CELL DIFFERENTIATION, GROWTH, AND APOPTOSIS IN ORAL CARCINOGENESIS

口腔癌发生中的细胞分化、生长和凋亡

• 批准号: 6218960
• 负责人: REUBEN LOTAN
• 金额: $ 19.15万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6218960
• 关键词: apoptosis; butyrates; carcinogenesis; carcinogenesis inhibitor; cell growth regulation; drug screening /evaluation; human tissue; oral pharyngeal neoplasm; organ culture; preneoplastic state; retinoids; tissue /cell culture

Cancers of the oral cavity account for about 4% of new cancer cases and for 2% of deaths from cancer. The overall survival rate (50%) among these patients has remained unchanged for the last three decades. Clearly, there is an urgent need to develop approaches to the prevention and therapy of oral cancer. One of the strategies to suppress oral carcinogenesis is to use biologic agents that modulate cell growth and differentiation. Such agents include vitamin A analogs (retinoids) and sodium butyrate and its derivatives. Retinoids modulate the proliferation and differentiation of normal oral mucosa cells and some head and neck squamous cell carcinoma cells and may play important regulatory roles in oral cancer development and growth. Butyrate is a known modulator of cellular differentiation and can enhance squamous cell differentiation of epidermal keratinocytes, however, the potential of butyrate or its derivatives in prevention or treatment of oral cancer has not been investigated. The progress of research on oral carcinogenesis is hindered by the methods employed to investigate the modulation of cell growth and differentiation of normal, premalignant, and malignant oral cells. Most of the current systems rely on cell lines established from oral cancer in monolayer culture. The culturing of normal cells is quite complicated, and there are no successful methods for culturing genuine premalignant oral cells. Here we propose to use a unique tissue slice organ culture (TSOC) method to investigate the effects of retinoids and butyrate derivatives on normal, premalignant, and malignant oral tissue. The Objectives of this project are to establish the TSOC system for oral normal, premalignant, and malignant tissues and to identify and characterize biological agents that reverse abnormalities in cell proliferation and differentiation and induce apoptosis. The Hypotheses to be tested in this project are: A. Short-term organ culture of slices of oral premalignant and malignant tissues can provide a unique system to investigate effects of various agents on cell growth, apoptosis, and differentiation under conditions that preserve tissue organization, cellular interactions, and cell function and, therefore, resemble the in vivo conditions better than monolayer cell culture. B. Retinoids and butyrate derivatives alone or in combination can reverse aberrations in cell growth and differentiation and induce apoptosis in premalignant and malignant oral cancer. To test these hypotheses we will establish optimal conditions for short-term organ cultures of tissue slices of fresh human oral squamous cell carcinoma and adjacent dysplastic and normal tissue and investigate the effects of several retinoids, which exhibit nuclear receptor specificity, and butyrate and its derivative, and the combination of these agents on the expression of nuclear retinoid receptors, cell proliferation, differentiation, and apoptosis in short-term cultures of tissue slices. Such agent could be used alone or in combination with existing approaches and add new therapeutic approaches to the prevention and therapy of oral cancer.

口腔的癌症约占新癌症病例的4％ 癌症死亡的2％。 其中的总生存率（50％） 在过去的三十年中，患者一直保持不变。 清楚地， 迫切需要开发预防方法的方法 口腔癌的治疗。 抑制口头的策略之一 致癌作用是使用调节细胞生长和 分化。 这样的药物包括维生素A类似物（类视黄素）和 丁酸钠及其衍生物。 视网膜类动物调节增殖 以及正常口服粘膜细胞和一些头和颈的分化 鳞状细胞癌细胞，可能在 口腔癌的发展和生长。 丁酸酯是已知的调节剂 细胞分化，可以增强鳞状细胞分化 然而，表皮角质形成细胞的潜力 预防或治疗口腔癌的衍生物尚未 调查。 口服癌变的研究进展受到阻碍 通过研究细胞生长的调节和 正常，预调子和恶性口腔细胞的分化。 最多 目前的系统依赖于从口腔癌中建立的细胞系 单层文化。 正常细胞的培养非常复杂， 而且没有成功的方法来培养真正的预先态度 口腔细胞。 在这里，我们建议使用独特的组织切片器官培养 （TSOC）研究类维生素类似和丁酸酯的作用的方法 衍生物在正常，预调和剂和恶性口腔组织上。 这 该项目的目标是建立口头的TSOC系统 正常，预先和恶性组织，并识别和 表征逆转细胞异常的生物学剂 增殖和分化并诱导凋亡。 假设 在该项目中进行测试是：A。短期器官培养 口服预调子和恶性组织可以为 研究各种药物对细胞生长，凋亡和 在保存组织组织的条件下的分化， 细胞相互作用和细胞功能，因此类似于IN 体内条件比单层细胞培养更好。 B.类维生素类动物和 单独或组合丁酸酯衍生物可以逆转 细胞的生长和分化，并诱导过凋亡的细胞凋亡和 恶性口腔癌。 为了检验这些假设，我们将建立最佳 新鲜人类组织切片的短期器官培养的条件 口服鳞状细胞癌以及相邻的发育不良和正常组织，以及 研究表现出核的几类类视丁素的作用 受体特异性和丁酸酯及其衍生物以及组合 这些药物在核性类维生素受体的表达，细胞的表达 短期培养物的增殖，分化和凋亡 组织切片。 该代理可以单独使用，也可以与 现有方法并为预防添加新的治疗方法 和口腔癌的治疗。