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: 7013980
• 负责人: Guido Erwin Michael Eibl
• 金额: $ 27.84万
• 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/7013980
• 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，人们已经认识到炎症与癌症发展之间的因果关系。前列腺素由环氧合酶 (COX) 活性产生，在炎症和肿瘤病理生理学中发挥重要作用。诱导型环氧合酶-2 (COX-2) 异构体的抑制剂已在慢性炎症性疾病中进行了广泛研究，目前正处于临床试验中作为实体恶性肿瘤的治疗方法。尽管近年来人们对COX-2在人类恶性肿瘤中的作用有了广泛的了解，但COX-2对胰腺癌病理生理学的确切作用以及选择性COX-2抑制剂在胰腺癌中的治疗潜力尚不清楚。我们假设 1) COX-2 在胰腺癌病理生理学（增殖、凋亡、侵袭、血管生成）中至关重要，2) 选择性 COX-2 抑制将抑制表达 COX-2 的 PaCa 肿瘤的生长、侵袭和血管生成，3) COX-2 缺陷型 PaCa 肿瘤中的 COX-2 抑制剂会导致肿瘤进展和较差的预后。我们将追求以下具体目标。 1) 体外确定COX-2抑制剂和PPAR-γ配体对人胰腺癌细胞侵袭和血管生成的作用。从而探讨COX-2阳性和阴性人胰腺癌细胞中COX-2与PPAR-γ的关系、选择性COX-2抑制剂和PPAR-γ配体对人胰腺癌细胞侵袭和血管生成的影响以及将确定选择性 COX-2 抑制剂对 PPAR-γ 激活的影响。 2)确定COX-2的作用以及选择性COX-2抑制剂和PPAR-γ配体对胰腺癌代谢的影响。 3）评价选择性COX-2抑制剂和PPAR-γ配体对人胰腺癌体内生长、侵袭和血管生成的影响。这些实验将阐明 COX-2 在胰腺癌侵袭和血管生成中的作用，这两者对于胰腺癌进展和转移都至关重要，从而为选择性 COX-2 抑制剂在胰腺癌患者中的治疗应用提供依据。我们还将阐明 COX-2 对胰腺癌代谢的贡献。这些实验的结果将为胰腺癌细胞代谢改变的机制提供新的见解，从而为临床应用药物和策略的开发提供另一个基础。