Brain tumor growth and progression is dependent upon vascularity, and is associated with altered
ganglioside composition and distribution. In this study, we examined the influence of
gangliosides on growth and vascularity in a malignant mouse
astrocytoma, CT-2A.
Ganglioside distribution was altered in CT-2A
tumor cells using an antisense construct to
beta-1,4-N-acetylgalactosaminyltransferase (GalNAc-T), a key
enzyme that uses the simple
ganglioside GM3 as a substrate for the synthesis of the more complex
gangliosides, GM2, GM1 and GD1a. GalNAc-T gene expression was significantly lower in CT-2A cells stably transfected with the antisense GalNAc-T plasmid, pcDNA3.1/TNG (CT-2A/TNG) than in either non-transfected CT-2A or mock-transfected (CT-2A/V) control
tumor cells. GM3 was elevated from 16% to 58% of the total
ganglioside distribution, whereas GM1 and GD1a were reduced from 17% and 49% to 10% and 17%, respectively, in CT-2A/TNG
tumor cells. Growth, vascularity (blood vessel density and
Matrigel assay) and
vascular endothelial growth factor (
VEGF) expression was significantly less in CT-2A/TNG
tumors than in control CT-2A
brain tumors. In addition, the expression of
VEGF,
hypoxia-inducible factor 1alpha (HIF-1alpha) and
neuropilin-1 (NP-1) was significantly lower in CT-2A/TNG
tumor cells than in control CT-2A
tumor cells. These data suggest that gene-linked changes in
ganglioside composition influence the growth and angiogenic properties of the CT-2A
astrocytoma.