TGF BETA SIGNALING AND SKIN CARCINOGENESIS

TGF Beta 信号传导与皮肤癌发生

• 批准号: 6500580
• 负责人: Xiao-Jing Wang
• 金额: $ 0.75万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6500580
• 关键词: animal genetic material tag; apoptosis; benzanthracenes; biological signal transduction; bromodeoxyuridine; chemical carcinogen; chemical carcinogenesis; cutaneous papilloma; drug interactions; gene induction /repression; genetically modified animals; growth factor receptors; laboratory mouse; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic process; phorbols; protein structure function; tissue /cell culture; transforming growth factors; tumor suppressor genes; tumor suppressor proteins

Transforming growth factor beta1 (TGFbeta1) is a potent growth inhibitor of epithelial cells; however, its role in carcinogenesis has not been clearly defined. Previous studies have suggested that TGFbeta1 plays seemingly contradictory roles in carcinogenesis: suppressing tumor growth at earlier stages, but promoting malignant progression at later stages. This proposal will investigate in vivo mechanisms underlying the functional switch of TGFbeta1 in skin carcinogenesis. To achieve this, transgenic mice have been generated have been generated in which a TGFbeta1 transgene can be focally induced in the epidermis by total application of a sub-pharmacological dose of a progesterone antagonist (e.g., ZK98.734). TGFbeta1 transgenic mice will be exposed to a chemical carcinogenesis protocol that allows tumorigenesis to develop in the discrete stages of initiation, promoting and malignant conversion. By applying ZK98.734 to a focal of the skin or to tumors at different stages, TGFbeta1 transgene expression can be induced in situ, thus, stage-specific roles of TGFbeta1 over-expression in carcinogenesis can be assessed. Additionally, to determine the consequence of blocking TGFbeta signaling in skin carcinogenesis, transgenic mice expressing a dominant negative TGFbeta type II receptor (deltabetaRII) in the epidermis have been generated, and will be tested for susceptibility to chemical carcinogenesis. Downstream targets of TGFbeta1 involved in multistage carcinogenesis will also be identified from these two complementary mouse models. To assess whether TGFbeta1 induces tumor progression via effects on the stroma, TGFbeta1 mice will be matured with the deltabetaRII mice. Because the deltabetaRII is only expressed in the epidermis and blocks TGFbeta1-induced growth inhibition in keratinocytes. TGFbeta1 will exert its paracrine effect n the dermis where cells still possess functional TGFbeta receptors. Once chemically-induced non-invasive tumors arise in these mice, ZK98.734 will be applied to tumors to observe whether TGFbeta1 induction accelerates tumor invasion and metastasis. Although not a specific aim in this proposal, transgenic mice that develop TGFbeta- resistant tumors, which have an invasive and metastatic phenotype, will provide useful models for testing therapeutic approaches.

转化生长因子beta1（TGFBETA1）是一种有效的生长抑制剂 上皮细胞；但是，其在癌变中的作用尚未 明确定义。先前的研究表明TGFBETA1播放 在癌变中看似矛盾的作用：抑制肿瘤生长 在较早的阶段，但在后期促进恶性发展。 该提议将调查基于的体内机制 TGFBETA1在皮肤致癌作用中的功能转换。为此， 已经产生了转基因小鼠 TGFBETA1转基因可以在表皮中局部诱导。 孕酮拮抗剂的亚药理学剂量的施用 （例如ZK98.734）。 TGFBETA1转基因小鼠将暴露于化学 致癌方案，允许肿瘤发生在 启动，促进和恶性转换的离散阶段。经过 将ZK98.734应用于皮肤的焦点或在不同阶段的肿瘤， TGFBETA1转基因表达可以原位诱导，因此，阶段特异性 可以评估TGFBETA1过表达在癌变中的作用。 此外，确定阻止TGFBETA信号的结果 在皮肤致癌作用中，表达显性阴性的转基因小鼠 表皮中的TGFBETA II型受体（Deltabetarii）已经 生成，并将测试化学敏感性 致癌作用。 TGFBETA1的下游目标参与了多阶段 还将从这两种互补小鼠中鉴定出致癌 型号。评估TGFBETA1是否通过影响诱导肿瘤进展 在基质上，TGFBETA1小鼠将与Deltabetarii小鼠成熟。 因为deltabetarii仅在表皮和块中表达 TGFBETA1诱导角质形成细胞的生长抑制作用。 TGFBETA1将发挥作用 它的旁分泌作用N在细胞仍然具有功能的真皮中 TGFBETA受体。一旦化学诱导的非侵入性肿瘤就会在 这些小鼠ZK98.734将应用于肿瘤，以观察TGFBETA1是否存在 诱导加速肿瘤侵袭和转移。虽然不是 在此提案中的具体目的，发展tgfbeta-的转基因小鼠 具有侵入性和转移性表型的抗性肿瘤将 为测试治疗方法提供有用的模型。