COX-2 Driven Pancreatic Adenocarcinoma

COX-2驱动的胰腺腺癌

基本信息

批准号：
7268125
负责人：
SUSAN M FISCHER
金额：
$ 19.37万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-13 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7268125
关键词：
Age-Months Animal Disease Models Anti-Inflammatory Agents Anti-inflammatory Apoptosis Aspirin Automobile Driving Biological Biological Factors Biological Markers Bos taurus Cattle Characteristics Chemoprevention Chronic Consumption Coxibs Data Disease Disease Progression Epidermis Epigallocatechin Gallate Etiology Fish Oils Future Gelatinase B Genistein Goals Human Incidence Infiltration Inflammation Laboratories Link Location Longevity Lymphocyte Malignant Neoplasms Malignant neoplasm of pancreas Modeling Molecular Mus Mutation Neoplasm Metastasis Neoplastic Processes Omega-3 Fatty Acids Pancreatic Adenocarcinoma Pathology Phenotype Prevention Prostaglandin Antagonists Prostaglandin-Endoperoxide Synthase Prostaglandins Research Risk Role Severities Severity of illness Signal Pathway Skin Skin Carcinogenesis TP53 gene Time Transgenic Mice Up-Regulation Validation Vascular Endothelial Growth Factors Work caspase-3 celecoxib chronic pancreatitis cyclooxygenase 1 cyclooxygenase 2 epidemiology study human disease interest keratin 5 macrophage promoter research study silibinin size tumor

项目摘要

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.

描述（由申请人提供）：作为我们关于环氧合酶-2 (COX-2) 及其下游前列腺素产物在癌症中的作用的研究的一部分，我们最近生成了一种转基因小鼠，该小鼠在角蛋白5启动子。这些被称为 K5.COX-2 的小鼠会产生自发性胰腺腺癌，其组织学特征与人类疾病有许多相同的特征。初步证据表明，这种情况的发生率为 100%，并且在 6 至 7 个月大时致命。发展中的肿瘤高度发炎，表现为反应性基质以及淋巴细胞和巨噬细胞的浸润。给予选择性 COX-2 抑制剂塞来考昔可显着延长它们的寿命，这表明 COX-2 中的前列腺素正在驱动肿瘤过程。我们的目标是进一步描述这种胰腺癌新模型的发展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。我们假设具有抗炎活性的天然产物将减轻疾病的严重程度，并可能减轻侵袭和转移，从而延长寿命。具体目标是： 1) 表征 K5.COX-2 模型的病理学、疾病的发病时间和进展、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可能被激活； 2) 确定已知具有抗炎活性的天然产物（绿茶多酚 (GTP)、金雀异黄素、水飞蓟宾和鱼油）是否会改变疾病的发病率、严重程度、转移或寿命。这将与增殖、细胞凋亡和炎症的生物标志物相关。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。该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、COX-2 和胰腺癌之间的联系，拟议的工作应该提供有关这种疾病的所需信息。