S. Matsumotoyoshitomi et al., AUTOCRINE TRANSFORMATION BY FIBROBLAST GROWTH-FACTOR-9 (FGF-9) AND ITS POSSIBLE PARTICIPATION IN HUMAN ONCOGENESIS, International journal of cancer, 71(3), 1997, pp. 442-450
Transfection of human fibroblast growth factor 9 (FGF-9) cDNA into mou
se BALB/c 3T3 clone A31 cells led to morphological transformation of t
he cells and foci formation 4 weeks later. Isolated transformants had
a higher saturation density than parental A31 cells, could grow in sof
t agar, and secreted FGF-9 into the culture supernatant. The introduct
ion 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 FG
F-9, failed to lead to foci formation. Although FGF-9 is a secretory p
rotein, it does not have a typical secretory signal sequence, and the
secreted protein retains the full sequence coded in the cDNA except fo
r the initiating methionine. The produced FGF-9 N33 was not secreted a
nd remained within the cell. It is possible that FGF-9 has an uncleava
ble signal sequence within the first 33 N-terminal amino acids. All of
the phenotypes acquired by transformation could be arrested by treatm
ent 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 exis
ting tumors to regress. Our results suggest that the cellular transfor
mation 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-5
21. The growth of NMC-G1 was not affected by MAb 150-59, but that of A
Z-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 a
rrested by antibody treatment. The possibility of a participation of F
GF-9 in the formation of human tumors is suggested. (C) 1997 Wiley-Lis
s, Inc.