title: Fibroblast growth factor 2 induces differentiation and apoptosis of Askin tumour cells.
abstract: Peripheral primitive neuroectodermal tumour (PNET)/Ewing's sarcoma (ES) and neuroblastoma (NB) are related tumours of neural crest origin with primitive neural characteristics. Fibroblast growth factor 2 (FGF2) is a critical signalling molecule for primitive neural crest cells. The treatment of NB cells with FGF2 variably affects biological characteristics such as growth and differentiation, while in PNET/ES, FGF2 predominantly induces apoptosis. The JK-GMS Askin tumour cell line can be induced to differentiate upon treatment with nerve growth factor (NGF), indicating the integrity of the cellular machinery necessary for differentiation. The present study assesses whether FGF2 can induce differentiation in JK-GMS cells. JK-GMS cells expressed high-affinity FGF receptors (FGFRs), and treatment with FGF2 induced phosphorylation of FGFR1 together with activation of extracellular signal-regulated kinases (ERK1/ERK2) and c-Jun N-terminal kinase (JNK). Subsequent biological effects were growth inhibition, neuronal differentiation, and apoptosis, and these changes were associated with increased expression of neurofilaments, reduction of c-myc and bcl-2 expression, and activation of caspase 3. Treatment of the cells with a specific inhibitor of the MAPK/extracellular signal-regulated kinase (MEK)-1, PD98059, predominantly inhibited the effects of FGF2 on growth, differentiation, and apoptosis, while an inhibitor of JNK reduced apoptosis, indicating that the ERK1/2 and JNK pathways are critical components of FGF2-mediated effects in JK-GMS cells. Additional comparative analyses of FGF2-mediated effects in two ES cell lines (CADO-ES, RD-ES) and a PNET cell line (SK-N-MC) showed pronounced differentiation in SK-N-MC, but not in CADO-ES or RD-ES cells. This study demonstrates that FGF2 can induce neuronal differentiation of PNET including Askin tumour. These findings clearly indicate that the FGF2-mediated signalling pathway plays a critical role in controlling the major properties of PNET cells and may provide a potential therapeutic target for PNET.
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Min-Suk
authors.initials: MS
authors.lastname: Kim
authors.forename: Chong Jai
authors.initials: CJ
authors.lastname: Kim
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Jung
authors.forename: Mi Ran
authors.initials: MR
authors.lastname: Seo
authors.forename: Yong-Sung
authors.initials: YS
authors.lastname: Juhnn
authors.forename: Hee Young
authors.initials: HY
authors.lastname: Shin
authors.forename: Hyo Seop
authors.initials: HS
authors.lastname: Ahn
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Thiele
authors.forename: Je G
authors.initials: JG
authors.lastname: Chi
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D008854:Microscopy, Electron / Q000379:methods; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018241:Neuroectodermal Tumors, Primitive, Peripheral / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D011233:Precipitin Tests; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D017468:Receptors, Fibroblast Growth Factor / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012512:Sarcoma, Ewing / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases