title: Regulation of metastatic ability and drug resistance in pulmonary adenocarcinoma by matrix rigidity via activating c-Met and EGFR.
abstract: Lung fibrosis is a poor prognostic factor for pulmonary adenocarcinoma, and the effect of a rigid microenvironment on cancer behavior is unclear. We cultured A549 cells on matrices of 0.2, 2, and 25 kPa to mimic the rigidities of normal lung parenchyma, progressive fibrotic change, and lung fibrosis, respectively. Lung tissue from patients with pulmonary adenocarcinoma was used to confirm the in vitro findings. Increased matrix rigidity promoted cell proliferation and upregulated the epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-Met), and Snail expression in A549 cells. A549 cells became more resistant to the EGFR inhibitor (Erlotinib) and c-Met inhibitor (PHA-665752) when matrix rigidity increased; however, a high concentration of PHA-665752 reversed the rigidity-induced morphological pleomorphism. In human lung tissue, expression of type I collagen was more consistent with clinical fibrosis than the expression of alpha-smooth muscle antibody was. c-Met- and Snail-expressing tumor cells, rather than EGFR-experssing cells, were localized with lung parenchyma rich in type I collagen. Our findings suggest that c-Met causes the rigidity-induced biophysical reaction in pulmonary adenocarcinoma. Treatment targeting both EGFR and c-Met should be considered for patients with lung fibrosis and who are abundant type I collagen expression in the tumor mass.
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; Department of Thoracic Medicine, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Center for Stem Cell Research and Clinical Trial, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ting-Lieh
authors.initials: TL
authors.lastname: Hsieh
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
authors.forename: Tung-Yu
authors.initials: TY
authors.lastname: Tiong
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chi-Hao
authors.initials: CH
authors.lastname: Hsiao
authors.affiliation: Center for Stem Cell Research and Clinical Trial, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Andrea Tung-Qian
authors.initials: AT
authors.lastname: Ji
authors.affiliation: Center for Stem Cell Research and Clinical Trial, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Tse
authors.initials: WT
authors.lastname: Hsu
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Orthopaedic Surgery, Taipei City Hospital, Taipei, Taiwan. Electronic address: oscarlee9203@gmail.com.
authors.forename: Oscar K
authors.initials: OK
authors.lastname: Lee
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; Center for Stem Cell Research and Clinical Trial, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Ophthalmology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: wh9801@yahoo.com.tw.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Ho
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D001696:Biomechanical Phenomena; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000032:analysis / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D005355:Fibrosis; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D016023:Integrins / Q000032:analysis / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D040542:Mechanotransduction, Cellular; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D024042:Collagen Type I; D007211:Indoles; D016023:Integrins; D047428:Protein Kinase Inhibitors; D013450:Sulfones; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met
keywords: Adenocarcinoma; Drug resistance; Epidermal growth factor receptor; Lung fibrosis; Matrix rigidity; c-Met