The Role of COX-2 and PPAR-Gamma in Pancreatic Cancer

COX-2 和 PPAR-γ 在胰腺癌中的作用

• 批准号: 6851675
• 负责人: Guido Erwin Michael Eibl
• 金额: $ 28.44万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6851675
• 关键词: angiogenesis; apoptosis; athymic mouse; carcinogenesis; cell proliferation; clinical research; enzyme inhibitors; enzyme linked immunosorbent assay; high performance liquid chromatography; human subject; inflammation; metastasis; neoplasm /cancer invasiveness; neoplastic process; pancreas neoplasms; peroxisome proliferator activated receptor; prostaglandin endoperoxide synthase; western blottings

DESCRIPTION (provided by applicant): A causal relationship between inflammation and cancer development has been recognized for many years. Prostaglandins, generated by cyclooxygenase (COX) activity, play an important role in inflammation and tumor pathophysiology. Inhibitors of the inducible cyclooxygenase-2 (COX-2) isoform have been extensively studied in chronic inflammatory diseases and are now in clinical trials as therapy for solid malignancies. Although in recent years an extensive knowledge about the contribution of COX-2 in human malignancies has been accumulated, the exact contribution of COX-2 to pancreatic cancer pathophysiology and the therapeutic potential of selective COX-2 inhibitors in pancreatic cancer are not known. We hypothesize that 1) COX-2 is critical in pancreatic cancer pathophysiology (proliferation, apoptosis, invasion, angiogenesis), 2) selective COX-2 inhibition will restrain growth, invasion and angiogenesis in COX-2 expressing PaCa tumors and 3) treatment with COX-2 inhibitors in COX-2 deficient PaCa tumors results in tumor progression and a poorer prognosis. We will pursue the following specific aims. 1) Determine the role of COX-2 inhibitors and PPAR-gamma ligands on invasion and angiogenesis in human pancreatic cancer cells in vitro. Thereby, the relationship between COX-2 and PPAR-gamma in COX-2 positive and negative human pancreatic cancer cells, the effects of selective COX-2 inhibitors and PPAR-gamma ligands on invasion and angiogenesis of human pancreatic cancer cells, and the effects of selective COX-2 inhibitors on PPAR-gamma activation will be determined. 2) Determine the role of COX-2 and the effects of selective COX-2 inhibitors and PPAR-gamma ligands on pancreatic cancer metabolism. 3) Evaluation of the effects of selective COX-2 inhibitors and PPAR-gamma ligands on the growth, invasion and angiogenesis of human pancreatic cancer in vivo. The experiments will elucidate the role of COX-2 in pancreatic cancer invasion and angiogenesis, both critical for pancreatic cancer progression and metastases, and will thus provide the rationale for the therapeutic use of selective COX-2 inhibitors in patients with pancreatic cancer. We will also clarify the contribution of COX-2 to pancreatic cancer metabolism. Findings from these experiments will provide new insights into mechanism of the altered metabolism in pancreatic cancer cells and thus provide another basis for the development of agents and strategies for clinical application.

描述（由申请人提供）：多年来，炎症与癌症发育之间存在因果关系。由环氧酶（COX）活性产生的前列腺素在炎症和肿瘤病理生理学中起重要作用。诱导性环氧酶-2（COX-2）同工型的抑制剂已在慢性炎症性疾病中进行了广泛研究，现在正在临床试验中作为固体恶性肿瘤的治疗。尽管近年来积累了有关COX-2在人类恶性肿瘤中的贡献的广泛知识，但COX-2对胰腺癌病理生理学的确切贡献以及胰腺癌选择性COX-2抑制剂的治疗潜力尚不清楚。 We hypothesize that 1) COX-2 is critical in pancreatic cancer pathophysiology (proliferation, apoptosis, invasion, angiogenesis), 2) selective COX-2 inhibition will restrain growth, invasion and angiogenesis in COX-2 expressing PaCa tumors and 3) treatment with COX-2 inhibitors in COX-2 deficient PaCa tumors results in tumor progression and a poorer prognosis.我们将追求以下特定目标。 1）确定COX-2抑制剂和PPAR-GAMMA配体在体外人类胰腺癌细胞中侵袭和血管生成的作用。因此，COX-2和PPAR-GAMMA在COX-2阳性和负人胰腺癌细胞中的关系，选择性COX-2抑制剂和PPAR-GAMMA配体对人类胰腺癌细胞的浸润和血管生成的影响，以及选择性COX-2抑制剂对PPAR-Gamma抑制剂对PPAR-GAMMA活化的影响。 2）确定COX-2的作用以及选择性COX-2抑制剂和PPAR-GAMMA配体对胰腺癌代谢的影响。 3）评估选择性COX-2抑制剂和PPAR-GAMMA配体对体内人类胰腺癌生长，侵袭和血管生成的影响。该实验将阐明Cox-2在胰腺癌进展和转移酶至关重要的胰腺癌侵袭和血管生成中的作用，因此将为胰腺癌患者的选择性COX-2抑制剂提供治疗使用的基本原理。我们还将阐明COX-2对胰腺癌代谢的贡献。这些实验的发现将为胰腺癌细胞改变新陈代谢的机制提供新的见解，从而为临床应用的制剂和策略提供了另一个基础。