β-adrenergic mitogenic signal transduction in peripheral lung adenocarcinoma: Implications for individuals with preexisting chronic lung disease

Abstract

Peripheral adenocarcinoma (PAC) of the lung has increased dramatically over the last 20 years and is today the leading histological type of lung cancer in smokers and nonsmokers in industrialized countries. There is no apparent explanation for the steep rise in the number of individuals developing this cancer type. Using assays for the assessment of cell proliferation, receptor binding, and production of cyclic AMP (cAMP), we have identified a beta-adrenergic receptor-mediated mitogenic pathway, which activates cAMP down-stream, in cell lines derived from human peripheral adenocarcinomas that express features of Clara cells. Agonists of beta-adrenergic receptors strongly stimulated cell proliferation, whereas antagonists of this receptor and its associated second messenger, cAMP, were potent inhibitors of this effect. Agonists of beta-adrenergic receptors are the active ingredients of many decongestants and bronchodilators, and such medications are, therefore, likely to stimulate this pathway in vivo. Patients suffering from chronic upper and lower respiratory tract diseases and treated with such medications over many years may, therefore, be at a higher risk than the average population to develop PAC, particularly when simultaneously exposed to carcinogenic environmental factors such as smoking. Because the incidence of chronic respiratory tract diseases has risen in industrialized countries during the same time frame as PAC, a potential etiological link between the therapy of such nonneoplastic diseases with beta-adrenergic agonists and the risk for PAC should be investigated.