Inflammation and Cancer

自由基在我们的身体中无处不在，由正常的生理过程产生，包括有氧代谢和炎症反应，以消除入侵的病原微生物。慢性炎症会增加癌症风险。我们正在研究一氧化氮（NO）和p53之间的相互作用，作为一个重要的途径，在炎症介导的致癌作用。我们已经表明，NO诱导ATM和ATR依赖性p53翻译后修饰，导致p53应激反应在体外的人细胞中，在体外活化的巨噬细胞和人细胞的混合物中，以及在溃疡性结肠炎患者的结肠组织中，溃疡性结肠炎是一种癌症易感的慢性炎症性疾病。我们还发现了一种新的机制，微卫星不稳定性所造成的适应性不平衡的碱基切除修复酶在这些患者。慢性炎症也可以增加溃疡性结肠炎中的p53突变负荷。此外，我们还比较了炎症在溃疡性结肠炎和克罗恩病结肠癌发生中的作用。动物模型是我们综合生物学策略的关键方面，因此我们利用了基因敲除，例如，p53和诱导型一氧化氮合酶，以研究炎症相关癌症的机制。NO的适度增加会导致生长停滞和细胞凋亡，从而延迟肿瘤形成，而较高的NO含量与炎症和肿瘤形成增加有关。我们还将探讨肥胖增加的癌症风险与促炎状态有关的假设。

Free radicals are ubiquitous in our body and are generated by normal physiological processes, including aerobic metabolism and inflammatory responses, to eliminate invading pathogenic microorganisms. Chronic inflammation can increase cancer risk. We are investigating the interaction between nitric oxide (NO∙) and p53 as a crucial pathway in inflammatory-mediated carcinogenesis. We have shown that NO∙ induces ATM- and ATR-dependent p53 posttranslational modifications leading to a p53 stress response in human cells in vitro, in an admixture of activated macrophages and human cells in vitro, and in colon tissue from patients with ulcerative colitis, a cancer prone, chronic inflammatory disease. We also discovered a novel mechanism of microsatellite instability caused by an adaptative imbalance in base excision repair enzymes in these patients. Chronic inflammation can also increase p53 mutation load in ulcerative colitis. In addition, we are comparing the role of inflammation in colon carcinogenesis in ulcerative colitis versus Crohn's disease. Animal models are a critical facet of our integrative biology strategy, hence we have utilized genetic knockouts, e.g., p53 and inducible nitric oxide synthase, to investigate mechanisms of inflammation-associated cancer. Modest increases in NO∙ cause growth arrest and apoptosis to delay tumor formation, whereas higher NO∙ amounts are associated with inflammation and increased tumor formation. We will also explore the hypothesis that the increased cancer risk with obesity is related to a proinflammatory state.