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Tumors stimulate angiogenesis to develop the adequate vascular system needed to expand beyond a certain minimal size. Soluble tumor-derived angiogenic/growth factors such as VEGF facilitate this. Since the extent of the angiogenic response by endothelial cells in the tumor microenvironment will depend on the magnitude of growth factor release by the tumor cells, other factors may also play a role. We assessed whether gangliosides, which are shed in substantial quantities by many tumor cells and are taken up and bind efficiently to host cells that are found in the tumor microenvironment (e.g., fibroblasts and antigen presenting cells) enhance the angiogenic response to VEGF. We exposed HUVEC to a highly purified ganglioside, GD1a, washed away unincorporated molecules, and then observed the effects of membrane enrichment with exogenous ganglioside molecules. Exposure of HUVEC to GD1a resulted in (a) significant incorporation (25 nmol GD1a /108 cells), (b) increased proliferation of HUVEC exposed to 1 ng VEGF/ml in a 3 hours proliferation assay ( 92% increase in DNA synthesis, compared to an only 28% increase in control cells; p=0.002), (c)increased 125I-VEGF binding, from 3.6±0.2 ×104moleculas/cell (control) to 6.0±0.34 ×104/cell (ganglioside enriched), (d) increased VEGFR-2 dimerization and autophosphorylation, and increased downstream (PI-3K, PKC, and MAPK) activity. The enrichment of vascular and endothelial cell membranes in gangliosides, which tumor cells actively release, striking sensitizes these cells to the VEGF stimulation. The findings suggest that gangliosides shed by tumor cells are potent enhancers of VEGF signaling and responses by HUVEC. An increase in sensitivity of the target cell, caused by a change in membrane ganglioside composition, can enhance a growth factor response, which may facilitate, ultimately, vessel formation. This work was supported by NIH grant CA61010.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]