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

剖析炎症在吸烟和衰老相关肺癌中的作用

• 批准号: 10454873
• 负责人: James V Degregori
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454873
• 关键词: Address; Age; Aging; Anti-Inflammatory Agents; Biopsy; Cells; Cessation of life; Chronic Obstructive Pulmonary Disease; Clinical Chemoprevention; Clinical Trials; Clonal Expansion; Clone Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Complementary DNA; Complex; Costs and Benefits; Defect; Development; Diagnosis; Diesel Fuels; Early Diagnosis; Elderly; Environment; Epithelial Cells; Event; Evolution; Fire - disasters; Gene Frequency; Genetically Engineered Mouse; Genotype; Guide prevention; Gulf War; Histology; Hospitals; Human; Iloprost; Immune; Immunity; Impairment; Incidence; Individual; Induced Mutation; Inflammation; Intervention; Lead; Link; Lung; Lung diseases; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Methods; Modeling; Molecular; Mus; Mutation; Natural Selections; Non-Small-Cell Lung Carcinoma; Oils; Oncogenic; Oral; Pharmacology; Phase; Phenotype; Population; Preventable cancer cause; Prevention; Prevention strategy; Prostaglandins I; Pulmonary Emphysema; Risk; Risk Factors; Role; Series; Smoke; Smoker; Smoking; Smoking History; Structure; Structure of parenchyma of lung; Testing; Time; Tissues; Tobacco; Transgenic Organisms; Veterans; Viral; adaptive immunity; aged; cancer risk; cancer type; candidate marker; carcinogenicity; design; fitness; former smoker; high risk; human old age (65+); improved; injury and repair; insight; lung cancer screening; lung development; military service; mouse model; mutant; non-smoker; novel strategies; patient population; promoter; pulmonary function; screening; service member; smoking exposure; smoking prevalence; smoking-related cancer; stem cells; treatment strategy; tumorigenesis; vector

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.

烟草是肺癌的主要原因，并且与突变发生率增加和 肺组织结构和功能的显着改变。此外，美国约 15% 的肺癌是由肺癌引起的。 与吸烟无关，主要发生在老年，这也与大量吸烟有关 肺结构和功能的破坏。我们不明白肺组织景观的这些变化是如何发生的 影响肺癌的发展。退伍军人中有吸烟史，其中许多人都是 年龄的增长，共同导致退伍军人肺癌发病率大幅上升。这 该提案将为解决几个重大问题提供基本见解，这些问题对 肺癌的早期发现以及预防和治疗策略的设计： 为什么肺癌在吸烟者中更常见，而对于非吸烟者来说与老年高度相关，以及为什么 特定的致癌突变在吸烟相关的癌症中比在衰老相关的癌症中更常见 肺癌，反之亦然？我们对吸烟或衰老等条件如何改变身体几乎一无所知 肺组织适应性景观，改变对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部微环境产生不同的影响， 从而选择不同的致癌事件，并探索潜在的分子机制。这些研究 还可以建议候选生物标志物（例如致癌克隆扩增或组织变化） 可以用作随后癌症发展的风险指标。 减轻衰老和吸烟对肺部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？利用药理和 小鼠转基因方法和伊洛前列素肺癌化学预防临床试验的活检，我们将 探索可能恢复肺部景观（即使是部分恢复）的抗炎干预措施，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因素 人们认为它是通过增强促癌表型来实现的。相反，我们建议吸烟 暴露（和衰老）会导致肺祖细胞群的适应性降低（主要是通过改变 他们的微环境），这导致适应性突变的选择增加。了解如何 调节炎症和其他微环境改变可以影响致癌选择可能有助于 指导人类的预防策略。 虽然主流范式主要考虑老年在癌症中的作用，以反映癌症发生所需的时间。 致癌突变的积累，以及吸烟通过诱导致癌突变的作用， 这些研究可能表明，衰老和吸烟引起的微环境改变会影响 对肺部肿瘤发生有重大影响。