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 variety of cellular events via their glycosaminoglycan (GAG) chains. The effects of all known glycosaminoglycans (GAGs) produced by normal cells and tissues on the proliferation of two human malignant mesothelioma cell lines, one with fibroblast-like morphology and the other with epithelial differentiation - both able to produce hyaluronan (HA), galactosaminoglycans (GalAGs) and heparan sulphate (HS) containing proteoglycans - have been studied. Cell proliferation was assessed by measuring [3H]thymidine incorporation and cell number. GalAGs, i.e. chondroitin sulphates (CSs) and dermatan sulphate (DS), strongly stimulate the proliferation of fibroblast-like cells in a dose-dependent manner (170-250% at 100 microg/ml), independently of their sulphation pattern. In epithelial cells, however, only DS stimulates cell proliferation. The effects of CSs on proliferation of epithelial cells are not depended on their sulphation pattern. Thus, CSs either with -[GlcA-GalNAc-(-6-O-SO(3)-)]- or -[GlcA-GalNAc-(-4-O-SO(3)-]- as the commonest unit, had no significant effect. L-Iduronic acid (IdoA)-rich heparin and fast-moving HS (fm-HS), a HS fraction with a heparin-like structure, had significant antiproliferative effects on mesothelioma cells of both types (30-70% at 1.0 microg/ml and 85-90% at 100 microg/ml, respectively). GlcA-rich HS, however, had no significant effects. HA inhibits only the proliferation of fibroblast-like cells by 25% at 50 and 100 microg/ml. Keratan sulphate suppresses cell proliferation (10-30%) in both cell lines. In the view of these findings, a structure-function relationship of GAGs on cell proliferation of the two human malignant mesothelioma cell lines is discussed. Other factors, such as chain conformation and geometry, as well as interactions of growth factors with GAGs, possibly involved in the regulation of cell proliferation, are also discussed.