Fibroblast growth factor receptor 2 limits and receptor 1 accelerates tumorigenicity of prostate epithelial cells.
Progressive loss of the differentiated phenotype and communication with stroma accompanies the transition of nonmalignant rat prostate epithelial cells to anaplastic, malignant tumors. Here we show that cell surface expression of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase is reduced in malignant tumor cell populations (type II) and undetectable at the mRNA level in 30% of cells. This is in addition to the irreversible loss by splice switching of the FGFR2 ectodomain that abrogates response to FGF-7 and homologues from the stroma. One hundred % of type II malignant cells express FGFR1, which is normally expressed in the stroma. Expression of the FGFR1 kinase in premalignant type I tumor epithelial cells by transfection accelerated progression to the malignant phenotype. In contrast to the FGFR2 kinase fused to the ectodomain of FGFR1, the FGFR1 kinase failed initially to support a mitogenic response to FGF-2 in type I tumor cells. However, the FGFR1-transfected cells acquired a mitogenic response after extensive proliferation of the cell population. Resident FGFR2 and ectopic FGFR1 appeared to be partitioned in the type I cells, because neither full-length nor truncated isoforms of FGFR1 affected the mitogenic response of the other. Restoration of the FGFR2IIIb kinase to malignant cells expressing FGFR1 depressed tumor growth rates, restored responsiveness to stromal cells, and restored epithelial cell differentiation. These observations reveal that homologous FGFR1 and FGFR2 kinases play very different roles in cell growth and differentiation and in development and support of the malignant phenotype.
Feng
S
S
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.
Wang
F
F
Matsubara
A
A
Kan
M
M
McKeehan
W L
WL
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D007633:Keratins / Q000032:analysis / Q000096:biosynthesis; D008297:Male; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000473:pathology / Q000503:physiopathology*; D011467:Prostate / Q000473:pathology* / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D012326:RNA Splicing; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000502:physiology*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; D016222:Fibroblast Growth Factor 2; D007633:Keratins; C496350:Fgfr1 protein, rat; C496356:Fgfr2 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2