Expression of fibroblast growth factor-1 (FGF-1), FGF-2 and FGF receptor-1 in a human salivary-gland adenocarcinoma cell line: Evidence of autocrine growth

Myoken, Yoshinari; Okamoto, Tomoyoshi; Kan, Mikio; McKeehan, Wallace L.; Sato, Jun; Takada, Kazuaki

doi:10.1002/(sici)1097-0215(19960301)65:5<650::aid-ijc15>3.0.co;2-b

Cited by 28 publications

(20 citation statements)

References 32 publications

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“…The antisense ODN to bFGF1 was 5'-GCTGAATGTGCTGGTC-3' (referred to as AS-F1) and the corresponding sense ODN was 5'-GACCAGCACATT-CAGC-3' (referred to as S-F1). It has been demonstrated that the addition of AS-F1 to adenocarcinoma HSY cells, inhibits endogenous FGF1-dependent cell proliferation (Myoken et al, 1996). Two phosphodiester sense and antisense ODNs directed against Bcl-x were designed based on the published sequence of the human Bcl-x (hBcl-x) gene (Boise et al, 1993).…”

Section: Oligonucleotides and Oligonucleotide Treatment Of Cellsmentioning

confidence: 99%

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Bryckaert

Guillonneau²,

Hecquet³

et al. 1999

Oncogene

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Retinal pigmented epithelial (RPE) cells are of central importance in the maintenance of neural retinal function. Changes in the RPE cells associated with repair activities have been described as metaplasia, while RPE cell apoptosis is responsible for the development of a variety of retinal degenerations. We investigated the regulation of the anti-apoptotic properties of the ®broblast growth factors (FGF) 2 in serum-free cultures of RPE cells. In the absence of serum, con¯uent stationary RPE cells died by apoptosis via a caspase 3-dependent pathway. The addition of FGF2 greatly reduced apoptosis over a 7-day culture period. We demonstrated the involvement of an autocrine loop involving endogenous FGF1 in the mechanisms that govern FGF2-induced resistance to apoptosis by showing: (1) higher levels of apoptosis in cells treated with antisense FGF1 oligonucleotide or after neutralization of excreted FGF1; (2) the long-term activation of FGFR1 and of ERK2, (3) the inhibition of FGFR1 and ERK2 activation and an increase in apoptosis if excreted FGF1 was neutralized. FGF2 also increased the de novo synthesis and the production of Bcl-xl before the onset of apoptosis. Both inhibition of ERK2 activation, which decreased Bcl-xl synthesis, and downregulation of Bcl-x by antisense oligonucleotide treatment inhibited the survival-promoting activity of FGF2. Thus, FGF2-induced cell survival is a progressive adaptive phenomenon involving ERK2 activation by excreted FGF1 and ERK2-dependent Bcl-x production.

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Section: Oligonucleotides and Oligonucleotide Treatment Of Cellsmentioning

confidence: 99%

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Bryckaert

Guillonneau²,

Hecquet³

et al. 1999

Oncogene

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“…Translocations involving the kinase domain of FGFR1 have been demonstrated in haematopoietic malignancies (Xiao et al, 1998), and the activation of FGFR3 by point mutations is a frequent event in bladder cancer (50% of cases) Billerey et al, 2001). The activation of FGFR1 by overexpression has been suggested in a wide variety of cancers, including astrocytoma Yamaguchi et al, 1994), salivary adenocarcinoma (Myoken et al, 1996) and lung carcinoma (Volm et al, 1997;Berger et al, 1999). Splice forms with transforming activity, not expressed in normal tissues, have been reported in gastric cancer for FGFR2 and in pituitary tumours for FGFR4 (Itoh et al, 1994;Ishii et al, 1995;Lorenzi et al, 1997;Ezzat et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of human bladder tumour cell growth by fibroblast growth factor receptor 2b is independent of its kinase activity. Involvement of the carboxy-terminal region of the receptor

et al. 2004

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The b isoform of fibroblast growth factor receptor 2, FGFR2b/FGFR2-IIIb/Ksam-IIC1/KGFR, a tyrosine kinase receptor, is expressed in a wide variety of epithelia and is downregulated in several human carcinomas including prostate, salivary and urothelial cell carcinomas. FGFR2b has been shown to inhibit growth in tumour cell lines derived from these carcinomas. Here, we investigated the molecular mechanisms underlying the inhibition of human urothelial carcinoma cell growth following FGFR2b expression. Using a nylon DNA array, we analysed the gene expression profile of the T24 bladder tumour cell line, transfected or not with a construct encoding FGFR2b. The expression of FGFR2b in T24 cells decreased insulin-like growth factor (IGF)-II mRNA levels. This decrease was correlated with a decrease in IGF-II secretion and may have been responsible for the observed inhibition of cell growth because the addition of exogenous IGF-II restored growth rates to normal levels. Using SU5402, an inhibitor of FGFR tyrosine kinase activity, and a kinase dead mutant of the receptor, FGFR2b Y659F/Y660F, we also demonstrated that the growth inhibition and decrease in IGF-II secretion induced by FGFR2b did not require tyrosine kinase activity. Finally, we demonstrated the involvement of the distal carboxy-terminal domain of the receptor in decreasing IGF-II expression and inhibiting T24 cell growth, as Ksam-IIC3, a variant of FGFR2b carrying a short carboxy-terminus, neither downregulated IGF-II nor inhibited cell proliferation. Our data suggest that FGFR2b inhibits the growth of bladder carcinoma cells by reducing IGF-II levels via its carboxy-terminal domain, independent of its tyrosine kinase activity.

