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 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.

The anti-apoptotic and prognostic value of fibroblast growth factor 9 in gastric cancer

“…FGF signal play an important role in cellular function, including growth, invasion, and epithelial-to-mesenchymal transition(EMT) [14, 15]. Mutations or gene amplification of FGFR1, FGFR2, and FGFR3 have been reported in different kinds of solid cancers [16–19].…”

“…For example, FGF9 may inhibit osteogenesis in mesenchymal stem cells in vitro [21] and participate in the development of GC by its autocrine stimulation pattern [15]. FGF2, FGF9 and FGF10 can stimulate proliferation, treatment sensitivity, and apoptosis of lung cancer cells [7].…”

FGF9 from cancer-associated fibroblasts is a possible mediator of invasion and anti-apoptosis of gastric cancer cells

“…Since FGF9 serves as mitogen for prostate or ovarian cancer [ 17 , 24 ], we first investigated the proliferation of gastric cancer cells in the presence of FGF9 in vitro . Subsequently, FGF9 failed to promote the proliferation of both AGS and MKN28 gastric cancer cell lines; however, we cannot exclude the possibility that FGF9 may serve as mitogen for other types of gastric cancer cells because FGF9 promotes the proliferation of other gastric cancer cells such as AZ521 or SGC-7901 [ 25 , 26 ]. On the other hand, we clarified in the present study that FGF9 has an anti-apoptotic effect on gastric cancer cells, in accord with the findings of several previous studies [ 26 , 27 ].…”

Association between Fibroblast Growth Factor Receptor 4 Gly388Arg Polymorphism and Ischaemic Stroke

“…29 For example, autocrine growth stimulation through the coexpression of FGF and FGFR in the same cell results in the transformation of BALB/c 3T3 cells. 30 A high level of FGFR4 expression has been found in pancreatic, breast and renal cell carcinomas. 31–34 The FGF–FGFR system is also important in the pathology of human atherosclerosis, 8 and the Gly388Arg polymorphism has been associated with coronary artery disease.…”