Effects of glycosaminoglycans on proliferation of epithelial and fibroblast human malignant mesothelioma cells: a structure-function relationship

Proteoglycans interact with other effective macromolecules regulating a var iety of cellular events via their glycosaminoglycan (GAG) chains. The effec ts of all known glycosaminoglycans (GAGs) produced by normal cells and tiss ues on the proliferation of two human malignant mesothelioma cell lines, on e with fibroblastlike morphology and the other with epithelial differentiat ion - both able to produce hyaluronan (HA), galactosaminoglycans (Ga1AGs) a nd heparan sulphate (HS) containing proteoglycans - have been studied. Cell proliferation was assessed by measuring [H-3]thymidine incorporation and c ell number. Ga1AGs, i.e, chondroitin sulphates (CSs) and dermatan sulphate (DS), strongly stimulate the proliferation of fibroblast-like cells in a do se-dependent manner (170-250% at 100 mu g/ml), independently of their sulph ation pattern. In epithelial cells, however, only DS stimulates cell prolif eration. The effects of CSs on proliferation of epithelial cells are not de pended on their sulphation pattern. Thus, CSs either with -[G1cA-Ga1NAc-(-6 -O-SO3-)]- or -[G1cA-Ga1NAc-(-4-O-SO3-)]- as the commonest unit, had no sig nificant effect. L-Iduronic acid (IdoA)-rich heparin and fast-moving HS (fm -HS), a HS fraction with a heparin-like structure, had significant antiprol iferative effects on mesothelioma cells of both types (30-70% at 1.0 mu g/m l and 85-90% at 100 mu g/ml, respectively). G1cA-rich HS, however, had no s ignificant effects. HA inhibits only the proliferation of fibroblast-like c ells by 25% at 50 and 100 mu g/ml. Keratan sulphate suppresses cell prolife ration (10-30%) in both cell lines. In the view of these findings, a struct ure-function relationship of GAGs on cell proliferation of the two human ma lignant mesothelioma cell lines is discussed. Other factors. such as chain conformation and geometry, as well as interactions of growth factors with G AGs, possibly involved in the regulation of cell proliferation, are also di scussed.