Role of inflammation in tumor promotion and progression

炎症在肿瘤促进和进展中的作用

• 批准号: 7767692
• 负责人: Michael Karin
• 金额: $ 45.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7767692
• 关键词: Angiogenic Factor; Animal Model; Antioxidants; Carcinoma; Cell Death; Cells; Cessation of life; Chemicals; Chemopreventive Agent; Development; Diethylnitrosamine; Epithelial Cells; Evaluation; Experimental Models; Exposure to; Genes; Growth; Growth Factor; Hepatocarcinogenesis; Hepatocyte; Hypoxia; Immunologic Receptors; Individual; Inflammation; Inflammatory; Inflammatory Response; Kupffer Cells; Laboratories; Lead; Liver; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Modeling; Molecular Genetics; Mus; Myeloid Cells; NF-kappa B; Necrosis; Neoplasm Metastasis; Nutrient; Oxygen; Pharmaceutical Preparations; Phosphotransferases; Premalignant; Primary carcinoma of the liver cells; Production; Radiation; Reactive Oxygen Species; Relative (related person); Role; Signal Transduction; Solid Neoplasm; Staging; Starvation; Testing; Therapeutic; Tumor Promotion; Tumor Tissue; Vascular blood supply; Vascularization; Virus; Work; angiogenesis; base; cancer cell; carcinogenesis; cytokine; exhaust; macrophage; mouse model; neutrophil; research study; response; transcription factor; tumor; tumor growth; tumor progression; tumor vascular supply

DESCRIPTION (provided by applicant): This collaborative project will investigate the role of necrosis, hypoxia and inflammation in cancer development, focusing on individual and interdependent contributions to tumor promotion and progression. We will test two related hypotheses that are based on preliminary results obtained in a model of chemically- induced liver cancer. 1. Inhibition of NF-kappaB activity in epithelial cells or carcinomas, brought about by certain cytokines or persistent NO production, can dismantle antioxidant defenses and lead to accumulation of reactive oxygen species (ROS). The latter can induce necrotic cell death through prolonged Jun kinase (JNK) activation. The necrotic death of premalignant hepatocytes during early tumor promotion and necrosis of nutrient- and oxygen-starved cancer cells during tumor progression trigger a localized inflammatory response that further augments tumor promotion and progression. 2. As solid tumors grow beyond a critical size they exhaust available supplies of oxygen, energy, nutrients and growth factors. Decreased oxygen supply results in tumor hypoxia and activation of the HIF-1 transcription factor in both cancer cells and tumor- and tissue-associated macrophages. Necrosis, causing the release of normal cellular constituents, leads to activation of tumor-infiltrating macrophages and triggers an inflammatory response dependent on transcription factor NF-kappaB. Within inflammatory cells, HIF-1 and NF-kappaB collaborate to induce expression of growth and angiogenesis factors that increase tumor blood supply and stimulate tumor growth and progression. We propose that this constant cycle of tumor growth, tumor starvation, hypoxia and necrosis, tumor-induced activation of inflammatory cells and re-stimulation of tumor growth and angiogenesis is a major and critical contributor to cancer progression. We will test these hypotheses in a mouse model of hepatocellular carcinoma (HCC) that allows critical evaluation of effects on tumor promotion, progression, and angiogenesis. Mouse molecular genetics will be used to dissect the different mechanisms involved in tumor-driven inflammation and ROS accumulation and determine their contribution to early tumor promotion as well as to tumor progression and angiogenesis. While providing new information on the role of inflammation in carcinogenesis and tumor progression, this work can lead to development of chemopreventive and therapeutic strategies based on inhibition of necrosis-induced inflammation.

描述（由申请人提供）：该合作项目将研究坏死，缺氧和炎症在癌症发展中的作用，重点是对肿瘤促进和进展的个体和相互依赖的贡献。我们将检验两个相关的假设，这两个假设是基于在化学诱导肝癌模型中获得的初步结果。1.由某些细胞因子或持续的NO产生引起的上皮细胞或癌中NF-κ B活性的抑制可以破坏抗氧化防御并导致活性氧（ROS）的积累。后者可以通过延长Jun激酶（JNK）激活诱导坏死细胞死亡。在早期肿瘤促进期间癌前肝细胞的坏死性死亡和在肿瘤进展期间营养和氧饥饿的癌细胞的坏死触发局部炎症反应，其进一步增强肿瘤促进和进展。2.当实体瘤生长超过临界尺寸时，它们会耗尽氧气、能量、营养和生长因子的可用供应。氧供应减少导致肿瘤缺氧和癌细胞以及肿瘤和组织相关巨噬细胞中HIF-1转录因子的活化。坏死导致正常细胞成分的释放，导致肿瘤浸润性巨噬细胞的活化，并触发依赖于转录因子NF-κ B的炎症反应。在炎症细胞内，HIF-1和NF-κ B协同诱导生长和血管生成因子的表达，增加肿瘤血液供应并刺激肿瘤生长和进展。我们认为，肿瘤生长、肿瘤饥饿、缺氧和坏死、肿瘤诱导的炎症细胞活化以及肿瘤生长和血管生成的再刺激的这种恒定循环是癌症进展的主要和关键因素。我们将在小鼠肝细胞癌（HCC）模型中测试这些假设，该模型允许对肿瘤促进，进展和血管生成的影响进行关键评价。小鼠分子遗传学将用于剖析肿瘤驱动的炎症和ROS积累中涉及的不同机制，并确定它们对早期肿瘤促进以及肿瘤进展和血管生成的贡献。在提供关于炎症在致癌和肿瘤进展中的作用的新信息的同时，这项工作可以导致基于抑制坏死诱导的炎症的化学预防和治疗策略的发展。