MECHANISMS OF FIBER CARCINOGENESIS

纤维致癌机制

• 批准号: 2391625
• 负责人: Tom K. Hei
• 金额: $ 27.93万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-29 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2391625
• 关键词: asbestos; athymic mouse; carcinogenesis; carcinogens; catalase; deferoxamine; enzyme activity; free radical oxygen; gene induction /repression; gene mutation; human genetic material tag; human tissue; metastasis; neoplasm /cancer genetics; neoplasm /cancer pharmacology; polymerase chain reaction; protooncogene; respiratory epithelium; respiratory neoplasm; superoxide dismutase; tissue /cell culture; tumor suppressor genes

DESCRIPTION: Asbestos fibers are carcinogenic and induce both lung cancers and mesotheliomas of the pleura and peritoneum in humans. The underlying cellular and molecular mechanisms in fiber carcinogenesis, however, are not clear. One of the main difficulties in studying mechanisms of fiber carcinogenesis is the lack of a suitable human cell model whereby the various tumorigenic stages can be dissected and the molecular changes associated with each stage examined. The recent availability of a well characterized human bronchial epithelial cell transformation model together with our preliminary data demonstrating that chrysotile fibers can induce malignant transformation of these cells form the basis for this proposal. Transformed cells progress through several sequential stages before becoming tumorigenic and producing progressively growing tumors in nude mice. In this revised application, Dr. Hei proposes to examine the underlying cellular and molecular alterations in fiber carcinogenesis using this human papillomavirus-immortalized human bronchial epithelial cell model. A series of cellular and molecular assays will be conducted using isolated clonal cell lines at each stage of the carcinogenic process to identify the necessary changes essential for fiber carcinogenesis. The proposal has 2 main objectives: The first is to establish an in vitro human epithelial cell transformation model for asbestos carcinogenesis using two independent, immortalized bronchial epithelial cell lines: and the second goal is to examine the molecular changes, particularly loss of tumor suppressor gene(s), associated with each stage of the carcinogenic process. A series of 5 specific aims are proposed to address 4 testable hypotheses. The BEP2D cells are anchorage dependent and do not form tumors in immunosuppressed host animals. Cytogenetic and molecular alterations at the gene level will be analyzed from tumors and intermediate transformation stages to provide a mechanistic basis for tumor induction by mineral fibers.

描述：石棉纤维具有致癌性，可诱发两种肺癌 以及人类胸膜和腹膜的间皮瘤。 底层的 然而，纤维致癌的细胞和分子机制并不明确。 清除。 研究纤维机理的主要难点之一 致癌是由于缺乏合适的人类细胞模型 可以剖析各个致瘤阶段和分子变化 与所检查的每个阶段相关。 最近有一口井可用 共同表征人支气管上皮细胞转化模型 我们的初步数据表明温石棉纤维可以诱导 这些细胞的恶性转化构成了该提议的基础。 转化细胞在变成之前要经历几个连续的阶段 致瘤并在裸鼠中产生逐渐生长的肿瘤。 在 在这个修改后的申请中，Hei 博士建议检查底层的 使用该人类细胞和分子改变纤维致癌作用 乳头瘤病毒永生化人支气管上皮细胞模型。 A系列 细胞和分子测定将使用分离的克隆进行 致癌过程各个阶段的细胞系，以识别 纤维致癌所必需的必要改变。 该提案有 2 主要目标：一是建立体外人上皮细胞 使用两个独立的石棉致癌细胞转化模型， 永生化支气管上皮细胞系：第二个目标是 检查分子变化，特别是肿瘤抑制因子的丧失 基因，与致​​癌过程的每个阶段相关。 A系列 提出了 5 个具体目标来解决 4 个可检验的假设。 BEP2D 细胞具有贴壁依赖性，在免疫抑制的情况下不会形成肿瘤 宿主动物。 基因水平上的细胞遗传学和分子改变将 从肿瘤和中间转化阶段进行分析，以提供 矿物纤维诱导肿瘤的机制基础。