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. 2017 Mar 1;19(3):383-393.
doi: 10.1093/neuonc/now175.

The angiogenic switch leads to a metabolic shift in human glioblastoma

Krishna M Talasila  1   2 , Gro V Røsland  1 , Hanne R Hagland  1 , Eskil Eskilsson  3 , Irene H Flønes  4 , Sabrina Fritah  5 , Francisco Azuaje  5 , Nadia Atai  6 , Patrick N Harter  7 , Michel Mittelbronn  7 , Michael Andersen  8 , Justin V Joseph  1   2 , Jubayer Al Hossain  1   2   8 , Laurent Vallar  9 , Cornelis J F van Noorden  6 , Simone P Niclou  2   5 , Frits Thorsen  2   10 , Karl Johan Tronstad  1 , Charalampos Tzoulis  4 , Rolf Bjerkvig  1   2   4 , Hrvoje Miletic  1   2   8
Affiliations

The angiogenic switch leads to a metabolic shift in human glioblastoma

Krishna M Talasila et al. Neuro Oncol. .

Abstract

Background: Invasion and angiogenesis are major hallmarks of glioblastoma (GBM) growth. While invasive tumor cells grow adjacent to blood vessels in normal brain tissue, tumor cells within neovascularized regions exhibit hypoxic stress and promote angiogenesis. The distinct microenvironments likely differentially affect metabolic processes within the tumor cells.

Methods: In the present study, we analyzed gene expression and metabolic changes in a human GBM xenograft model that displayed invasive and angiogenic phenotypes. In addition, we used glioma patient biopsies to confirm the results from the xenograft model.

Results: We demonstrate that the angiogenic switch in our xenograft model is linked to a proneural-to-mesenchymal transition that is associated with upregulation of the transcription factors BHLHE40, CEBPB, and STAT3. Metabolic analyses revealed that angiogenic xenografts employed higher rates of glycolysis compared with invasive xenografts. Likewise, patient biopsies exhibited higher expression of the glycolytic enzyme lactate dehydrogenase A and glucose transporter 1 in hypoxic areas compared with the invasive edge and lower-grade tumors. Analysis of the mitochondrial respiratory chain showed reduction of complex I in angiogenic xenografts and hypoxic regions of GBM samples compared with invasive xenografts, nonhypoxic GBM regions, and lower-grade tumors. In vitro hypoxia experiments additionally revealed metabolic adaptation of invasive tumor cells, which increased lactate production under long-term hypoxia.

Conclusions: The use of glycolysis versus mitochondrial respiration for energy production within human GBM tumors is highly dependent on the specific microenvironment. The metabolic adaptability of GBM cells highlights the difficulty of targeting one specific metabolic pathway for effective therapeutic intervention.

Keywords: angiogenesis; glioblastoma; glycolysis; hypoxia; invasion.

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Figures

Fig. 1.
Fig. 1.
The angiogenic switch is linked to proneural-to-mesenchymal transition in GBM. (A) Highest differentially expressed genes between invasive (untr) and angiogenic (DN) tumors. (B) Biological processes linked to up- and downregulated genes. (C) Heatmap of Verhaak classification shows that invasive tumors (untr) have a proneural phenotype, while angiogenic (DN) tumors have a mesenchymal phenotype. (D) Transcription factor association to upregulated genes (DN). untr = untransduced EGFR amplified cells.
Fig. 2.
Fig. 2.
Glycolysis is upregulated in angiogenic compared with invasive tumors. (A) MRS of invasive and angiogenic tumors. * P < .005; Lac=Lactate; mI=myo Inositol; Cr=creatine; Ch=choline; NAA+NAAG=; Glu+Gln=glutamine and glutamate; Tau=taurine; NAA+NAAG=N-acetylaspartate + N-acetyl-aspartylglutamate (B) Metabolic mapping of LDH activity in angiogenic compared with invasive tumors. Asterisk indicates necrotic area. (C) Quantification of metabolic mapping. (D) Lactate levels of invasive (P8) and angiogenic (P8-EGFRDN) human GBM cells in 48h and 120h of normoxia and hypoxia. *P < .05; ***P < .001.
Fig. 3.
Fig. 3.
LDH-A and GLUT1 are overexpressed in hypoxic areas of human GBM compared with nonhypoxic areas and low-grade glioma. (A) Immunohistochemistry for LDH-A and GLUT1 in glioma with different World Health Organization grades. Asterisk indicate necrotic areas. (B) Quantification of immunohistochemistry from (A). GLUT1: grade IV versus grade II, P=.0243; other comparisons n.s. LDH-A: grade IV versus II, P=.0087; grade IV versus grade III P=.0088. (C) Quantification of LDH-A and GLUT1 immunohistochemistry in invasive (I) and central (T) tumor areas of GBM. GLUT1, P=.0021; LDH-A, P=.0083.
Fig. 4.
Fig. 4.
Complex I is downregulated in angiogenic compared with invasive tumors. (A) Immunostaining for complex I and porin in invasive and angiogenic xenografts. Complex I is downregulated in angiogenic compared with invasive xenografts while porin is not differentially expressed. (B) Western blot with antibodies against HIF1A and VEGF. (C) Immunostaining for complex I and porin in low-grade glioma and GBM. Asterisks indicate necrotic areas.
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