title: Autocrine transformation by fibroblast growth factor 9 (FGF-9) and its possible participation in human oncogenesis.
abstract: Transfection of human fibroblast growth factor 9 (FGF-9) cDNA into mouse BALB/c 3T3 clone A31 cells led to morphological transformation of the cells and foci formation 4 weeks later. Isolated transformants had a higher saturation density than parental A31 cells, could grow in soft agar, and secreted FGF-9 into the culture supernatant. The introduction of FGF-9 N33 cDNA, which encodes a truncated protein that has 33 N-terminal amino acids deleted and has the same mitogenic potency as FGF-9, failed to lead to foci formation. Although FGF-9 is a secretory protein, it does not have a typical secretory signal sequence, and the secreted protein retains the full sequence coded in the cDNA except for the initiating methionine. The produced FGF-9 N33 was not secreted and remained within the cell. It is possible that FGF-9 has an uncleavable signal sequence within the first 33 N-terminal amino acids. All of the phenotypes acquired by transformation could be arrested by treatment with a neutralizing anti-human FGF-9 monoclonal antibody (MAb) 150-59. Additionally, transformants formed tumors in nude mice. Injection of MAb 150-59 suppressed tumor formation in nude mice and caused existing tumors to regress. Our results suggest that the cellular transformation mediated by FG F-9 is produced by autocrine stimulation. We have detected FGF-9 production in the human tumor cell lines glioma NMC-G1, from which FGF-9 was originally purified, and stomach carcinoma AZ-521. The growth of NMC-G1 was not affected by MAb 150-59, but that of AZ-521 was arrested by MAb 150-59 in the presence of heparin. Moreover, the growth of the AZ-521 cell tumor in nude mice could be partially arrested by antibody treatment. The possibility of a participation of FGF-9 in the formation of human tumors is suggested.
authors.affiliation: Molecular Pharmacology Laboratory, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Matsumoto-Yoshitomi
authors.forename: J
authors.initials: J
authors.lastname: Habashita
authors.forename: C
authors.initials: C
authors.lastname: Nomura
authors.forename: K
authors.initials: K
authors.lastname: Kuroshima
authors.forename: T
authors.initials: T
authors.lastname: Kurokawa
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D019556:COS Cells; D002455:Cell Division; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells; D018076:DNA, Complementary; D051525:Fibroblast Growth Factor 9; D005346:Fibroblast Growth Factors; D005910:Glioma / Q000473:pathology*; D006133:Growth Substances / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009857:Oncogenes; D011994:Recombinant Proteins / Q000096:biosynthesis; D013274:Stomach Neoplasms / Q000473:pathology*; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D018076:DNA, Complementary; C496459:FGF9 protein, human; C496460:Fgf9 protein, mouse; D051525:Fibroblast Growth Factor 9; D006133:Growth Substances; D011994:Recombinant Proteins; D005346:Fibroblast Growth Factors