Role of inflammation in tumor promotion and progression

描述(由申请者提供)：这个合作项目将调查坏死、缺氧和炎症在癌症发展中的作用，重点是个体和相互依赖的对肿瘤促进和进展的贡献。我们将测试两个相关的假设，这两个假设是基于在化学诱导的肝癌模型中获得的初步结果。1.某些细胞因子或持续的NO产生所引起的抑制上皮细胞或癌细胞中的核因子-kappaB活性，可以破坏抗氧化防御，导致活性氧物种(ROS)的积累。后者可通过延长Jun激酶(JNK)的激活而导致坏死性细胞死亡。癌前肝细胞在早期促癌过程中的坏死性死亡，以及在肿瘤进展过程中营养和缺氧的癌细胞的坏死，触发局部的炎症反应，进一步促进肿瘤的促进和进展。2.当实体肿瘤生长超过临界大小时，它们会耗尽可用的氧气、能量、营养物质和生长因子。氧气供应的减少会导致肿瘤缺氧和HIF-1转录因子在癌细胞以及肿瘤和组织相关的巨噬细胞中的激活。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激活，并触发依赖于转录因子NF-kappaB的炎症反应。在炎性细胞内，HIF-1和NF-kappaB协同诱导生长和血管生成因子的表达，从而增加肿瘤的血液供应，刺激肿瘤的生长和进展。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重新刺激的持续循环是癌症进展的主要和关键因素。我们将在肝细胞癌的小鼠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估。小鼠分子遗传学将被用来剖析肿瘤驱动的炎症和ROS积累的不同机制，并确定它们在早期肿瘤促进以及肿瘤进展和血管生成中的作用。在提供有关炎症在癌症发生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。

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.