Role of inflammation in tumor promotion and progression

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，重点关注个体和相互依赖的肿瘤促进和进展。我们将测试两个相关的假设，这些假设是基于在化学诱导肝癌模型中获得的初步结果。1. 某些细胞因子或持续NO产生导致上皮细胞或癌细胞中NF-kappaB活性的抑制，可破坏抗氧化防御并导致活性氧（ROS）的积累。后者可通过延长君激酶（JNK）激活时间诱导坏死细胞死亡。早期肿瘤促进过程中癌前肝细胞的坏死死亡和肿瘤进展过程中营养和缺氧的癌细胞的坏死触发局部炎症反应，进一步增强肿瘤的促进和进展。2. 当实体瘤生长超过临界尺寸时，它们会耗尽可用的氧气、能量、营养物质和生长因子。氧供应减少导致肿瘤缺氧和肿瘤细胞及肿瘤和组织相关巨噬细胞中HIF-1转录因子的激活。坏死引起正常细胞成分的释放，导致肿瘤浸润性巨噬细胞的激活，并触发依赖于转录因子NF-kappaB的炎症反应。在炎症细胞内，HIF-1和NF-kappaB协同诱导生长和血管生成因子的表达，从而增加肿瘤血液供应，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激活以及肿瘤生长和血管生成的再刺激是癌症进展的主要和关键因素。我们将在肝细胞癌（HCC）小鼠模型中验证这些假设，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估。小鼠分子遗传学将用于剖析肿瘤驱动炎症和ROS积累的不同机制，并确定它们对早期肿瘤促进、肿瘤进展和血管生成的贡献。在提供炎症在癌变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炎症的化学预防和治疗策略的发展。

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.