Inhibition of growth of malignant rat prostate tumor cells by restoration of fibroblast growth factor receptor 2.
A loss of expression of fibroblast growth factor (FGF) receptor 2 IIIb (FGFR2IIIb), which responds to stroma-derived FGF, accompanies progression of premalignant androgen-responsive rat prostate tumor epithelial cells to the malignant phenotype. Concurrently, the level of FGFR2 gene expression is reduced and lost altogether in over 30% of cells, whereas all malignant cells abnormally express FGFR1, which is normally confined to stromal cells (S. Feng et al., Cancer Res., 57:5369-5378, 1997). To determine the relative roles of the FGFR2 and FGFR1 kinases in growth of malignant cells, we transfected malignant prostate epithelial cells with the wild-type FGFR2IIIb kinase and an artificial chimeric construct (FGFR2IIIb/R1) composed of the FGFR2IIIb ectodomain and the FGFR1 kinase domain. Population growth kinetics, in both the absence and presence of FGF-7, which binds only the FGFR2IIIb ectodomain, were then examined in the transfected cell populations. In contrast to the untransfected malignant tumor cells and those expressing the FGFR2IIIb/R1 chimera, FGF-7 caused a dose-dependent net inhibition of the population growth rates of cells expressing the full-length FGFR2IIIb kinase. The results suggest that although the FGFR2 kinase can mediate positive mitogenic effects, it mediates a net restriction on the growth of prostate tumor epithelial cells relative to FGFR1. Highly malignant prostate tumor cells, which have lost the FGFR2 tyrosine kinase, retain the cellular response mechanisms to it. Restoration of the FGFR2 kinase to malignant tumors that are refractory to treatment may present a new avenue for gene therapy.
Matsubara
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A
Center for Cancer Biology and Nutrition, Albert B. Alkek Institute of Biosciences and Technology, and Department of Biochemistry and Biophysics, Texas A&M University, Houston 77030-3303, USA.
Kan
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Feng
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McKeehan
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WL
D000818:Animals; D002455:Cell Division / Q000502:physiology; D008297:Male; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000648:ultrastructure*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014162:Transfection
D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; C496356:Fgfr2 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2