Tobacco Smoke-induced Lung Cell Proliferation Mediated by Tumor Necrosis Factor α-converting Enzyme and Amphiregulin

Abstract

Cells dividing at the time of carcinogen exposure are at particular risk for neoplasia. Tobacco smoke contains numerous carcinogens, and we find that smoke, in the absence of exogenous growth factors, is capable of stimulating cell proliferation. The smoke-triggered mechanism includes the generation of oxygen radicals, which in turn stimulate tumor necrosis factor ␣-converting enzyme (a disintegrin and metalloproteinase (ADAM) 17) to cleave transmembrane amphiregulin, a ligand for the epidermal growth factor receptor (EGFR). The binding of amphiregulin to EGFR then stimulates proliferation of lung epithelial cells. These results shed light on the pathogenesis of lung cancer, suggest novel drug targets for the reduction of cancer risk in smokers, and provide insight into how EGFR integrates responses to diverse noxious stimuli.

Expression of ADAMs (“a disintegrin and metalloprotease”) in the human lung

“…The prominent apical distribution of ADAM17 in the bronchial epithelium may thus enable easy activation and hence a low threshold for rapid and early release of TNF-alpha in the airway lumen in the defense to diseaseinitiating inhaled substances. In addition, cigarette smoke exposure of human airway epithelial cells has been shown to lead to ADAM17-mediated release of amphiregulin, which is a ligand for the epidermal growth factor receptor (EGFR) [19]. This can be of clinical relevance since stimulation of EGFR on epithelial cells contributes to mucus production and epithelial cell proliferation.…”

Prenatal, perinatal, and heritable influences on cord blood immune responses

“…20 Maternal smoking can harm the human placental development by changing the balance between cytotrophoblast proliferation and differentiation, 29 and several studies report that cigarette smoke extracts in vitro can stimulate cell proliferation 30 not only of lymphocytes 31,32 but also of lung epithelial cells. 33 The cigarette component tobacco-related glycoprotein has been previously shown to induce peripheral T-cell proliferation. 31,34 Whether preferential placental transfer of tobacco-related glycoprotein over the immunosuppressants nicotine and polycyclic aromatic hydrocarbons could explain increased lymphoproliferation in CBMCs from smoking mothers remains to be determined.…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…Smoking is by far the most important risk factor for lung cancer and about 87% of lung cancers are thought to result directly from smoking. Tobacco smoke contains numerous carcinogens and primary bronchial epithelial cells as well as bronchial cell lines exposed to smoke components show an increased proliferation rate associated with EGFR phosphorylation [108]. This could be at least in part mediated by ADAM-17 which can activate several EGFR ligands [108].…”