma; epithelium; gene expression; human tissue; immunocytochemistry; intercellular connection; keratinocyte; neoplastic cell; neoplastic process; oral mucosa; oral pharyngeal neoplasm; phenotype; protein structure function; tissue /cell culture; transfection /expression vector

DESCRIPTION (Adapted from the Investigator's Abstract): Oral cancer begins as a premalignant lesion in which a small nest of dysplastic cells expands while in contact with normal cells. During the recent grant period, unique models were developed which mimic the human mucosal and cutaneous microenvironment in premalignant disease and which showed that direct cell-to-cell contact between neighboring keratinocytes is crucial in controlling the development of invasive cancer from a premalignant lesion. It is known that loss of cell-cell contact mediated by intercellular adhesion is a central factor leading to the progression of advanced cancer and metastasis. However, the role of changes in intercellular adhesion in progression of early neoplasia in stratified epithelium is not clear. The objective of this application is to discover the intercellular pathways, which direct this, control it, or cause it to be lost. Because cadherins and catenins integrate cell adhesion with growth signaling they are excellent molecular candidates to regulate cell-cell interactions in premalignant disease. The experimental plan in this proposal is to perturb cadherins and catenins models of premalignancy and to monitor intraepithelial tumor cell expansion in vitro and invasion in vivo. The Principal Investigator hypothesizes that cadherin/catenin-mediated cell-cell interactions can control premalignancy and that changes in adhesions can activate pathways leading to cancer. He will test if overexpression of E-cadherin (Aim 1) or overexpression of alpha-catenin (Aim 2) will increase adherens junctions and limit neoplastic progression. The Principal Investigator will then determine if decreased adhesive interactions will trigger cancer progression by overexpressing dominant negative forms of E-cadherin (Aim 3) and desmosomal cadherins (Aim 4) to disrupt adherens junctions and desmosomes, respectively. He will test his hypotheses in tissue models, which mimic premalignant human stratified epithelium. Adenoviral vectors will be used to express these exogenous genes in short-term, in vitro studies and retroviral vectors will be used for long-term, in vivo studies using our novel human skin/nude mouse chimera. He expects to find cadherin-catenin-mediated pathways and mechanisms that will drive or arrest early neoplastic progression. This insight will be an important step towards finding new therapies to block premalignant disease progression and prevent cancer.

描述（改编自研究者摘要）：口腔癌始于 癌前病变，其中一小群发育不良细胞在癌变过程中扩张 与正常细胞接触。在最近的资助期间，独特的模型被 开发了模仿人类粘膜和皮肤微环境的 癌前疾病，并表明细胞与细胞之间的直接接触 邻近的角质形成细胞对于控制侵袭性的发展至关重要 来自癌前病变的癌症。众所周知，细胞与细胞接触的丧失 细胞间粘附介导是导致细胞间粘附的核心因素 晚期癌症的进展和转移。然而，变化的作用 分层早期肿瘤进展中的细胞间粘附 上皮不清楚。该应用程序的目的是发现 细胞间通路，指导它、控制它或导致它丢失。 因为钙粘蛋白和连环蛋白将细胞粘附与生长信号传导整合在一起 它们是调节细胞间相互作用的优秀分子候选者 癌前疾病。本提案中的实验计划是扰乱 癌前钙粘蛋白和连环蛋白模型并监测上皮内 肿瘤细胞体外扩增和体内侵袭。首席研究员 假设钙粘蛋白/连环蛋白介导的细胞间相互作用可以控制 癌前病变和粘连的变化可以激活导致 癌症。他将测试 E-钙粘蛋白是否过度表达（目标 1）或过度表达 α-连环蛋白（目标 2）将增加粘附连接并限制肿瘤 进展。然后首席研究员将确定是否减少 粘附相互作用将通过过度表达引发癌症进展 E-钙粘蛋白（目标 3）和桥粒钙粘蛋白（目标 4）的显性失活形式 分别破坏粘附连接和桥粒。他将测试他的 组织模型中的假设，模拟癌前人类分层 上皮。腺病毒载体将用于表达这些外源基因 短期体外研究和逆转录病毒载体将用于长期、 使用我们的新型人类皮肤/裸鼠嵌合体进行体内研究。他期望 找到钙粘蛋白-连环蛋白介导的途径和机制，以驱动或 阻止早期肿瘤进展。这一见解将是重要的一步 寻找新的疗法来阻止癌前疾病的进展和 预防癌症。