Autocrine transformation by fibroblast growth factor 9 (FGF‐9) and its possible participation in human oncogenesis

• Published in: International journal of cancer 1997-05, Vol.71 (3), p.442-450
• Main Authors: Matsumoto‐Yoshitomi, Sumie, Habashita, Junko, Nomura, Chisako, Kuroshima, Ken‐ichi, Kurokawa, Tsutomu
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Antibodies, Monoclonal - pharmacology; Biological and medical sciences; Cell Division; Cell Line; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic; Clone Cells; COS Cells; DNA, Complementary; Fibroblast Growth Factor 9; Fibroblast Growth Factors; Fundamental and applied biological sciences. Psychology; Glioma - pathology; Growth Substances - biosynthesis; Growth Substances - immunology; Growth Substances - physiology; Humans; Mice; Mice, Nude; Molecular and cellular biology; Oncogenes; Recombinant Proteins - biosynthesis; Stomach Neoplasms - pathology; Transfection; Transplantation, Heterologous; Tumor Cells, Cultured
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/(SICI)1097-0215(19970502)71:3<442::AID-IJC23>3.0.CO;2-G

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 FGF‐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. Int. J. Cancer 71:442‐450, 1997. © 1997 Wiley‐Liss Inc.