Effects on glycosaminoglycan synthesis in cultured human mesothelioma cells of transforming, epidermal, and fibroblast growth factors and their combinations with platelet-derived growth factor.
Two human mesothelioma cell sublines with fibroblast-like and epithelial morphology produce hyaluronan, galactosaminoglycans, and heparan sulfate in amounts varying with their cell phenotype. The epithelially differentiated cells synthesize these glycosaminoglycans in 6- to 8-fold higher amounts than the fibroblast-like cells. Hyaluronan is mainly a secretory product (> 90%), a considerable proportion of galactosaminoglycans is present in the extracellular medium (> 80%), while more of the heparan sulfate (50-70%) is cell-associated. In both cell lines the rates of synthesis of glycosaminoglycans are affected by the addition of the exogenous growth factors. In fibroblast phenotype cells, TGF-beta 2, EGF, and bFGF increase the production of glycosaminoglycans from 1.6- to 2.0-fold, with the exception of HS, which is suppressed by the addition of bFGF. The combination of these growth factors with PDGF-BB showed that only EGF causes a synergistic action in the synthesis of all glycosaminoglycans and that no additive effect is obtained when PDGF-BB is combined with TGF-beta 2 and bFGF. In epithelially differentiated cells, the addition of exogenous TGF-beta 2 and bFGF has no significant effect on hyaluronan synthesis, which is increased by EGF to 45%. The synthesis of galactosaminoglycans is stimulated by EGF and TGF-beta 2 approximately 35%, whereas bFGF has no significant effect. Heparan sulfate production is considerably increased by the addition of EGF by 50%, whereas bFGF has no significant effect and TGF-beta 2 suppresses this synthesis. The combination of the various growth factors with PDGF-BB showed that only heparan sulfate synthesis is affected. Thus, combining PDGF-BB with TGF-beta 2 and EGF this synthesis is increased by 35 and 25%, whereas the combination of bFGF with PDGF-BB has no further effect. The remarkable differences found between the two mesothelioma sublines may well be related to the importance of glycosaminoglycan-growth factor interactions as a key factor in phenotypic cell differentiation.
Tzanakakis
G N
GN
Department of Immunology, Microbiology, Pathology and Infectious Diseases, Karolinska Institute, Huddinge University Hospital, Sweden.
Karamanos
N K
NK
Hjerpe
A
A
D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006025:Glycosaminoglycans / Q000096:biosynthesis* / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007231:Infant, Newborn; D008654:Mesothelioma / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D006025:Glycosaminoglycans; D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor