With regard to carcinogenic influences, there is strong evidence that cigarette smoking and, to a much lesser extent, other environmental carcinogens are the main culprits responsible for the mutations that give rise to lung cancers. About 90% of lung cancers occur in active smokers or those who stopped recently. Moreover, there is a nearly linear correlation between the frequency of lung cancer and pack-years of cigarette smoking. The increased risk is 60 times greater among habitual heavy smokers (two packs a day for 20 years) than among nonsmokers. For unclear reasons, women are more susceptibile to carcinogens in tobacco smoke than men. Although cessation of smoking decreases the risk for developing lung cancer over time, it never returns to baseline levels, and genetic changes that predate the full development of lung cancer can persist for many years in the bronchial epithelium of former smokers. Passive smoking (proximity to cigarette smokers) also increases the risk for developing lung cancer, as does smoking of pipes and cigars, albeit only modestly.
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Other carcinogenic influences associated with occupational exposures act in concert with smoking and may sometimes be responsible for lung cancer all by themselves; examples include work in uranium mines, work with asbestos, and inhalation of dusts containing arsenic, chromium, nickel, or vinyl chloride. A cardinal example of a synergistic interaction between two carcinogens is found in asbestos and tobacco smoking. Exposure to asbestos in nonsmokers increases the risk for developing lung cancer 5-fold, whereas in heavy smokers exposed to asbestos the risk is elevated approximately 55-fold.
Even though smoking and other environmental influences are paramount in the causation of lung cancer, not all individuals exposed to tobacco smoke develop cancer (about 11% of heavy smokers do). It is very likely that the mutagenic effect of carcinogens is modified by hereditary (genetic) factors. Recall that many chemicals require metabolic activation via the P-450 monooxygenase enzyme system for conversion into ultimate carcinogens (Chapter 6). Individuals with certain polymorphisms involving the P-450 genes have an increased capacity to activate procarcinogens found cigarette smoke, and are thus exposed to larger doses of carcinogens and incur a greater risk of developing lung cancer. Similarly, individuals whose peripheral blood lymphocytes undergo chromosomal breakages after exposure to tobacco-related carcinogens (mutagen sensitive genotype) have a greater than 10-fold increased risk for developing lung cancer over control subjects.
By analogy to the adenoma–carcinoma sequence in the colon, it is proposed that some invasive adenocarcinomas of the lung arise through an atypical adenomatous hyperplasia–adenocarcinoma in situ–invasive adenocarcinoma sequence. Studies of lung injury models in mice have identified a population of multipotent cells at the bronchioloalveolar duct junction, termed bronchioalveolar stem cells (BASCs). After lung injury, multipotent BASCs proliferate and replenish the normal cell types (bronchiolar Clara cells and alveolar cells) found in this location, thereby facilitating epithelial regeneration. It is postulated that BASCs incur the initiating hit (for example, a somatic KRAS mutation) that enables these cells to escape normal “checkpoint” mechanisms and results in pulmonary adenocarcinomas.
The sequential changes leading development of squamous cell carcinomas are well documented; there is a linear correlation between the intensity of exposure to cigarette smoke and the appearance of ever more worrisome epithelial changes that begin with rather innocuous basal cell hyperplasia and squamous metaplasia and progress to squamous dysplasia and carcinoma in situ, before culminating in invasive cancer.