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: 2463697
• 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/2463697
• 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 overexpressing a dominant negative form (DNR) of the type II TGF-beta receptor under the control of the metallothionein (MT) promoter, or the MMTV LTR, in order to knock out response to TGF-beta in select epithelia. In the MT-DNR animals, high level expression of the dominant negative receptor construct in the pancreas results in progressive atrophy of the exocrine pancreas, associated with ductal metaplasia and fatty replacement. Enhanced proliferation of acinar cells is observed, consistent with roles for TGF-betas in limiting proliferation and maintaining structural integrity of the exocrine pancreas. In the liver and mammary glands, no basal phenotype is observed but the mice appear to show enhanced susceptibility to chemical carcinogens, indicating that TGF-betas may normally protect against tumorigenesis in these organs. We see similarly enhanced susceptibility to chemical carcinogens in the lungs and livers of mice with only one TGF-beta1 allele. Furthermore, we are exploring the possible role of TGF-betas in prostatic development and tumorigenesis using retroviral transduction to introduce the DNR into rat prostatic cell lines of varying malignancy, and forming prostatic tissue recombinants with urogenital ridge mesenchyme in nude mice. 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 在许多人类中， 恶性肿瘤，其中一种机制是TGF-β功能丧失 有助于肿瘤的发展。 我们已经测试了 TGF-β系统在体内上皮内稳态中通过产生 转基因动物过表达显性阴性形式（DNR）的 金属硫蛋白（MT）控制下的II型TGF-β受体 启动子或MMTV LTR，以敲除对TGF-β的应答 在选择的上皮细胞中。 在MT-DNR动物中， 胰腺中的显性负性受体结构导致 胰腺外分泌进行性萎缩，与导管相关 化生和脂肪替代。 腺泡增殖增强 观察到细胞，与TGF-β在限制细胞增殖中的作用一致。 增殖和维持外分泌的结构完整性 胰腺 在肝脏和乳腺中， 观察到，但小鼠似乎显示出对 化学致癌物，表明TGF-β通常可以保护 对抗这些器官的肿瘤发生。 我们看到类似的增强 小鼠肺和肝对化学致癌物的敏感性 只有一个TGF-β 1等位基因 此外，我们正在探索 TGF-β在前列腺发育和肿瘤发生中的可能作用 逆转录病毒介导柔红霉素进入大鼠前列腺 不同恶性程度的细胞系，并形成前列腺组织 重组体与裸鼠的泌尿生殖嵴间充质。 结果 从这些实验中得出的结论应该能提供临床上有用的见解 TGF-β在肿瘤发生过程中的生理功能， 晋升和进步，并阐明如何系统可以是最 有效地用于新的化学预防策略。