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.