The impact of smoking and the influence of other factors on lung cancer

ABSTRACT

Introduction: Smoking is the main preventable cause of lung cancer. This review summarizes preclinical and clinical data on the mechanisms of smoking-associated cancer development of the major histological lung cancer types small cell lung carcinoma squamous cell carcinoma and pulmonary adenocarcinoma (PAC) and the impact of several factors other than smoking on this process.

Areas covered: The role of intracellular signaling induced by nicotinic receptors and beta-adrenergic receptors, the resulting increase in intracellular cyclic adenosine monophosphate (cAMP) as a key driver of PAC and the promoting effects of respiratory tract diseases and their therapeutics, psychological stress and global warming.

Expert opinion: Smoking has deleterious effects on the regulation of lung epithelia by neurotransmitter receptors that are further enhanced by gene mutations. Sensitization of the alpha-7 nicotinic receptor (α7nAChR) by COPD enhances the carcinogenic effects of smoking and turns nicotine into a carcinogen. Nicotine vaping may, therefore, cause cancer in individuals with chronic obstructive pulmonary disease. The opposing effects of cAMP on the major lung cancer types indicate that patients with PAC of Clara cell phenotype (PAC-Cl) will benefit from treatment with cAMP reducers and suggest that global warming-induced respiratory tract diseases and their therapeutics cause the global increase in the incidence of PAC.

KEYWORDS:

• Lung cancer
• smoking
• neurotransmitter receptors
• COPD
• psychological stress
• global warming

Article highlights

• Smoking is a major preventable risk factor for lung cancer.

• Although the number of smokers has decreased globally, the incidence of PAC has significantly increased and continues to rise globally.

• The activation of nicotinic acetylcholine receptors and beta-adrenergic receptors by nicotine and nicotine-derived nitrosamines and the resulting increase in intracellular cAMP are the major driving forces of PAC-Cl development and should be targeted by neoadjuvant therapy of this cancer.

• The nicotine-derived nitrosamines additionally cause mutations in the K-ras and p53 genes, thereby increasing their carcinogenic potency.

• Tobacco aldehydes cause mutagenic DNA adducts and induce beta-adrenergic receptor-mediated cAMP increase indirectly by activating stress responses associated with increased systemic levels of epinephrine and norepinephrine.

• Chronic respiratory tract inflammation, including rhinitis, bronchitis, asthma, and COPD and their therapeutics, increase intracellular cAMP and are therefore risk factors for PAC-Cl.

• Agents that reduce cAMP such as beta-blockers (established therapeutics for cardiovascular disease) and gamma-aminobutyric acid (GABA, widely used as nutritional supplement) should be used as adjuvant therapy for PAC-CL.

• In addition to smoking, allergies cause chronic respiratory diseases that are globally on the rise in response to increased pollen caused by global warming.

• Unless global warming and the associated allergic respiratory tract diseases are reduced internationally, global warming may soon surpass smoking as a risk factor for PAC.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.