title: Proteoglycan synthesis induced by transforming and basic fibroblast growth factors in human malignant mesothelioma is mediated through specific receptors and the tyrosine kinase intracellular pathway.
abstract: The effects and the mechanisms of action of transforming (TGF-beta 2) and basic fibroblast (bFGF) growth factors on the synthesis of hyaluronan and proteoglycans (PGs) in human malignant mesothelioma cells have been studied. Two cell lines, one with an epithelial differentiation (STAV-AB) and the other with a fibroblast-like phenotype (STAV-FCS) have been examined. Using monoclonal antibodies to growth factor receptors, the presence of a high density of the specific receptors for TGF-beta 2 and bFGF was immunochemically demonstrated in both mesothelioma cell lines. These cell lines synthesize hyaluronan, galactosaminoglycan containing PGs (GalAGPGs) and heparan sulphate containing PGs (HSPGs) at different levels; the epithelial differentiated cells produce a 6-8 times higher amount than those with the fibroblast-like morphology. In both cell lines the rates of proteoglycan synthesis were affected in a dose-dependent mode by TGF-beta 2 and bFGF. Maximal synthetic levels of both secreted and cell-bound proteoglycans were reached at 10 ng/mL whereafter they remained constant. TGF-beta 2 stimulated the synthesis of hyaluronan, GalAGPGs and of HSPGs in STAV-FCS, whereas this effect was pronounced only for GalAGPGs in STAV-AB. bFGF showed stimulatory effects for the synthesis of hyaluronan and cell associated GalAGPGs in STAV-FCS, whereas no significant enhancement was recorded for HSPGs. In the STAV-AB cell line the synthesis of hyaluronan and GalAGPGs remained unaltered by the addition of both growth factors. Although the synthesis of total HSPGs remained constant, this was due to a decrease in the secreted product and a similar increase of the cell-associated proteoglycan. The stimulatory mechanisms of both growth factors was examined by using the specific protein tyrosine kinase inhibitor genistein. Incubation of both cell lines with this isoflavonoid inhibited the enhanced synthesis of hyaluronan and all PGs induced by TGF-beta 2 and bFGF. It is suggested that most, if not all, of the stimulatory effects on the hyaluronan and PGs synthesis are mediated via protein tyrosine kinase activity elicited by receptor-ligand complexes. Decreased synthetic rates obtained when giving genistein to unstimulated mesothelioma cells may indicate the relation of hyaluronan and PGs synthesis with an autocrine stimulatory mechanisms.
authors.affiliation: Department of Immunology, Microbiology, Pathology and Infectious Diseases, Karolinska Institute, Huddinge, Sweden.
authors.forename: G N
authors.initials: GN
authors.lastname: Tzanakakis
authors.forename: A
authors.initials: A
authors.lastname: Hjerpe
authors.forename: N K
authors.initials: NK
authors.lastname: Karamanos
mesh_terms: D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006820:Hyaluronic Acid / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000201:enzymology; D008654:Mesothelioma / Q000201:enzymology / Q000378:metabolism*; D010997:Pleural Neoplasms / Q000201:enzymology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011509:Proteoglycans / Q000096:biosynthesis* / Q000187:drug effects; D000077294:Receptor, Transforming Growth Factor-beta Type II; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology*; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D011509:Proteoglycans; D017468:Receptors, Fibroblast Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D006820:Hyaluronic Acid; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II