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: 6104918
• 负责人: REUBEN LOTAN
• 金额: $ 0.03万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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/6104918
• 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.

口腔癌约占新发癌症病例的 4% 占癌症死亡人数的 2%。 其中总体生存率（50%） 过去三十年来，患者的情况一直没有改变。 清楚地， 迫切需要制定预防和预防措施 口腔癌的治疗。 抑制口语的策略之一 致癌作用是利用生物制剂调节细胞生长和 差异化。 此类药物包括维生素 A 类似物（类维生素A）和 丁酸钠及其衍生物。 类维生素A调节增殖 正常口腔粘膜细胞和一些头颈部细胞的分化和分化 鳞状细胞癌细胞，可能发挥重要的调节作用 口腔癌的发生和生长。 丁酸盐是一种已知的调节剂 细胞分化，并能增强鳞状细胞分化 然而，表皮角质形成细胞中丁酸盐或其衍生物的潜力 预防或治疗口腔癌的衍生物尚未被证实 调查了。 口腔癌发生研究进展受阻 通过用于研究细胞生长调节的方法和 正常、癌前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 单层培养。 正常细胞的培养相当复杂， 并且没有成功的方法来培养真正的癌前病变 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) 方法研究类维生素A和丁酸盐的影响 正常、癌前和恶性口腔组织的衍生物。 这 该项目的目标是建立口腔TSOC系统 正常组织、癌前组织和恶性组织，并识别和 表征逆转细胞异常的生物制剂 增殖和分化并诱导细胞凋亡。 假设 本项目要测试的是： A. 切片的短期器官培养 口腔癌前组织和恶性组织可以提供独特的系统 研究不同药物对细胞生长、凋亡的影响 在保留组织组织的条件下分化， 细胞相互作用和细胞功能，因此类似于 体内条件优于单层细胞培养。 B. 类视黄醇和 丁酸酯衍生物单独或组合可以逆转畸变 细胞生长和分化并诱导癌前和癌前细胞凋亡 恶性口腔癌。 为了检验这些假设，我们将建立最优 新鲜人体组织切片短期器官培养条件 口腔鳞状细胞癌和邻近的不典型增生组织和正常组织以及 研究几种类维生素A的作用，这些类维生素A表现出核 受体特异性、丁酸盐及其衍生物、以及组合 这些药物对核视黄醇受体表达的影响 短期培养物中的增殖、分化和凋亡 组织切片。 此类药剂可单独使用或与 现有方法并在预防中添加新的治疗方法 和口腔癌的治疗。