Prostaglandins in Epithelial Injury

上皮损伤中的前列腺素

• 批准号: 6875797
• 负责人: WILLIAM F. STENSON
• 金额: $ 30.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6875797
• 关键词: angiogenesis; apoptosis; biological signal transduction; cell cycle; disease /disorder model; flow cytometry; laboratory mouse; neoplasm /cancer immunology; neoplastic cell; neoplastic growth; nonsteroidal antiinflammatory agent; prostaglandin E; radiation carcinogenesis; sarcoma

DESCRIPTION (provided by applicant): Studies over the past few years have established important roles for cyclooxygenase expression and prostaglandin production in tumorigenesis in a variety of human malignancies particularly colon cancer. There is great interest in the potential role of NSAIDs and selective Cox-2 inhibitors as chemopreventive agents. Although impressive progress has been made in this area a number of fundamental questions remain unanswered: 1. What specific biologic events are affected by prostaglandins to mediate their effects on tumorigenesis? 2. Are the relevant prostaglandins made by the host or the tumor? 3. What intracellular signaling events mediate the effects of prostaglandins? Our central hypothesis is that PGE2 promotes tumorigenesis by suppressing tumor cell apoptosis, by promoting escape from cell cycle arrest and by suppressing immune rejection. To test this hypothesis we will pursue three Specific Aims: 1. To define the effects of prostaglandins on apoptosis, cell cycle events, and angiogenesis in cancer in vivo and to determine if the prostaglandins that affect these events are derived from the tumor itself or surrounding stromal ceils. 2. To define the intracellular signaling events that mediate the effects of PGE2 on apoptosis and the cell cycle in cancer cells. 3. To define the role of prostaglandins in regulating the immune rejection of cancers. To address these Specific Aims we have developed a series of sarcomas induced by injecting methylcholanthrene in WT, Cox-1-/- and Cox-2-/- mice. In the proposed studies WT, Cox-1-/- and Cox-2-/- sarcomas will be injected into WT, Cox-1-/- and Cox-2-/- mice in "mix and match" in vivo growth studies. Similarly we have identified a Cox-2-expressing mouse colon cancer cell line (MCA38-LD) and a Cox-2- non-expressing mouse colon cancer cell line (MCA38). These cell lines will also be injected into WT, Cox- 1-/- and Cox-2-/- mice and their growth assessed. Preliminary data from in vitro studies suggests that the effects of PGE2 on apoptosis are mediated through Akt activation and inhibition of Bax translocation. In vivo growth studies of Cox-1-/- and Cox-2-/- sarcomas in WT and Rag-1-/- mice suggest that suppression of the host immune response by tumor PGE2 markedly enhances tumor growth.

描述（由申请人提供）：在过去的几年中，研究确立了在各种人类恶性肿瘤（尤其是结肠癌）中肿瘤发生中环氧酶表达和前列腺素产生的重要作用。 NSAIDS和选择性COX-2抑制剂作为化学预防剂的潜在作用引起了极大的兴趣。尽管在这一领域取得了令人印象深刻的进展，但许多基本问题仍未得到解答：1。哪些特定的生物学事件受前列腺素影响哪些特定的生物事件来介导其对肿瘤发生的影响？ 2。相关的前列腺素是由宿主或肿瘤制造的吗？ 3。哪些细胞内信号事件介导了前列腺素的作用？我们的中心假设是，PGE2通过抑制肿瘤细胞凋亡，通过促进细胞周期停滞和抑制免疫排斥来促进肿瘤发生。 为了检验这一假设，我们将追求三个具体的目的：1。定义前列腺素对体内癌症凋亡，细胞周期事件和血管生成的影响，并确定影响这些事件的前列腺素是否来自肿瘤本身或周围的基质天花板。 2。定义介导PGE2对癌细胞凋亡和细胞周期影响的细胞内信号传导事件。 3。定义前列腺素在调节癌症免疫排斥反应中的作用。为了解决这些特定目的，我们开发了一系列通过在WT，Cox-1 - / - 和Cox-2 - / - 小鼠中注入甲基胆碱诱导的肉瘤。在拟议的研究中，WT，Cox-1 - / - 和Cox-2 - / - 肉瘤将被注入WT，Cox-1 - / - 和Cox-2 - / - 小鼠在体内生长研究中的“混合与匹配”中。同样，我们已经确定了表达COX-2的小鼠结肠癌细胞系（MCA38-LD）和COX-2-非表达的小鼠结肠癌细胞系（MCA38）。这些细胞系还将注入WT，Cox-1 - / - 和Cox-2 - / - 小鼠，并评估了它们的生长。来自体外研究的初步数据表明，PGE2对凋亡的影响是通过AKT激活和BAX易位抑制来介导的。 WT和RAG-1 - / - 小鼠中COX-1 - / - 和COX-2 - / - 肉瘤的体内生长研究表明，肿瘤PGE2对宿主免疫反应的抑制显着增强了肿瘤的生长。