COX-2 Driven Pancreatic Adenocarcinoma

COX-2驱动的胰腺腺癌

• 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
• 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

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）：作为我们关于癌症中环氧合酶-2（COX-2）及其下游前列腺素产品作用的研究的一部分，我们最近产生了一种转基因小鼠，该小鼠在控制蛋白5启动子的控制下过表达COX-2。这些小鼠被称为K5.cox-2，会发展出自发的胰腺腺癌，它们具有许多与人类疾病相同的组织学特征。初步证据表明，这种情况发生在100％的发病率中，在6至7个月大时致命。发育中的肿瘤被反应性基质和淋巴细胞和巨噬细胞的浸润高度发炎。选择性COX-2抑制剂Celecoxib的施用显着延长了其寿命，表明COX-2的前列腺素正在推动肿瘤过程。我们的目标是进一步描述这种胰腺癌的新模型，这些模型涉及发育中的肿瘤的生物学和分子表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会降低疾病的严重程度，也许会减少侵袭和转移，从而延长寿命。具体目的是：1）在病理学，疾病的发作和进展，转移的发生和位置，K-RAS或其他RAS突变的存在以及可能激活与Prostaglandins和炎症相关的信号传导途径的激活； 2）确定已知具有抗炎活性的天然产物（绿茶多酚（GTP），染料黄酮，硅蛋白酶和鱼油）是否会改变疾病的发病率，严重程度，转移或寿命。这将与用于增殖，凋亡和炎症的生物标志物相关。拟议的研究很重要，因为胰腺癌是所有人类恶性肿瘤中最致命的癌症之一。缺乏这种疾病的良好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，拟议的工作应贡献有关该疾病的所需信息。