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

Slevin, Mark, Kumar, Shant, He, Xiaotong and Gaffney, John (1999) Physiological concentrations of gangliosides GM1, GM2 and GM3 differentially modify basic-fibroblast-growth-factor-induced mitogenesis and the associated signalling pathway in endothelial cells. International journal of cancer, 82 (3). pp. 412-23. ISSN 0020-7136

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Abstract

It has been suggested that gangliosides can influence the growth of cells by modulation of growth-factor-receptor signalling. The activation of endothelial cells (EC) during angiogenesis is crucial for tumour growth and for metastasis, also for numerous other physiological and pathological situations. Pre-treatment of bovine aortic endothelial cells (BAEC) with GM1 or GM2 (5-20 microM) inhibited basic-fibroblast-growth-factor (bFGF)-induced mitogenesis, but GM3 (0.1-20 microM) acted synergistically, increasing proliferation above that of bFGF alone (p < 0.05). The mitogenic effect of all 3 gangliosides was markedly reduced if the cells were washed to remove excess gangliosides from the medium before addition of bFGF. We further show that GM1 and to a lesser extent GM2 modify bFGF binding to its receptor and inhibit the associated mitogenic signal-transduction pathway of protein-tyrosine phosphorylation of 40 to 120 kDa, PLCgamma1, MAP kinase and protein-kinase-C activation. In contrast, GM3 increased tyrosine phosphorylation and MAP kinase activity, as compared with bFGF alone. The observed differential modulation of bFGF-induced mitogenesis by GM1, GM2 and GM3 was at concentrations routinely occurring in the serum of cancer patients. The results suggest that circulating gangliosides may have a role in regulating solid-tumour growth by modulating angiogenesis.