Disruption of TGF-beta pathway in mouse pancreatic cancer development

描述（由申请人提供）：胰腺癌是美国癌症死亡的第五大原因，并且在所有胃肠道癌症中预后最差，5年生存率低于5%。因此，建立胰腺癌早期病变的模型系统，对胰腺癌的诊断和治疗具有重要意义。本申请的目的是使用我们最近产生的转基因小鼠模型研究TGF-β在胰腺癌发病机制中的作用。TGF-β被认为在胰腺癌的发展中起重要作用，因为超过50%的人类胰腺癌携带Smad 4突变，Smad 4是TGF-β信号传导所需的关键蛋白质。我们建立了胰腺特异性过表达Smad 7（一种TGF-β信号传导的特异性抑制剂）的转基因小鼠模型。在6个月大时，大多数转基因动物在胰腺中出现癌前病变，具有胰腺上皮内瘤变（PanIN）的特征，这是浸润性胰腺癌的前兆。我们将利用这种独特的小鼠模型来分析TGF-β和环境因素之间的功能相互作用以及胰腺癌肿瘤发生中的其他遗传变化。(1)我们将确定TGF-β信号传导的中断是否能够加速化学致癌物诱导的胰腺癌形成。具体地，我们将分析具有胰腺特异性Smad 7表达的小鼠对由烷化剂NMU（N-亚硝基-N-甲基脲）诱导的恶性病变的易感性。(2)我们将确定TGF-β和p53在胰腺癌形成中的功能相互作用。我们将研究Smad 7过表达对TGF-β的破坏能够与p53的丢失合作加速胰腺癌形成的假设。总之，这些研究不仅有助于了解胰腺癌的分子发病机制，而且有助于未来设计早期检测和早期治疗策略，以对抗这种致命的疾病。通俗语言描述：本项目拟利用动物模型研究TGF-β通路在胰腺癌发生中的作用。 修订日期：2006年2月27日（参见修订注释）

DESCRIPTION (provided by applicant): Pancreatic cancer represents the fifth leading cause of cancer death in the United States and has the worst prognosis of all gastrointestinal cancers with 5 year survival rates less than 5 percent. It is of paramount importance to develop model systems with early lesions of pancreatic cancers to facilitate the diagnosis and therapy for this deadly disease. The purpose of this application is to study the role of TGF-beta in pancreatic cancer pathogenesis using a transgenic mouse model that we recently generated. TGF-beta has been postulated to play an important role in the development of pancreatic cancers as more than 50 percent of human pancreatic cancers bear mutations of Smad4, a critical protein required for TGF-beta signaling. We generated a transgenic mouse model with pancreas-specific overexpression of Smad7, a specific inhibitor of TGF-beta signaling. At 6 months of age, most transgenic animals developed premalignant ductal lesions in the pancreas with characteristics of pancreatic intraepithelial neoplasia (PanIN), a precursor to invasive pancreatic cancers. We will utilize this unique mouse model to analyze the functional interaction between TGF-beta and environmental factors and other genetic changes in the tumorigenesis of pancreatic cancers. (1) We will determine if disruption of TGF-beta signaling is able to accelerate chemical carcinogen-induced pancreatic cancer formation. Specifically, we will analyze the susceptibility of the mice with pancreas- specific Smad7 expression to the malignant lesions induced by an alkylating agent NMU (N-Nitroso-N-Methyl Urea). (2) We will determine the functional interaction between TGF-beta and p53 in pancreatic cancer formation. We will study the hypothesis that TGF-beta disruption by Smad7 overexpression is able to cooperate with loss of p53 to accelerate pancreatic cancer formation. Taken together, these studies will not only help to understand the molecular pathogenesis of pancreatic cancers, but also aid in future designs of strategies for early detection and early therapy to combat this deadly disease. Lay language description: This proposal is to use animal models to study the function of TGF-beta pathway in carcinogenesis of pancreatic cancers. REVISED: February 27, 2006 (See Revision Note)