EPITHELIAL HOMEOSTASIS AND CARCINOGENESIS IN TGF BETA COMPROMISED MOUSE MODELS

TGF Beta 受损小鼠模型中的上皮稳态和致癌作用

• 批准号: 6160974
• 负责人: L M WAKEFIELD
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6160974
• 关键词: animal genetic material tag; athymic mouse; chemical carcinogen; chemical carcinogenesis; disease /disorder model; epithelioma; epithelium; genetic promoter element; genetically modified animals; growth factor receptors; homeostasis; laboratory rat; liver neoplasms; lung neoplasms; metallothionein; mouse mammary tumor virus; neoplasm /cancer genetics; nucleic acid repetitive sequence; pancreas neoplasms; prostate neoplasms; transforming growth factors; virus genetics

Transforming growth factor-betas (TGF-betas) are potent inhibitors of epithelial cell growth. Recently the type II TGF-beta receptor has been shown to be diminished or absent in a number of human malignancies, implicating loss of TGF-beta function as one mechanism contributing to tumor development. We have tested the importance of the TGF-beta system in epithelial homeostasis in vivo by generating transgenic animals locally overexpressing a dominant negative mutant form of the type II TGF-beta receptor (DNR) in order to knock out response to TGF-beta in select epithelia. High level expression of the DNR construct in the exocrine pancreas results in progressive atrophy of the acinar compartment, associated with ductal metaplasia and fatty replacement. Enhanced proliferation of acinar cells is observed, consistent with a key role for endogenous TGF-betas in limiting proliferation and maintaining structural integrity of the exocrine pancreas. Overexpression of the DNR in the mammary glands results in increased lobulo-alveolar side-branching and, importantly, in an enhanced susceptibility to tumorigenesis induced by the carcinogen dimethylbenzanthracene. Similarly, introduction of the DNR into a premalignant rat prostate cell line causes the cells to become tumorigenic in nude mice. These studies provide the first in vivo demonstration of the tumor suppressor function of the TGF-beta receptor. We have also shown that loss of just one TGF-beta1 allele is sufficient to cause increases in cell turnover rates and enhanced susceptibility to tumorigenesis in the liver and lung of genetically modified mice. Since the resulting tumors retain the remaining wildtype TGF-beta1 allele, this distinguishes TGF-beta1 from classical tumor suppressor genes. We are currently analyzing the underlying molecular mechanisms. Results from all these experiments should give clinically useful insights into the physiological functions of TGF-betas during tumor initiation, promotion and progression, and illuminate how the system could be most effectively used in novel chemopreventive strategies.

转化生长因子-β（TGF-β）是一种有效的肿瘤生长抑制剂， 上皮细胞生长最近，II型TGF-β受体已被发现， 在许多人类恶性肿瘤中显示减少或不存在， 提示TGF-β功能丧失是导致 肿瘤发展我们已经测试了TGF-β系统的重要性 通过产生转基因动物， 局部过表达II型显性失活突变体 TGF-β受体（DNR），以敲除对TGF-β的反应， 选择上皮细胞。DNR构建体在大肠杆菌中的高水平表达 胰腺外分泌导致腺泡进行性萎缩 与导管化生和脂肪替代有关。 观察到腺泡细胞的增殖增强，与 内源性TGF-β在限制增殖和 维持外分泌胰腺的结构完整性。 乳腺中DNR的过表达导致乳腺癌细胞中 小叶肺泡侧支，重要的是，在一个增强的 对致癌物诱发肿瘤的易感性 二甲基苯并蒽同样，将DNR引入到 癌前大鼠前列腺细胞系导致细胞成为 裸鼠致瘤性。这些研究提供了第一个体内 证明TGF-β受体的肿瘤抑制功能。 我们还表明，仅仅一个TGF-β 1等位基因的丢失就足够了。 导致细胞更新率增加和易感性增强 转基因小鼠肝脏和肺部的肿瘤发生。 由于产生的肿瘤保留了剩余的野生型TGF-β 1 等位基因，这将TGF-β 1与经典的肿瘤抑制因子 基因.我们目前正在分析潜在的分子机制。 所有这些实验的结果应该会对临床有用 深入了解TGF-β在肿瘤发生过程中的生理功能 启动，促进和发展，并阐明如何系统 可以最有效地用于新的化学预防策略。