COX-2 Driven Pancreatic Adenocarcinoma

描述(申请人提供)：作为我们对环氧合酶-2(COX-2)及其下游前列腺素产物在癌症中作用的研究的一部分，我们最近培育了一只在角蛋白5启动子控制下过表达COX-2的转基因小鼠。这些被称为K5.COX-2的小鼠会患上自发性胰腺癌，这种癌症具有许多与人类疾病相同的组织学特征。初步证据表明，这种情况的发病率为100%，并在6至7个月大时致命。发展中的肿瘤是高度炎症的，表现为反应性间质和淋巴细胞和巨噬细胞的渗透。选择性COX-2抑制剂塞来昔布的应用显著延长了肿瘤的寿命，这表明COX-2产生的前列腺素正在推动肿瘤过程。我们的目标是从发展中的肿瘤的生物学和分子特征以及天然产物改变疾病过程的能力方面进一步描述这种新的胰腺癌模型。我们假设，具有抗炎活性的天然产品将降低疾病的严重性，可能还会降低侵袭和转移，从而延长寿命。其具体目的是：1)就K5.COX-2模型的病理、发病和进展时间、转移的发生率和位置、K-ras或其他ras突变的存在以及与前列腺素和炎症相关的信号通路的可能激活来表征K5.COX-2模型；2)确定已知具有抗炎活性的天然产物(绿茶多酚、染料木素、水飞蓟宾和鱼油)是否可以改变疾病的发病率、严重性、转移或寿命。这将与增殖、凋亡和炎症的生物标记物相关。这项拟议的研究意义重大，因为胰腺癌是所有人类恶性肿瘤中最致命的一种。这种疾病缺乏良好的动物模型，严重阻碍了对其病因、预防和治疗的研究。由于慢性炎症、环氧合酶-2和胰腺癌之间的联系，这项拟议的工作应该会为这种疾病提供必要的信息。

DESCRIPTION (provided by applicant): As part of our studies on the role of cyclooxygenase-2 (COX-2) and its downstream prostaglandin products in cancer, we recently generated a transgenic mouse that over-expresses COX-2 under the control of a keratin 5 promoter. These mice, referred to as K5.COX-2, develop spontaneous pancreatic adenocarcinomas that have many of the same histological characteristics as the human disease. Preliminary evidence indicates that this occurs with a 100% incidence and is fatal by 6 to 7 months of age. The developing tumors are highly inflamed as denoted by the reactive stroma and infiltration of lymphocytes and macrophages. Administration of the selective COX-2 inhibitor, celecoxib, significantly extends their lifespan, suggesting that prostaglandins from COX-2 are driving the neoplastic process. Our goal is to further characterize this new model for pancreatic cancer with regard to a biological and molecular characterization of the developing tumors and the ability of natural products to alter the course of the disease. We hypothesize that natural products that have anti-inflammatory activity will reduce the severity of the disease and perhaps invasion and metastasis, thus prolonging lifespan. The specific aims are to: 1) Characterize the K5.COX-2 model with regard to the pathology, time of onset and progression of the disease, the incidence and location of metastases, the presence of K-ras or other ras mutations, and the possible activation of signaling pathways associated with prostaglandins and inflammation; 2) Determine whether natural products known to have anti-inflammatory activity (green tea polyphenols (GTP), genistein, silibinin and fish oil,) alter disease incidence, severity, metastases or lifespan. This will be correlated with biomarkers for proliferation, apoptosis and inflammation. The proposed studies are significant because pancreatic cancer is one of the most fatal of all human malignancies. The lack of good animal models for this disease has severely hampered research into its etiology, prevention and treatment. Because of the links between chronic inflammation, COX-2 and pancreatic cancer, the proposed work should contribute needed information on this disease.