title: Rapid induction of lung adenocarcinoma by fibroblast growth factor 9 signaling through FGF receptor 3.
abstract: Fibroblast growth factors (FGF) are expressed in many non-small cell lung carcinoma (NSCLC) primary tumors and derived cell lines, and mutations in FGF receptor 3 (FGFR3) have been identified in human lung adenocarcinoma. FGF9 has been implicated in the pathogenesis of NSCLC by synergizing with EGFR pathways or by providing an escape pathway mediating resistance to EGFR inhibition. To model pathogenic mechanisms mediated by FGF signals, we have established a mouse model in which FGF9 expression can be induced in adult lung epithelium. Here, we show that induced expression of FGF9 in adult lung leads to the rapid proliferation of distal airway epithelial cells that express the stem cell marker, Sca-1, and the proximal and distal epithelial markers, Sftpc and CC10, the rapid formation of Sftpc-positive adenocarcinomas, and eventual metastasis in some mice. Furthermore, we have identified FGFR3 as the obligate receptor mediating the FGF9 oncogenic signal. These results identify an FGF9-FGFR3 signal as a primary oncogenic pathway for lung adenocarcinoma and suggest that this pathway could be exploited for customized therapeutic applications for both primary tumors and those that have acquired resistance to inhibition of other signaling pathways.
authors.affiliation: Authors' Affiliations: Departments of Developmental Biology, Radiology, and Medicine, Washington University School of Medicine, Saint Louis, Missouri; Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan; and Department of Thoracic Surgery, Beijing Chaoyang Hospital, China Capital Medical University, Beijing, China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Yin
authors.forename: Tomoko
authors.initials: T
authors.lastname: Betsuyaku
authors.forename: Joel R
authors.initials: JR
authors.lastname: Garbow
authors.forename: Jinbai
authors.initials: J
authors.lastname: Miao
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Govindan
authors.forename: David M
authors.initials: DM
authors.lastname: Ornitz
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D051525:Fibroblast Growth Factor 9 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D037721:Pulmonary Surfactant-Associated Protein C; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014598:Uteroglobin / Q000235:genetics / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; C496460:Fgf9 protein, mouse; D051525:Fibroblast Growth Factor 9; D036341:Intercellular Signaling Peptides and Proteins; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D010455:Peptides; D037721:Pulmonary Surfactant-Associated Protein C; D012333:RNA, Messenger; C556390:Scgb1a1 protein, mouse; C489680:Sftpc protein, mouse; D014598:Uteroglobin; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3