Cyclooxygenase-2 Induced Pancreatic Cancer

环氧合酶 2 诱发胰腺癌

• 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
• 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

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(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一直非常有限。最近产生的一种转基因小鼠，在角蛋白5启动子K5.COX-2的控制下过度表达COX-2，发生自发性胰腺炎，导致胰腺癌，具有许多与人类疾病相同的组织和分子特征。这种情况发生的几率为100%，在8个月大的时候是致命的。前列腺素(PG)的主要产物PGE2与4个EP受体中的一个或多个结合。EP2和EP4与腺苷环化酶相连，导致cAMP升高，随后蛋白激酶A(PKA)激活，CREB磷酸化。初步研究表明，在K5.COX-2小鼠胰腺损伤前，cAMP/PKA/pCREB通路高度激活，而MAPK/Akt/NFkB通路也高度激活。我们假设，与炎症反应一样，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，炎症是驱动化生和肿瘤改变的因素。目的1通过建立野生型背景下可诱导的、靶向激活的CREB和K5.COX-2背景下显性负性CREB的转基因小鼠，确定在腺癌发生发展过程中通过cAMP/PKA/pCREB途径对PG信号的需求。目的2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信号通路在腺癌发生中的关键作用。C-Src、EGF受体、Erk、Akt和NFkB的激活将在K5.COX-2胰腺的野生型、病变前和病变中进行评估。目标3将确定前列腺素是否通过提高细胞因子然后招募白细胞来推动腺样化生。用塞来昔布抑制COX-2，或用己酮茶碱抑制细胞因子合成，对细胞因子表达、炎性细胞浸润以及腺样化生和胰腺癌的发展的影响将被评估。还将确定抑制COX-2或细胞因子合成对已建立的皮损中炎性细胞渗透的影响，以评估这是否将防止疾病的进一步进展或逆转。公共卫生相关性：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和人类胰腺癌之间的联系，这项拟议的工作可能会产生关于信号通路和受体的信息，这些信息是胰腺癌发展中的关键决定因素，这些信息应该有助于指导未来的化学预防和治疗研究。