Abstract 3916: Oncogenic potential of FGF9 in lung cancer
Authors: Kota Ishioka, Kenzo Sejima, Hiroyuki Yasuda, Junko Hamamoto, Ahmed Hegab, Tetsuo Tani, Aoi Kuroda, Daisuke Arai, Keiko Ohgino, Takashi Sato, Terai Hideki, Ichiro Kawada, Katsuhiko Naoki, Yuichiro Hayashi, Tomoko Betsuyaku
Journal: Cancer Research (2015)

Abstract Rationale: Recently, the importance of fibroblast growth factor (FGF) and its receptor (FGFR) signals has been emphasized in various types of cancer, including lung cancer. FGFs and FGFRs are reported to be related to drug resistance, cell proliferation, differentiation and motility. Among various FGFs, FGF9 is a developmentally important FGF associated with epithelial airway branching, and its expression is repressed in normal adult lungs. We have previously shown that FGF9 is highly expressed in NSCLC cells, and FGF9 expression was associated with poor prognosis of NSCLC patients. Furthermore, we reported that induction of FGF9 in adult lung results in the rapid formation of adenocarcinoma in specific gene engineered mouse model. However, the exact roles of FGF9 in lung epithelial cells remain elusive. Objectives: The objective of this study is to clarify the roles of FGF9 in lung epithelial cells. Methods: For in vitro experiments, a stable cell line with constitutive expression of FGF9 in MLE12 (a mouse lung alveolar type II cell line transformed by SV40 large T antigen) was established by retroviral infection. The effect of FGF9 on proliferation, colony formation capacity and downstream signaling was evaluated by MTS assay, softagar colony formation assay and Western blotting, respectively. For in vivo experiments, the cells were transplanted into immunodeficient mice subcutaneously, and the size of tumor was measured. To evaluate the efficacy of FGFR inhibitors for FGF9-driven lung cancers, AZD4547, selective FGFR inhibitor, was orally administered. For pathological characterization of the tumors, immunohistochemical staining was performed. Fifteen surgically-resected SCLC samples were obtained and the expression of FGF9 was evaluated by immunohistochemistry. Results: FGF9 has oncogenic ability in vitro and its effect may be exerted by the activation of MAPK pathway through FGFR1 and FGFR3 in MLE12 cells. Unexpectedly, pathological analysis revealed FGF9-driven tumors exhibited SCLC histology. Selective FGFR inhibitor, AZD4547 suppressed tumor growth of FGF9-driven MLE12 tumors. FGF9 is highly expressed in human SCLC samples (67%). Conclusions: These results suggest that FGF9 has roles of tumor initiation and progression in lung cancer, especially in SCLC. SCLC which highly expresses FGF9 may be a target of FGFR inhibitors. Citation Format: Kota Ishioka, Kenzo Sejima, Hiroyuki Yasuda, Junko Hamamoto, Ahmed Hegab, Tetsuo Tani, Aoi Kuroda, Daisuke Arai, Keiko Ohgino, Takashi Sato, Terai Hideki, Ichiro Kawada, Katsuhiko Naoki, Yuichiro Hayashi, Tomoko Betsuyaku. Oncogenic potential of FGF9 in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3916. doi:10.1158/1538-7445.AM2015-3916