Autocrine transformation by chimeric signal peptide-basic fibroblast growth factor: reversal by suramin.
NIH 3T3 cells transfected with basic fibroblast growth factor (bFGF) fused to an immunoglobulin signal peptide sequence are transformed in vitro and tumorigenic in vivo. The transformed phenotype of chimeric signal peptide-bFGF (spbFGF) cells is characterized by an enhanced proliferation rate compared to parental NIH 3T3 cells, density- and anchorage-independent growth, a transformed morphology, and lack of cell adhesion. The rate of spbFGF cell proliferation is not diminished by anti-bFGF neutralizing antibodies. 125I-labeled bFGF receptor cross-linking and binding studies suggest that surface FGF receptors in spbFGF cells are unavailable and down-regulated. The FGF receptors are also down-regulated in K-fgf-transformed cells but not in parental 3T3, native bFGF-transfected, and ras-transformed NIH 3T3 cells. The addition of suramin to spbFGF and K-fgf cells rapidly promotes the up-regulation of FGF receptors. Suramin also induces lowering of the proliferation rate to that of parental cells, anchorage-dependent growth, assembly of cytoskeletal filaments, cellular adhesion, and spreading. These results suggest that spbFGF cells undergo autocrine transformation, possibly by an internal autocrine loop, in which there is constitutive activation of the FGF receptor. Suramin inhibits autocrine transformation, leading to a normal untransformed phenotype.
Yayon
A
A
Department of Surgery, Children's Hospital, Boston, MA 02115.
Klagsbrun
M
M
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002478:Cells, Cultured; D002678:Chimera; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D021382:Protein Sorting Signals / Q000235:genetics / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D013498:Suramin / Q000494:pharmacology*; D014162:Transfection
D021382:Protein Sorting Signals; D011956:Receptors, Cell Surface; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D013498:Suramin; D005346:Fibroblast Growth Factors