PATHOGENESIS OF MESENCHYMAL TUMORS INDUCED BY ASBESTOS

石棉诱发的间质肿瘤的发病机制

• 批准号: 3251307
• 负责人: Agnes B Kane
• 金额: $ 22.93万
• 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 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3251307
• 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.

接触石棉纤维会导致间皮瘤，恶性肿瘤 源于人类和人类的胸膜或腹膜衬里 实验动物 开发了一种新的模型系统， 在30-50次每周注射后， 200 μ g青石棉纤维。 拟议的实验 将探讨负责发展 这些肿瘤。 肿瘤发展的两个重要步骤是 生长调节和诱导血管生成。 特异性聚- 参与这两个关键步骤的肽介质将是 在这个模型系统中。 据推测，转化生长因子（TGF-β） 间皮细胞增殖的抑制剂。 的影响 外源性TGF-β对反应性癌前病变增殖的影响。 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 旁分泌或自分泌机制。 TGF-β mRNA的表达 腹膜巨噬细胞和间皮细胞将通过 北方印迹分析和原位杂交。 TGF-β是 作为潜伏的蛋白质结合复合物分泌。 TGF-β的活化 接触石棉的巨噬细胞或间皮细胞将释放β-淀粉样蛋白， 使用体外生物测定进行测试。 为了使肿瘤 间皮细胞自主增殖，这是假设 使它们摆脱了TGF-β的抑制。 下面的逃生 将探讨各种机制： 分泌和激活TGF-β的腹腔巨噬细胞， 激活内源性TGF-β的能力，或降低反应 转化为活跃的TGF-β 腹腔注射石棉纤维诱导血管生成 在两周后的间皮瘤衬里中。 它是假设 这种早期血管生成反应由血管生成因子介导 从腹腔巨噬细胞释放出来 mRNA的表达 通过北方印迹分析测定血管生成因子， 原位杂交 血管生成的诱导也是一种 恶性肿瘤的性质。 血管生成因子的释放 肿瘤性间皮细胞将使用体内 血管生成测定。 这些介质在体内间皮瘤生长中的作用 将使用封闭抗体和特异性拮抗剂进行测试。 这些实验可能会导致一种合理的方法来延迟或 中断导致发展的事件顺序 间皮瘤在个人暴露于石棉。