Pre-malignant processes of smoking-induced lung adenocarcinoma development: A conceptual biological model

Chronic exposure to cigarette smoke is the leading cause of human lung cancer and its most prevalent form, adenocarcinoma. However, the mechanisms by which smoking induces adenocarcinoma are largely inferred from the analysis of fully developed tumors. The current work focuses on the early events that precede the existence of clinically detectable tumors and where the progressive mechanisms are believed to be different from the ones driving established tumor growth. Biological information was drawn from the literature and generalized into a conceptual model, or framework, which describes and integrates the main processes involved in the early stages of smoking-induced lung adenocarcinoma development. No such integrative representation currently exists. The biological framework presented here is based on the “field of injury” of the lung. It covers the smoking-induced stepwise transition of unexposed (naive) lung tissue to the first appearance of neoplastic cells through defined tissue states referred to as pre-field and field. Each tissue state exhibits its own formalized characteristics (or phenotype properties), which evolve as a result of the combined effects of smoking, the interactions between the different tissue properties, and the local environment represented in the framework as lung inflammation and immune surveillance. The resulting network of influences between the lung tissue states and properties provides a good understanding of the early events involved in lung adenocarcinoma triggered by smoking. The resulting conceptual model—an integrative mechanistic hypothesis—can explain a broad range of cigarette smoking and smoking cessation scenarios.