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: 6100874
• 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/6100874
• 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) 是有效的抑制剂 上皮细胞生长。最近，II 型 TGF-β 受体被 在许多人类恶性肿瘤中显示出减少或不存在， 暗示 TGF-β 功能的丧失是导致 肿瘤的发展。我们测试了 TGF-beta 系统的重要性 通过产生转基因动物来维持体内上皮稳态 局部过度表达 II 型显性失活突变体形式 TGF-β受体（DNR）以消除对TGF-β的反应 选择上皮细胞。 DNR 构建体的高水平表达 胰腺外分泌导致腺泡进行性萎缩 隔室，与导管化生和脂肪替代相关。 观察到腺泡细胞增殖增强，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 的过度表达会导致乳腺中 DNR 的增加 小叶-肺泡侧支，重要的是，在增强的 对致癌物诱导的肿瘤发生的易感性 二甲基苯并蒽。同样，将 DNR 引入 癌前大鼠前列腺细胞系导致细胞变成 在裸鼠中具有致瘤性。这些研究首次提供了体内 证明 TGF-β 受体的肿瘤抑制功能。 我们还表明，仅丢失一个 TGF-β1 等位基因就足够了 导致细胞更新率增加和易感性增强 影响转基因小鼠肝脏和肺部肿瘤的发生。 由于产生的肿瘤保留了剩余的野生型 TGF-β1 等位基因，这将 TGF-β1 与经典肿瘤抑制因子区分开来 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给出临床上有用的 深入了解 TGF-β 在肿瘤过程中的生理功能 启动、提升和进展，并阐明该系统如何 可以最有效地用于新型化学预防策略。