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.

口腔癌约占新发癌症病例的4%， 2%死于癌症的人。其中的总存活率(50%) 在过去的三十年里，患者数量一直保持不变。显然， 迫切需要制定预防和预防的方法。 口腔癌的治疗。抑制口交的策略之一 致癌是使用生物制剂来调节细胞生长和 差异化。这类药物包括维生素A类似物(维甲酸)和 丁酸钠及其衍生物。维甲酸对细胞增殖的调节作用 正常口腔黏膜细胞和某些头颈部细胞的分化 鳞状细胞癌细胞，并可能在 口腔癌的发生和生长。丁酸盐是一种已知的调节剂 细胞分化并可促进鳞状细胞分化 然而，表皮角质形成细胞，丁酸盐或其 衍生物在预防或治疗口腔癌中的作用尚未被 调查过了。口腔癌变的研究进展受到阻碍 通过所采用的方法来研究细胞生长和 正常、癌前和恶性口腔细胞的分化。多数 目前的系统依赖于从口腔癌建立的细胞系 单层培养。正常细胞的培养是相当复杂的， 目前还没有成功的方法来培养真正的癌前病变 口腔细胞。在这里，我们建议使用一种独特的组织切片器官培养 (TSOC)方法研究维甲酸和丁酸的作用 正常口腔组织、癌前病变组织和恶性口腔组织上的衍生物。这个 本项目的目标是建立口腔TSOC系统 正常、癌前和恶性组织，并鉴定和 描述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 在这个项目中测试的是：a.切片的短期器官培养 口腔癌前病变和恶性组织可以提供一种独特的系统来 研究不同药物对细胞生长、细胞凋亡和细胞生长的影响 在保存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In 体内条件优于单层细胞培养。B.维甲酸和维甲酸 丁酸衍生物单独或联合使用可逆转像差 癌前和癌前病变中细胞的生长分化和诱导细胞凋亡 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的条件 口腔鳞状细胞癌及其邻近的异型增生和正常组织 研究几种表现为核的维甲酸的影响 受体特异性，以及丁酸盐及其衍生物，以及它们的组合 这些药物对核维甲酸受体表达的影响 细胞的短期培养中的增殖、分化和凋亡 组织切片。这种试剂可以单独使用，也可以与 现有的方法和增加新的治疗方法来预防 以及口腔癌的治疗。