Dissecting the Role of Inflammation in Smoking and Aging Associated Lung Cancers

烟草是肺癌的主要原因，并与突变发生率增加和 肺组织结构和功能发生戏剧性变化。此外，在美国，大约15%的肺癌。 与吸烟无关，主要发生在老年，这也与 肺结构和功能的紊乱。我们不知道这些肺组织景观的变化是如何 影响肺癌的发展。吸烟史在退伍军人中很普遍，其中许多人 达到较高的年龄，共同导致退伍军人肺癌发病率大幅上升。这 提案将为解决几个大问题提供基本见解，这些问题对以下几个方面具有明显影响 肺癌的早期发现和预防和治疗策略的设计： 为什么肺癌在吸烟者中更常见，并与非吸烟者的老年密切相关？为什么？ 特定的致癌基因突变在与吸烟相关的癌症中比在与衰老相关的癌症中更常见吗 肺癌，和卖淫对吗？我们几乎不知道吸烟或衰老等情况是如何改变人的健康的 肺组织适应性景观，改变不同致癌事件的选择。使用鼠标模型，我们将 探索衰老和吸烟的不同背景如何对肺微环境和 从而筛选出不同的致癌事件，并探索其潜在的分子机制。这些研究 也可以提示候选生物标记物(如致癌克隆扩张或组织改变) 可以作为后续癌症发展的风险指标。 减轻衰老和吸烟对肺微环境影响的干预措施能否减少 致癌适应，从而降低肺癌的发病率？使用药理学和 小鼠的转基因方法和伊洛前列素肺癌化学预防临床试验的活检组织，我们将 探索可能恢复肺部状况的抗炎干预措施(即使是部分)，从而限制 致癌适应。虽然吸烟引起的炎症被描述为肺癌的促进剂 发展，它被认为是通过增强亲癌表型来做到这一点。相反，我们建议吸烟 暴露(和衰老)导致肺祖细胞群体适合性降低(主要通过改变 它们的微环境)，这导致对适应性突变的选择增加。了解如何 调节炎症和其他微环境变化可能会影响致癌基因的选择 指导人类的预防策略。 虽然主要范式主要考虑老年在癌症中的作用，以反映 致癌突变积累，以及吸烟通过诱导致癌突变所起的作用， 这些研究可能表明，衰老和吸烟引起的微环境变化 对肺部肿瘤发生的实质性影响。

Tobacco is the leading cause of lung cancer, and is associated with both increased mutation occurrence and dramatic alterations in lung tissue structure and function. Furthermore, about 15% of lung cancers in the U.S. are not associated with smoking, and primarily occur in old age, which is also associated with substantial disruptions in lung structure and function. We do not understand how these changes in lung tissue landscapes impact lung cancer development. A history of smoking is prevalent among veterans, many of whom are reaching older ages, together contributing to substantially higher lung cancer incidence among veterans. This proposal will provide fundamental insight to address several big questions, which have clear implications for early detection and the design of both prevention and treatment strategies for lung cancers: Why are lung cancers more common in smokers, and highly associated with old age for non-smokers, and why are particular oncogenic mutations much more common in smoking related cancers than in aging-associated lung cancers, and vice versus? We know almost nothing about how conditions like smoking or aging alter the lung tissue adaptive landscape, altering selection for different oncogenic events. Using mouse models, we will explore how the different contexts of aging and smoking differentially impact the lung microenvironment and thus select for distinct oncogenic events, and explore the underlying molecular mechanism. These studies could also suggest candidate biomarkers (such as oncogenic clonal expansions or tissue changes) which could be used as indicators of risk for subsequent cancer development. Can interventions that lessen the impacts of aging and smoking on lung microenvironments decrease oncogenic adaptation, and thus decrease the incidence of lung cancers? Using pharmacological and transgenic methods in mice and biopsies from an iloprost lung cancer chemoprevention clinical trial, we will explore anti-inflammatory interventions that might restore the lung landscape (even if partially), thus limiting oncogenic adaptations. While smoking-induced inflammation has been described as a promoter of lung cancer development, it is thought to do so by enhancing pro-cancer phenotypes. We instead propose that smoking exposure (and aging) lead to reductions in the fitness of lung progenitor cell populations (primarily by altering their microenvironment), which leads to increased selection for adaptive mutations. Understanding how modulating inflammation and other microenvironmental alterations can impact oncogenic selection could help guide prevention strategies in humans. While the predominant paradigm largely considers the role of old age in cancer to reflect the time required for oncogenic mutation accumulation, and the role for smoking to be through induction of oncogenic mutations, these studies could indicate that microenvironmental alterations induced by aging and smoking exert substantial influences on oncogenesis in the lung.