EPITHELIAL HOMEOSTASIS AND CARCINOGENESIS IN TGF BETA COMPROMISED MOUSE MODELS

转化生长因子-β(TGF-β)是一种有效的血管紧张素转换酶抑制剂 上皮细胞生长。最近，II型转化生长因子-β受体已经被 在许多人类恶性肿瘤中表现为减少或缺失， 暗示转化生长因子-β功能的丧失是导致 肿瘤的发展。我们已经测试了转化生长因子-β系统的重要性 通过产生转基因动物在体内实现上皮内环境的稳定 局部过表达II型显性负性突变形式 转化生长因子-β受体(DNR)在体内对转化生长因子-β的敲除反应 选择上皮细胞。DNR构建物在大肠杆菌中的高效表达 胰腺外分泌导致腺泡进行性萎缩 间室，与导管化生和脂肪替代有关。 观察到腺泡细胞增殖增强，与 内源性转化生长因子-β在限制细胞增殖和 维持胰腺外分泌的结构完整性。 DNR在乳腺中的过度表达导致乳腺组织中 小叶-肺泡侧支，更重要的是，在强化的 致癌物对肿瘤的易感性 二甲基苯并菲。同样，将DNR引入到 癌前大鼠前列腺细胞系导致细胞 在裸鼠体内致癌。这些研究提供了第一个活体实验 转化生长因子-β受体的肿瘤抑制功能。 我们还表明，仅丢失一个转化生长因子-β1等位基因就足够了。 导致细胞周转率增加和易感性增强 转基因小鼠肝脏和肺中的肿瘤发生。 由于由此产生的肿瘤保留了剩余的野生型转化生长因子-β1 等位基因，这是转化生长因子-β1与经典肿瘤抑制因子的区别 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都应该在临床上有用 转化生长因子-β在肿瘤中的生理作用 启动、推广和发展，并说明系统如何 可最有效地用于新的化学预防策略。

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.