Physiological concentrations of gangliosides GM1, GM2 and GM3 differentially modify basic-fibroblast-growth-factor-induced mitogenesis and the associated signalling pathway in endothelial cells

It has been suggested that gangliosides can influence the growth of cells b y modulation of growth-factor-receptor signalling. The activation of endoth elial cells (EC) during angiogenesis is crucial for tumour growth and for m etastasis, also for numerous other physiological and pathological situation s. Pre-treatment of bovine aortic endothelial cells (BAEC) with GM1 or GM2 (5-20 mu M) inhibited basic-fibroblast-growth-factor (bFGF)-induced mitogen esis, but GM3 (0.1-20 mu M) acted synergistically, increasing proliferation above that of bFGF alone (p < 0.05). The mitogenic effect of all 3 ganglio sides was markedly reduced if the cells were washed to remove excess gangli osides from the medium before addition of bFGF. We further show that GM1 an d to a lesser extent GM2 modify bFGF binding to its receptor and inhibit th e associated mitogenic signal-transduction pathway of protein-tyrosine phos phorylation of 40 to 120 kDa, PLC gamma 1, MAP kinase and protein-kinase-C activation. In contrast, GM3 increased tyrosine phosphorylation and MAP kin ase activity, as compared with bFGF alone. The observed differential modula tion of bFGF-induced mitogenesis by GM I, GM2 and GM3 was at concentrations routinely occurring in the serum of cancer patients. The results suggest t hat circulating gangliosides may have a role in regulating solid-tumour gro wth by modulating angiogenesis. Int. J. Cancer 82:412-423, 1999. (C) 1999 W iley-Liss, Inc.