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“…Malignant salivary tumors exhibit enhanced expression of both FGF-1 and FGF-2 compared with normal salivary gland (8). FGF-1 and FGF-2 can act in an autocrine manner to stimulate the proliferation of salivary adenocarcinoma cells (8,9). Normal salivary gland epithelial cells and benign salivary gland tumors exclusively express the KGFR gene.…”

mentioning

confidence: 99%

Growth inhibition by keratinocyte growth factor receptor of human salivary adenocarcinoma cells through induction of differentiation and apoptosis

Zhang

Wang

Toratani

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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We have reported that normal human salivary gland-derived epithelial cells exclusively express keratinocyte growth factor receptor (KGFR). In the process of malignant transformation of human salivary gland tumors, KGFR gene expression disappeared concomitantly with the de novo expression of the fibroblast growth factor receptor 1 (FGFR1) and FGFR4 genes. In the present study, we introduced wild-type KGFR cDNA or chimeric KGFR͞ FGFR1 cDNA, which encoded the extracellular domain of KGFR and the intracellular domain of FGFR1, into the HSY human salivary adenocarcinoma cell line. The KGFR tyrosine kinase suppressed the activity of FGF receptor substrate 2 (FRS2) and inhibited the growth of HSY by inducing differentiation and apoptosis in vitro and in vivo. Our results provided significant insight into the mechanism of KGFR tumor suppression and suggest that KGFR gene therapy might be a viable method of inhibiting human salivary adenocarcinoma growth. K eratinocyte growth factor (KGF͞FGF7) is a member of the fibroblast growth factor (FGF) family (1). Its activity is largely restricted to epithelial cells, which express the KGF receptor (KGFR), a transmembrane tyrosine kinase encoded by the IIIb splice variant of FGFR2 (FGFR2-IIIb) (2, 3). KGFR binds KGF and FGF-1 with high affinity. In contrast, FGFR2-IIIc, another splice variant of FGFR2, binds FGF-1 and FGF-2, but not KGF (3, 4). Analysis of KGF and KGFR expression during embryonic development, including that of mammary glands, has provided evidence that KGF is an important mesenchymal mediator of epithelial growth and differentiation. In normal human skin, KGFR immunostaining localizes to the suprabasal layers (5, 6). The lack of KGFR in basal cell progenitors in skin suggests that KGFR might regulate keratinocyte differentiation (7).Malignant salivary tumors are highly aggressive neoplasms that readily invade adjacent tissues and metastasize to distant organs at early stages of the disease. Malignant salivary tumors exhibit enhanced expression of both FGF-1 and FGF-2 compared with normal salivary gland (8). FGF-1 and FGF-2 can act in an autocrine manner to stimulate the proliferation of salivary adenocarcinoma cells (8,9). Normal salivary gland epithelial cells and benign salivary gland tumors exclusively express the KGFR gene. During the malignant transformation of salivary gland epithelial cells, the expression of the KGFR gene is abolished, whereas the FGFR1-IIIc and FGFR4 genes are activated (10). The exclusive expression of the KGFR gene in both normal and premalignant salivary epithelial cells correlates well with the slow-growing and differentiated phenotype of premalignant tumors. In contrast, the loss of the KGFR gene and the expression of both the FGFR1 gene and its specific ligand FGF-2 in malignant tumor cells are associated with the emergence of the malignant phenotype. Thus, the loss of normal KGFR gene function may promote tumorigenicity, whereas KGFR may function to suppress human salivary adenocarcinomas.The Ras-MAP kinase signaling pathway plays...

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Expression of fibroblast growth factor-1 (FGF-1), FGF-2 and FGF receptor-1 in a human salivary-gland adenocarcinoma cell line: Evidence of autocrine growth

Cited by 28 publications

References 32 publications

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Inhibition of human bladder tumour cell growth by fibroblast growth factor receptor 2b is independent of its kinase activity. Involvement of the carboxy-terminal region of the receptor

Growth inhibition by keratinocyte growth factor receptor of human salivary adenocarcinoma cells through induction of differentiation and apoptosis

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