CARCINOGENESIS OF XENOTRANSPLANTED HUMAN EPITHELIA

异种移植的人类上皮细胞的致癌作用

• 批准号: 3187908
• 负责人: ANDRES J KLEIN-SZANTO
• 金额: $ 17.66万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-04-01 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3187908
• 关键词: athymic mouse; benzanthracenes; carcinoembryonal antigen; cell differentiation; cell growth regulation; cellular oncology; chemical carcinogen; chemical carcinogenesis; cocarcinogen; electron microscopy; environment related neoplasm /cancer; epithelium; histochemistry /cytochemistry; human tissue; immunochemistry; laboratory mouse; laboratory rat; lung neoplasms; oncogenes; preneoplastic state; respiratory neoplasm; simian virus 40; tissue /cell culture; toxin metabolism; transfection; tumor antigens; tumor promoters; viral carcinogenesis; virus infection mechanism; xenotransplantation

The overall purpose of the proposed research is to demonstrate the gradual appearance of phenotypically altered cells during in vivo carcinogenesis of xeno-transplanted human respiratory tract epithelium. Using carcinogen- or genetically-altered human cells that repopulate de-epithelialized rat tracheas transplanted s.c. into nude mice, we will monitor their in vivo behavior and sensitivity to exposure or re-exposure to environmentally relevant carcinogens and promoters. The sensitivity of normal and altered cells to chemical agents will be demonstrated by histological detection of metaplastic-dysplastic lesions and histochemical markers of preneoplastic growth. Utilizing an in vivo - in vitro technique, these same tissues will be used to assess increased survival and resistance to terminal differentiation in selective culture media that do not permit growth of normal human tracheobronchial epithelial cells. Immortalized cell lines or cells with increased in vitro survival will be used for further in vivo experiments of xenotransplantation into de-epithelialized tracheas to assess their tumorigenicity and eventual increased sensitivity to chemical agents. Similarly and again to test in an alternative model the hypothesis that a prior history of exposure to chemical or biological carcinogens increases the sensitivity of human cells to promoters or chemical carcinogens, we will determine if immortalized tumorigenic and non-tumorigenic cells of tracheo-bronchial origin produced by viral infection (SV40- adenovirus) transfection (SV40, T antigen gene, B myc, c-Ha-ras, c-Ki-ras) or in vitro exposure to chemicals (TPA, MNNG, cigarette smoke condensate) exhibit progressive changes when exposed in vivo after repopulation in transplanted tracheas. These changes will be evaluated not only in tumorigenesis experiments, but also with histological sequential follow-up studies using histochemical markers and by monitoring the appearance of the late neoplastic or invasive-metastasizing phenotype, i.e., cell surface changes, (such as alterations in binding to laminin, fibronectin and lectins), demonstration of invasive behavior and colonization potential using biological assays.

拟议研究的总体目的是证明 细胞表型改变的逐渐出现 异种移植人呼吸道的体内致癌作用 上皮。 使用致癌物或基因改变的人体细胞 重新填充皮下移植的去上皮大鼠气管 进入裸鼠，我们将监测它们的体内行为并 对暴露或再次暴露于相关环境的敏感性 致癌物和促进剂。 正常和改变的敏感性 细胞对化学试剂的影响将通过组织学证明 检测化生-不典型增生病变和组织化学 肿瘤前生长的标志物。 利用体内-体外 技术，这些相同的组织将用于评估增加 选择性生存和终末分化抗性 不允许正常人生长的培养基 气管支气管上皮细胞。 永生化细胞系或细胞 随着体外存活率的增加，将用于进一步的体内研究 去上皮异种移植实验 气管以评估其致瘤性并最终增加 对化学试剂的敏感性。 类似地再次测试 替代模型假设之前有接触史 对化学或生物致癌物的敏感性增加 人类细胞对促进剂或化学致癌物，我们将 确定是否永生化致瘤细胞和非致瘤细胞 病毒感染产生的气管-支气管起源（SV40- 腺病毒）转染（SV40、T抗原基因、B myc、c-Ha-ras、 c-Ki-ras）或体外接触化学品（TPA、MNNG、 香烟烟雾冷凝物）表现出渐进变化 在移植气管中重新增殖后体内暴露。 这些变化不仅会在肿瘤发生中进行评估 实验，而且还进行组织学连续随访 使用组织化学标记并通过监测 晚期肿瘤或侵袭性转移的出现 表型，即细胞表面的变化（例如 与层粘连蛋白、纤连蛋白和凝集素结合），证明 利用生物的入侵行为和定殖潜力 化验。