PATHOGENESIS OF MESENCHYMAL TUMORS INDUCED BY ASBESTOS

石棉诱发的间质肿瘤的发病机制

• 批准号: 3251308
• 负责人: Agnes B Kane
• 金额: $ 22.5万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-06-15 至 1994-03-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3251308
• 关键词: asbestos; cellular immunity; chemical related neoplasm /cancer; disease /disorder model; electron microscopy; environment related neoplasm /cancer; fluorescence spectrometry; histochemistry /cytochemistry; immunofluorescence technique; laboratory mouse; lymph nodes; macrophage; macrophage activating factor; mesothelioma; model design /development; neoplasm /cancer immunology; northern blottings; peritoneum; tissue /cell culture

Exposure to asbestos fibers causes mesotheliomas, malignant tumors arising from the pleural or peritoneal lining, in humans and in experimental animals. A new model system was developed to induce mesotheliomas in mice after 30-50 weekly injections of 200 ug of crocidolite asbestos fibers. The proposed experiments will explore the mechanisms responsible for the development of these tumors. Two important steps in tumor development are loss of growth regulation and induction of angiogenesis. Specific poly- peptide mediators involved in these two critical steps will be identified in this model system. It is hypothesized that transforming growth factor (TGF-beta) is an inhibitor of mesothelial cell proliferation. The effects of exogenous TGF-beta on proliferation of reactive, preneoplastic. and neoplastic cell lines will be studied in intro and in vivo. regulation of mesothelial cell proliferation may occur by a paracrine or autocrine mechanism. Expression of TGF-beta mRNA by peritoneal macrophages and mesothelial cells will be determined by Northern blot analysis and in situ hybridization. TGF-beta is secreted as a latent, protein-bound complex. Activation of TGF- beta by macrophages or mesothelial cells exposed to asbestos will be tested using an in vitro bioassay. In order for neoplastic mesothelial cells to proliferate autonomously, it is hypothesized that they escape from inhibition by TGF-beta. The following escape mechanisms will be explored: physical migration away from peritoneal macrophages which secrete and activate TGF-beta, loss of ability to activate endogenous TGF-beta, or decreased response to active TGF-beta. Intraperitoneal injection of asbestos fibers induces angiogenesis in the mesothelial lining after 2 weeks. It is hypothesized that this early angiogenic response is mediated by angiogenic factors released from peritoneal macrophages. Expression of mRNA for angiogenic factors will be determined by Northern blot analysis and in situ hybridization. Induction of angiogenesis is also a property of malignant tumors. Release of angiogenic factors from neoplastic mesothelial cells will be determined using an in vivo angiogenesis assay. The role of these mediators in the growth of mesotheliomas in vivo will be tested using blocking antibodies and specific antagonists. These experiments may lead to a rational approach to delay or interrupt the sequence of events leading to the development of mesotheliomas in individuals exposed to asbestos.

暴露在石棉纤维中会导致间皮瘤、恶性肿瘤 发生于胸膜或腹膜衬里，在人类和 实验动物。开发了一种新的模型系统来归纳 每周注射30-50次阿司匹林后的小鼠间皮瘤 200微克青石棉纤维。拟议中的实验 将探讨负责开发 这些肿瘤。肿瘤发展中的两个重要步骤是丢失 生长调节和血管生成的诱导。特定的多聚- 参与这两个关键步骤的多肽介质将是 在这个模型系统中被识别。 假设转化生长因子(TGF-β)是 间皮细胞增殖的抑制剂。的影响 外源性转化生长因子-β对反应性、癌前病变的增殖作用。 肿瘤细胞系将在体内和体内进行研究。 间皮细胞增殖的调节可能通过一种 旁分泌或自分泌机制。重组人转化生长因子-β基因的表达 腹膜巨噬细胞和间皮细胞将通过 Northern印迹分析和原位杂交。转化生长因子-β是 以潜伏的蛋白质结合复合体的形式分泌。转化生长因子-1的激活 暴露于石棉的巨噬细胞或间皮细胞的β-反应 用体外生物测定法进行检测。为了治疗肿瘤 间皮细胞自主增殖，这是假设的 它们逃脱了转化生长因子-β的抑制。下面的转义 将探索机制：物理迁移从 分泌和激活转化生长因子-β的腹膜巨噬细胞 激活内源性转化生长因子-β的能力，或反应减弱 以激活转化生长因子-β。 腹膜腔内注射石棉纤维诱导血管生成 2周后植入间皮衬里。据推测， 这种早期的血管生成反应是由血管生成因子介导的。 从腹膜巨噬细胞释放出来。目的基因的表达 血管生成因子将通过Northern印迹分析和 原位杂交。诱导血管生成也是一种 恶性肿瘤的财产。血管生成因子的释放 肿瘤间皮细胞将在体内使用 血管生成试验。 这些介质在间皮瘤体内生长中的作用 将使用封闭抗体和特定的拮抗剂进行测试。 这些实验可能会导致一种合理的方法来延迟或 中断导致发展的一系列事件 接触石棉的人中的间皮瘤。