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2014 ; 17
(3
): 563-71
Nephropedia Template TP
Angiogenesis
2014[Jul]; 17
(3
): 563-71
PMID24165965
show ga
Tumor cells shed gangliosides and populate their microenvironment with these
biologically active membrane glycosphingolipids. In vitro, ganglioside enrichment
amplifies receptor tyrosine kinase signaling and activation of vascular
endothelial cells. However, a long-standing question is whether in the actual
microenvironment of a neoplasm, in vivo, tumor cell ganglioside shedding
stimulates angiogenesis. Here we tested the hypothesis that tumor gangliosides
have a critical proangiogenic role in vivo using novel murine tumor cells,
GM3synthase/GM2synthase double knockout (DKO) cells, genetically completely
incapable of ganglioside synthesis and impaired in tumor growth versus wild-type
(WT) ganglioside-rich cells. We studied angiogenesis during tumor formation by
these ganglioside-depleted cells, quantifying vessel formation, angiogenic factor
production/release, and consequences of reconstitution with purified WT
gangliosides. DKO cells formed virtually avascular tumors, much smaller than
ganglioside-rich WT tumors and displaying a striking paucity of blood vessels,
despite levels of VEGF and other angiogenic factors that were similar to those of
WT cells. Transient enrichment of the ganglioside milieu of the DKO cell inoculum
by adding purified WT gangliosides partially restored angiogenesis and tumor
growth. We conclude that tumor gangliosides trigger robust angiogenesis important
for tumor growth. Our findings suggest strategies to eliminate their synthesis
and shedding by tumor cells should be pursued.
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