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

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2020 · —

## Abstract

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 oncogene...

## Key facts

- **NIH application ID:** 9894635
- **Project number:** 5I01BX004495-02
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** James V Degregori
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894635

## Citation

> US National Institutes of Health, RePORTER application 9894635, Dissecting the Role of Inflammation in Smoking and Aging Associated Lung Cancers (5I01BX004495-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9894635. Licensed CC0.

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