The role of epidermal, fibroblast and endothelial cell COX-2 in skin cancer

表皮、成纤维细胞和内皮细胞COX-2在皮肤癌中的作用

• 批准号: 7633349
• 负责人: Harvey R. Herschman
• 金额: $ 29.26万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7633349
• 关键词: Adverse effects; Animals; Benign; Biological; Blood Vessels; Breast; Carcinoma; Cardiovascular system; Cells; Clinical; Colon Carcinoma; Data; Development; Diagnostic Neoplasm Staging; Eicosanoid Production; Endothelial Cells; Epidemiology; Epithelial; Epithelial Cells; Evolution; Exhibits; Fibroblasts; Gene Deletion; Gene Silencing; Genes; Human; Inflammatory; Knock-out; Knockout Mice; Lesion; Literature; Lung; Malignant Neoplasms; Mediating; Modeling; Molecular; Monitor; Mus; PTGS2 gene; Papilloma; Pathway interactions; Physiological; Play; Population; Premalignant; Preventive; Process; Production; Prostaglandin Production; Prostaglandins; Public Health; Research; Research Personnel; Role; Skin; Skin Cancer; Skin Carcinogenesis; Staging; Stream; Tamoxifen; Therapeutic; Time; Tissues; Transgenic Mice; Tumor Promotion; carcinogenesis; cell type; genetic analysis; inhibitor/antagonist; neoplastic; precursor cell; prevent; programs; receptor; recombinase; research study; response; tumor; tumor progression

DESCRIPTION (provided by applicant): Clinical evidence, epidemiological results and experimental animal studies overwhelmingly suggest that COX-2 over-expression plays a modulatory and even causal role in development of many epithelial cancers. Recent studies demonstrate that stromal fibroblasts and blood vessel endothelial cells modulate epithelial tumor formation. There also exist substantial correlative data suggesting that COX-2 expression in stromal fibroblasts and blood vessel endothelial cells - and not in the initiated epithelial tumor precursor cells - may mediate pre-neoplastic emergence and subsequent progression of epithelial cancers. However, existing COX-2 pharmacologic experiments and global Cox2 knockout mice do not permit either physiological or genetic analyses to determine the specific cell populations - fibroblasts, epithelial or blood vessel endothelial cells - in which COX-2 over expression plays a critical role(s) in tumor development. We have developed (i) COX2 COE transgenic mice, in which we can conditionally over-express COX-2 in targeted cells and tissues and (ii) Cox2flox mice, in which we can conditionally delete the Cox2 gene in targeted cells and tissues. By crossing COX2 COE mice and Cox2flox mice to transgenic mice in which a tamoxifen-regulated CreERT recombinase is expressed in either epithelial cells, stromal fibroblasts or blood vessel endothelial cells, we will be able to determine (1) whether COX-2 over production in epithelial cells, fibroblasts and/or blood vessel endothelial cells modulates cancer development and (2) whether COX-2 expression is required in epithelial cells, fibroblasts or blood vessel endothelial cells for cancer development. Skin cancer is among the best-studied epithelial tumor induction models. We chose skin cancer to study the role(s) of COX-2 in epithelial cells, stromal fibroblasts and blood vessel endothelial cells during development of epithelial cancer because of the extensive literature on this model, the ease with which tumors can be monitored non-invasively, and the ease with which CreERT can be activated locally. The "broad, long-term objectives and specific aims" of this application are to determine (1) whether COX-2 plays a modulatory and/or a required role(s) in development of epithelial cancer and (2) in which cell(s) - initiated epithelial tumor precursor cell and/or stromal fibroblast and/or blood vessel endothelial cell - COX-2 modulates either pre-malignant epithelial tumor development or progression of benign tumors to carcinomas. The relevance of this research to public health. COX-2 inhibitors are still investigated as therapeutic and preventive agents for epithelial cancers, despite cardiovascular side effects. "Down-stream" COX-2 pathway effectors (prostanoid synthases and receptors) have become targets for similar research. If we can pinpoint the cell type(s) in which COX-2 expression and the prostanoid effectors regulate cancer development, we may be able to target those steps with lower concentrations and less prolonged application of pharmacologic agents. We anticipate we will be able to define the critical cells and times for COX-2 cancer enhancement.

描述（由申请人提供）：临床证据，流行病学结果和实验动物研究绝大多数表明COX-2过表达在许多上皮癌的发展中起着调节性甚至因果作用。 最近的研究表明，基质成纤维细胞和血管内皮细胞调节上皮肿瘤的形成。 还有大量的相关数据表明，基质成纤维细胞和血管内皮细胞中的Cox -2表达（而不是在开始的上皮肿瘤前体细胞中）可能介导前肿瘤前的出现，并随后进展上皮癌。 但是，现有的COX -2药理实验和全球COX2敲除小鼠不允许生理或遗传分析来确定特定的细胞群体 - 成纤维细胞，上皮或血管内皮细胞 - 其中Cox -2在肿瘤发育中表达在表达上起着关键作用。 我们已经开发了（i）Cox2 COE转基因小鼠，其中我们可以在靶向细胞和组织中有条件地过表达COX-2和（ii）Cox2Flox小鼠，其中我们可以在其中有条件地删除目标细胞和组织中的Cox2基因。 By crossing COX2 COE mice and Cox2flox mice to transgenic mice in which a tamoxifen-regulated CreERT recombinase is expressed in either epithelial cells, stromal fibroblasts or blood vessel endothelial cells, we will be able to determine (1) whether COX-2 over production in epithelial cells, fibroblasts and/or blood vessel endothelial cells modulates cancer development and （2）在上皮细胞，成纤维细胞或血管内皮细胞中是否需要COX-2表达才能发育。 皮肤癌是研究最佳的上皮肿瘤诱导模型之一。 我们选择皮肤癌来研究Cox-2在上皮细胞中的上皮细胞，基质成纤维细胞和血管内皮细胞在上皮癌期间的作用，这是由于该模型的广泛文献，并且可以轻松地对肿瘤进行非侵入性监测，以及可与Creert易于激活的地方。 The "broad, long-term objectives and specific aims" of this application are to determine (1) whether COX-2 plays a modulatory and/or a required role(s) in development of epithelial cancer and (2) in which cell(s) - initiated epithelial tumor precursor cell and/or stromal fibroblast and/or blood vessel endothelial cell - COX-2 modulates either pre-malignant epithelial tumor development or progression of良性肿瘤到癌。 这项研究与公共卫生的相关性。 尽管心血管副作用，但仍将COX-2抑制剂研究为上皮癌的治疗和预防剂。 “下游” COX-2途径效应子（前列腺素合酶和受体）已成为类似研究的靶标。 如果我们可以确定COX-2表达和前列腺素效应子调节癌症发展的细胞类型，那么我们可能能够以较低浓度且延长药理学剂的延长应用来瞄准这些步骤。 我们预计我们将能够定义COX-2癌症增强的关键细胞和时间。