Disruption of TGF-beta pathway in mouse pancreatic cancer development

描述(申请人提供)：胰腺癌是美国第五大癌症死亡原因，是所有胃肠道癌症中预后最差的，5年生存率不到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。这一应用的目的是利用我们最近建立的转基因小鼠模型来研究转化生长因子-β在胰腺癌发病机制中的作用。转化生长因子-β被认为在胰腺癌的发展中起重要作用，因为超过50%的人胰腺癌携带Smad4的突变，Smad4是转化生长因子-β信号转导所需的关键蛋白。我们建立了一个胰腺特异性过表达Smad7的转基因小鼠模型，Smad7是一种转化生长因子-β信号的特异性抑制物。在6个月大时，大多数转基因动物在胰腺出现癌前导管病变，具有胰腺上皮内瘤变(Panin)的特征，这是侵袭性胰腺癌的前驱症状。我们将利用这一独特的小鼠模型来分析转化生长因子-β与环境因素之间的功能相互作用以及胰腺癌发生中的其他基因变化。(1)我们将确定干扰转化生长因子-β信号是否能够加速化学致癌物诱导的胰腺癌的形成。具体地说，我们将分析胰腺特异表达Smad7的小鼠对烷化剂NMU(N-亚硝基-N-甲基尿素)诱导的恶性病变的敏感性。(2)探讨转化生长因子-β与P53在胰腺癌形成中的功能相互作用。我们将研究一种假说，即Smad7过表达破坏转化生长因子-β能够协同P53的丢失加速胰腺癌的形成。综上所述，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发现和早期治疗的策略，以对抗这种致命的疾病。本研究拟利用动物模型研究转化生长因子-β途径在胰腺癌发生发展中的作用。 修订日期：2006年02月27日(见修订备注)

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)