Cyclooxygenase-2 Induced Pancreatic Cancer

环氧合酶 2 诱发胰腺癌

基本信息

批准号：
7758221
负责人：
SUSAN M FISCHER
金额：
$ 31.96万
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：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7758221
关键词：
Adenocarcinoma Adenylate Cyclase Age-Months Animal Disease Models Animal Model Automobile Driving Binding CREB1 gene Calcium Cells Characteristics Chemoprevention Chronic Coxibs Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclin D1 Data Development Dinoprostone Disease Dominant-Negative Mutation Epidermal Growth Factor Receptor Etiology Future GTP-Binding Proteins Genes Human In Vitro Incidence Infiltration Inflammation Inflammatory Inflammatory Response Inositol Investigation Lesion Leukocytes Link Lymphocyte MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Metaplasia Metaplastic Molecular Mus Neoplastic Processes Pancreas Pancreatic Adenocarcinoma Pancreatitis Pathway interactions Phenotype Phosphorylation Play Prevention Prostaglandins Protein Kinase C Receptor Activation Recruitment Activity Research Role SRC gene Signal Pathway Signal Transduction Signaling Molecule Skin Small Interfering RNA Therapeutic Tissues Transgenic Mice Up-Regulation Vascular Endothelial Growth Factors Work celecoxib chronic pancreatitis cyclooxygenase 2 cytokine human WFDC2 protein human disease inhibitor/antagonist keratin 5 macrophage neoplastic pancreatic neoplasm prevent promoter public health relevance receptor response transcription factor tumor tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Investigations into the role of cyclooxygenase-2 (COX-2) in pancreatitis and pancreatic cancer have been very limited. A recently generated transgenic mouse that over- expresses COX-2 under the control of a keratin 5 promoter, K5.COX-2, develops spontaneous pancreatitis leading to pancreatic adenocarcinoma that has many of the same histological and molecular characteristics as the human disease. This occurs with a 100% incidence and is fatal by 8 months of age. The major prostaglandin (PG) product, PGE2, binds to one or more of the 4 EP receptors. EP2 and EP4 are linked to adenylate cyclase causing an increase in cAMP and subsequent activation of protein kinase A (PKA) and phosphorylation of CREB. Preliminary data indicate that the cAMP/PKA/pCREB pathway is highly activated in pre-lesion pancreata of K5.COX-2 mice, however, the MAPK/Akt/NFkB pathway is also highly activated. We hypothesize that activation of both the cAMP/PKA/pCREB and MAPK/Akt/NFkB signaling pathways are required for a full neoplastic response as is the inflammatory response, and that inflammation is driving the metaplastic and neoplastic changes. Aim 1 will determine the requirement for PG signaling through the cAMP/PKA/pCREB pathway for adenocarcinoma development by generating transgenic mice with inducible, targeted activated CREB on a wildtype background, and dominant negative (dn)CREB on the K5.COX-2 background. Aim 2 will determine the critical involvement of MAPK/Akt/NFkB signaling in adenocarcinoma development through the use dnAkt/K5.COX-2 bitransgenic mice and the use of MAPK and NFkB inhibitors. Activation of c-Src, EGF receptors, Erk, Akt and NFkB will be assessed in wild type, pre-lesion and lesions from K5.COX-2 pancreata. Aim 3 will determine whether prostaglandins are driving acinar metaplasia by elevating cytokines that then recruit leukocytes. The effect of inhibition of COX-2 with celecoxib, or of inhibiting cytokine synthesis with pentoxyfylline, on cytokine expression, inflammatory cell infiltration and the development of acinar metaplasia and pancreatic cancer will be assessed. The effect of inhibition of COX-2 or cytokine synthesis on inflammatory cell infiltration in established lesions will also be determined to assess whether this will prevent further progression or reversion of the disease. PUBLIC HEALTH RELEVANCE: The proposed studies are significant because pancreatic cancer is one of the most fatal of all human malignancies and the lack of good animal models has severely hampered research into its etiology, prevention and treatment. Because of the associations between chronic inflammation, COX-2 and human pancreatic cancer, it is likely that the proposed work will generate information on the signaling pathways and receptors that are critical determinants in pancreatic cancer development, which should be useful for guiding future studies on chemoprevention and therapy.

描述（由申请人提供）：对环氧合酶-2（COX-2）在胰腺炎和胰腺癌中的作用的研究非常有限。最近产生的转基因小鼠在角蛋白5启动子K5.COX-2的控制下过度表达COX-2，产生自发性胰腺炎，导致胰腺癌，其具有许多与人类疾病相同的组织学和分子特征。这种情况的发生率为 100%，并且在 8 个月大时致命。主要前列腺素 (PG) 产物 PGE2 与 4 种 EP 受体中的一种或多种结合。 EP2 和 EP4 与腺苷酸环化酶相关，导致 cAMP 增加，随后激活蛋白激酶 A (PKA) 和 CREB 磷酸化。初步数据表明，K5.COX-2小鼠病变前胰腺中cAMP/PKA/pCREB通路高度激活，而MAPK/Akt/NFkB通路也高度激活。我们假设 cAMP/PKA/pCREB 和 MAPK/Akt/NFkB 信号通路的激活是完整的肿瘤反应所必需的，炎症反应也是如此，并且炎症正在驱动化生和肿瘤变化。目标 1 将通过生成在野生型背景上具有可诱导的、靶向激活的 CREB 和在 K5.COX-2 背景上具有显性失活 (dn)CREB 的转基因小鼠，确定腺癌发展中通过 cAMP/PKA/pCREB 途径对 PG 信号传导的需求。目标 2 将通过使用 dnAkt/K5.COX-2 双转基因小鼠以及使用 MAPK 和 NFkB 抑制剂来确定 MAPK/Akt/NFkB 信号传导在腺癌发展中的关键参与。将在来自 K5.COX-2 胰腺的野生型、损伤前和损伤中评估 c-Src、EGF 受体、Erk、Akt 和 NFkB 的激活。目标 3 将确定前列腺素是否通过提高随后招募白细胞的细胞因子来驱动腺泡化生。将评估用塞来考昔抑制 COX-2 或用己酮茶碱抑制细胞因子合成对细胞因子表达、炎症细胞浸润以及腺泡化生和胰腺癌发展的影响。还将确定抑制 COX-2 或细胞因子合成对已形成病变中炎症细胞浸润的影响，以评估这是否会阻止疾病的进一步进展或逆转。公共健康相关性：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，而良好的动物模型的缺乏严重阻碍了对其病因学、预防和治疗的研究。由于慢性炎症、COX-2 和人类胰腺癌之间的关联，拟议的工作很可能会产生有关信号通路和受体的信息，这些信号通路和受体是胰腺癌发展的关键决定因素，这应该有助于指导未来的研究化学预防和治疗。