Targets of fibroblast growth factor 1 (FGF-1) and FGF-2 signaling involved in the invasive and tumorigenic behavior of carcinoma cells.
Fibroblast growth factor (FGF)-1 and -2 have potent biological activities implicated in malignant tumor development. Their autocrine and nonautocrine activity in tumor progression of carcinoma was investigated in the NBT-II cell system. Cells were manipulated to either produce and be autocrine for FGF-1 or -2 or to only produce but not respond to these factors. The autocrine cells are highly invasive and tumorigenic and the determination of specific targets of FGF/fibroblast growth factor receptor (FGFR) signaling was assessed. In vitro studies showed that nonautocrine cells behave like epithelial parental cells, whereas autocrine cells have a mesenchymal phenotype correlated with the overexpression of urokinase plasminogen activator receptor (uPAR), the internalization of E-cadherin, and the redistribution of beta-catenin from the cell surface to the cytoplasm and nucleus. uPAR was defined as an early target, whereas E-cadherin and the leukocyte common antigen-related protein-tyrosine phosphatase (LAR-PTP) were later targets of FGF signaling, with FGFR1 activation more efficient than FGFR2 at modulating these targets. Behavior of autocrine cells was consistent with a decrease of tumor-suppressive activities of both E-cadherin and LAR-PTP. These molecular analyses show that the potential of these two growth factors in tumor progression is highly dependent on specific FGFR signaling and highlights its importance as a target for antitumor therapy.
Billottet
Clotilde
C
Laboratory of Cell Morphogenesis and Tumor Progression, UMR 144 CNRS, Institut Curie, Section de recherche, 75248 Paris Cedex 05, France.
Elkhatib
Nadia
N
Thiery
Jean-Paul
JP
Jouanneau
Jacqueline
J
D000818:Animals; D019898:Autocrine Communication; D015820:Cadherins / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D048430:Cell Shape; D003598:Cytoskeletal Proteins / Q000378:metabolism; D051180:Desmoplakins; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D051176:beta Catenin
D015820:Cadherins; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D051180:Desmoplakins; C524900:Plaur protein, rat; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D015534:Trans-Activators; D051176:beta Catenin; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1