COX-2 Driven Pancreatic Adenocarcinoma

描述（由申请人提供）：作为我们研究环氧合酶-2（考克斯-2）及其下游前列腺素产物在癌症中作用的一部分，我们最近培育了一种在角蛋白5启动子控制下过表达考克斯-2的转基因小鼠。这些被称为K5.COX-2的小鼠发展出自发性胰腺腺癌，其具有许多与人类疾病相同的组织学特征。初步证据表明，这种情况的发生率为100%，在6至7个月大时是致命的。发展中的肿瘤高度发炎，如反应性基质和淋巴细胞和巨噬细胞浸润所示。选择性考克斯-2抑制剂塞来昔布的施用显著延长了它们的寿命，这表明来自考克斯-2的异黄酮类化合物正在驱动肿瘤过程。我们的目标是进一步表征这种新的胰腺癌模型，包括发展中肿瘤的生物学和分子特征以及天然产物改变疾病进程的能力。我们推测，具有抗炎活性的天然产物将降低疾病的严重程度，并可能降低侵袭和转移，从而延长寿命。具体目标是：1）表征K5.COX-2模型的病理学、疾病的发作和进展时间、转移的发生率和位置、K-ras或其他ras突变的存在以及与异黄酮和炎症相关的信号传导途径的可能活化; 2）确定已知具有抗炎活性的天然产物是否（绿色茶多酚（GTP）、染料木黄酮、水飞蓟宾和鱼油）改变疾病发生率、严重程度、转移或寿命。这将与增殖、凋亡和炎症的生物标志物相关。这些研究是重要的，因为胰腺癌是所有人类恶性肿瘤中最致命的一种。由于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、考克斯-2和胰腺癌之间的联系，拟议的工作应该为这种疾病提供所需的信息。

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.