Purpose: The antiangiogenic and proapoptotic mechanisms of dietary caloric restriction (DR) are unknown. In this study, we evaluated the effects of moderate (40%) DR on the orthotopic growth of mouse and human brain tumors that differ in cell origin, angiogenicity, host environment, and biochemical composition.Experimental Design: A malignant mouse astrocytoma (CT-2A) and a human glioma (U87-MG) were highly angiogenic and fast growing, whereas a mouse ependymoblastoma was less vascularized and slower growing. The tumors were evaluated for growth, cell proliferation, microvessel density, and apoptosis under DR and ad libitum feeding. Serum vascular endothelial growth factor and insulin-like growth factor I levels were examined as angiogenic biomarkers.Results: DR significantly decreased vascularity (factor VIII) and increased apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling) in all tumors. These effects were associated with enhanced caspase-3 and poly-(ADP-ribose) polymerase cleavage in the CT-2A and ependymoblastoma tumors, but not in the U87-MG tumor. DR also caused reductions of serum insulin-like growth factor I and glucose levels.Conclusions: DR had significant antiangiogenic and proapoptotic effects in the three distinct brain tumor models. DR, however, had differential effects on cell proliferation, biomarkers of angiogenesis, and apoptosis, suggesting multiple mechanisms of action. Because extensive angiogenesis and resistance to apoptosis are hallmarks of gliomas, this study provides new insight into the molecular basis of the DR-induced inhibition of brain tumor growth.

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 b-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 1a (HIF-1a) 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.