title: Prevention of bronchial hyperplasia by EGFR pathway inhibitors in an organotypic culture model.
abstract: Lung cancer is the leading cause of cancer-related mortality worldwide. Early detection or prevention strategies are urgently needed to increase survival. Hyperplasia is the first morphologic change that occurs in the bronchial epithelium during lung cancer development, followed by squamous metaplasia, dysplasia, carcinoma in situ, and invasive tumor. This study was designed to determine the molecular mechanisms that control bronchial epithelium hyperplasia. Using primary normal human tracheobronchial epithelial (NHTBE) cells cultured by using the 3-dimensional (3D) organotypic method, we found that the epidermal growth factor receptor (EGFR) ligands, EGF, TGF-α, and amphiregulin induced hyperplasia, as determined by cell proliferation and multilayered epithelium formation. We also found that EGF induced increased cyclin D1 expression, which plays a critical role in bronchial hyperplasia; this overexpression was mediated by activating the mitogen-activated protein kinase pathway but not the phosphoinositide 3-kinase/Akt signaling pathway. Erlotinib, an EGFR tyrosine kinase inhibitor, and U0126, a MAP/ERK kinase (MEK) inhibitor, completely inhibited EGF-induced hyperplasia. Furthermore, a promoter analysis revealed that the activator protein-1 transcription factor regulates EGF-induced cyclin D1 overexpression. Activator protein-1 depletion by using siRNA targeting its c-Jun component completely abrogated EGF-induced cyclin D1 expression. In conclusion, we showed that bronchial hyperplasia can be modeled in vitro by using primary NHTBE cells maintained in a 3D organotypic culture. EGFR and MEK inhibitors completely blocked EGF-induced bronchial hyperplasia, suggesting that they have a chemopreventive role.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, Unit 432, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
authors.forename: Jangsoon
authors.initials: J
authors.lastname: Lee
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Ryu
authors.forename: Shin Myung
authors.initials: SM
authors.lastname: Kang
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Chung
authors.forename: Kathryn Ann
authors.initials: KA
authors.lastname: Gold
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kim
authors.forename: Walter N
authors.initials: WN
authors.lastname: Hittelman
authors.forename: Waun
authors.initials: W
authors.lastname: Ki Hong
authors.forename: Ja Seok
authors.initials: JS
authors.lastname: Koo
mesh_terms: D001980:Bronchi / Q000187:drug effects* / Q000473:pathology*; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D006965:Hyperplasia / Q000473:pathology*; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008954:Models, Biological; D009570:Nitriles / Q000494:pharmacology; D009924:Organ Culture Techniques / Q000379:methods; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D011799:Quinazolines; D034741:RNA, Small Interfering; C113580:U 0126; D019938:Cyclin D1; D000069347:Erlotinib Hydrochloride; D008156:Luciferases; D066246:ErbB Receptors; D020930:MAP Kinase Kinase Kinases