Rapid tumor development and potent vascularization are independent events in carcinoma producing FGF-1 or FGF-2.
FGF-1 and FGF-2 are pleiotropic growth factors for many cell types, operating through the activation of specific transmembrane FGF receptors (FGFRs). The role of these factors in tumor progression was investigated, with specific discrimination between their autocrine and non autocrine cellular activity. The rat bladder carcinoma NBT-II cells were engineered to produce FGF-1 or 18 kDa FGF-2 in the presence or absence of their specific receptor. Non-autocrine cells that produced FGF-1 or FGF-2 but lacked FGFRs were epithelial and reminiscent of the parental NBT-II cells. Whilst autocrine cells, which both constitutively produced and secreted the growth factor and expressed FGFRs, had a highly invasive mesenchymal phenotype. Correspondingly, the autocrine cells were highly tumorigenic in vivo compared to the parental and non-autocrine cells, which correlated with the increased production of uPAR and active uPA and increased in vitro invasive potential. Although all cells produced VEGF, only tumors derived from cells that produced FGF-1 or FGF-2 were highly vascularized, suggesting that these two growth factors could be involved in the angiogenic process by activating host endothelial cells. As a result of activation of the FGFR in autocrine cells, changes in cell morphology and an increase in the invasive and tumorigenic properties were observed, however no in vitro or in vivo differential functions between FGF-1 and FGF-2 could be identified in this system. In conclusion, our data demonstrates that rapid tumor development is not dependent upon increased tumor vascularization, suggesting that 'basal' angiogenesis, probably mediated by VEGF, is sufficient to support tumor growth.
Billottet
Clotilde
C
Laboratory of Cell Morphogenesis and Tumor Progression, UMR 144 CNRS, Institut Curie, Section de recherche, 26 rue d'Ulm, 75248 Paris, cedex 05, France.
Janji
Bassam
B
Thiery
Jean-Paul
JP
Jouanneau
Jacqueline
J
D000818:Animals; D019898:Autocrine Communication; D002277:Carcinoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D016228:Endothelial Growth Factors / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D008648:Mesoderm; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000502:physiology*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000503:physiopathology*; D010641:Phenotype; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000502:physiology; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017384:Sequence Deletion; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009363:Neoplasm Proteins; C524899:Plaur protein, mouse; C524900:Plaur protein, rat; D011956:Receptors, Cell Surface; D017468:Receptors, Fibroblast Growth Factor; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D019716:Tissue Inhibitor of Metalloproteinase-2; C496349:Fgfr1 protein, mouse; C496350:Fgfr1 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases