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

基本信息

项目摘要

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,并且与增加的突变发生率和 肺组织结构和功能的显著改变。此外,美国约15%的肺癌患者 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。我们不明白这些肺组织景观的变化 影响肺癌发展。吸烟史在退伍军人中很普遍,其中许多人是 这些因素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 肺癌的早期发现和预防及治疗策略的设计: 为什么肺癌在吸烟者中更常见,而在非吸烟者中与老年密切相关,为什么 吸烟相关癌症中的特定致癌突变比衰老相关癌症中的特定致癌突变更常见。 肺癌,反之亦然?我们几乎不知道吸烟或衰老等条件如何改变 肺组织适应性景观,改变不同致癌事件的选择。使用小鼠模型,我们将 探索衰老和吸烟的不同背景如何不同地影响肺部微环境, 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 也可能提示候选生物标志物(如致癌克隆扩增或组织变化), 可以作为后续癌症发展风险的指标。 减少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?使用药理学和 在小鼠中的转基因方法和来自伊洛前列素肺癌化学预防临床试验的活检中,我们将 探索可能恢复肺部景观(即使是部分)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, 发展,它被认为是通过增强促癌表型。相反,我们建议吸烟 暴露(和老化)导致肺祖细胞群体适应性的降低(主要通过改变 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, 指导人类的预防策略。 虽然主要的范例在很大程度上考虑了老年在癌症中的作用,以反映癌症所需的时间, 致癌突变的积累,吸烟的作用是通过诱导致癌突变, 这些研究可能表明,由衰老和吸烟引起的微环境改变, 对肺中的肿瘤发生有实质性影响。

项目成果

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James V Degregori其他文献

James V Degregori的其他文献

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{{ truncateString('James V Degregori', 18)}}的其他基金

Impact of aging and clonal hematopoiesis on epigenetic heterogeneity, evolvability, and leukemogenesis
衰老和克隆造血对表观遗传异质性、进化性和白血病发生的影响
  • 批准号:
    10700071
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Impact of aging and clonal hematopoiesis on epigenetic heterogeneity, evolvability, and leukemogenesis
衰老和克隆造血对表观遗传异质性、进化性和白血病发生的影响
  • 批准号:
    10353178
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
The impact of reduction of cellular senescence on age-related epigenetic heterogeneity
细胞衰老减少对年龄相关表观遗传异质性的影响
  • 批准号:
    10830053
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Impact of aging and clonal hematopoiesis on epigenetic heterogeneity, evolvability, and leukemogenesis
衰老和克隆造血对表观遗传异质性、进化性和白血病发生的影响
  • 批准号:
    10493345
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Aged tissue environments as drivers of oncogenic adaptation in hematopoiesis
老化的组织环境是造血过程中致癌适应的驱动因素
  • 批准号:
    10319990
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Aged tissue environments as drivers of oncogenic adaptation in hematopoiesis
老化的组织环境是造血过程中致癌适应的驱动因素
  • 批准号:
    10541835
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
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:
    10683147
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Amy Briggs Diversity Supplement R01AG067584
艾米·布里格斯多样性补充 R01AG067584
  • 批准号:
    10273522
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Determining how aging-associated changes in the microenvironment contribute to leukemogenesis
确定与衰老相关的微环境变化如何导致白血病发生
  • 批准号:
    10176352
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Determining how aging-associated changes in the microenvironment contribute to leukemogenesis
确定与衰老相关的微环境变化如何导致白血病发生
  • 批准号:
    10406996
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:

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