Abstract
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.
Highlights
Cigarette smoke (CS) consumption is causally related to a broad spectrum of adverse health effects, especially lung cancer, which is the leading cause of cancer deaths in the US and worldwide [1]
The systems viewpoint takes into account the known biological changes occurring in the cigarette smoker’s lung—from the naïve state to the initial malignant cells that may develop into full-blown lung adenocarcinoma
Cigarette smoke exposure is implicated in the etiology of numerous diseases [2], with strong evidence that these diseases are largely activated by skewed immune responses [25]
Summary
Cigarette smoke (CS) consumption is causally related to a broad spectrum of adverse health effects, especially lung cancer, which is the leading cause of cancer deaths in the US and worldwide [1]. While the smoking-related risk to develop squamous cell carcinoma of the lung (SCC) has remained stable, adenocarcinoma is the most prevalent form of lung cancer among smokers [2]. This is most likely due to changes in cigarette design and manufacture during the past several decades [4,5]. This paper provides an integrating conceptual model for the biology that underpins a plausible explanatory mechanism that underlies CS-dependent lung tissue remodeling from smokingonset to neoplastic transformation To our knowledge, such an integrative approach to this disease scenario is unique and has not been published before. The outcome of the resulting biological framework can be used for a variety of subsequent research efforts, including more refined versions
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