Excessive Lipid Production Shapes Glioma Tumor Microenvironment

Abstract

Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n = 18) and IDH1 mutant (IDH1-mt) astrocytoma (n = 12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical membraneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vasculature have lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Lipid excess in gliomas stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune responses, non-lipophilic drugs, and free radicals.

Keywords: astrocytoma; glioblastoma; glycolysis; immune evasion; lipid accumulation; mitochondrial dysfunction; oxidative phosphorylation; therapeutic strategies; tumor microenvironment; ultrastructural analysis.

Figure 1

The fate of pyruvate in cancer cells. The end product of glycolysis is pyruvate, which can enter into two pathways. The first is to be reduced to lactic acid through an exothermic reaction catalyzed by lactate dehydrogenase-A (LDH-A); the second is to be converted into acetyl-CoA in the mitochondria and processed through the TCA cycle and oxidative phosphorylation. However, when oxidative phosphorylation is dysfunctional in a cancer cell and acetyl-CoA accumulates in the mitochondria, acetyl-CoA is exported to the cytoplasm and gets assimilated into fatty acid synthesis, the building blocks of lipids.

Figure 2

Lipids in IDH1-WT glioblastoma tumors. A-C, lipid droplets inside tumor cells, lipid droplets fuse with each other and form larger droplets; C. a single lipid droplet surrounded by degenerate mitochondria, the cytoplasm is full of lipid and intermediate filaments. D-F, an overview of lipids interspersed between tumor cells in addition to lipid droplets inside tumor cells. G & H, lipid inside mitochondria that are in different degrees of degeneration, arrows in G point to the degenerate mitochondria. I, lipids within the vessel lumen, all cells in this image are tumor cells invading the vessel. Abbreviations: Lyso=Lysosome, L=lipid, M=mitochondrion, mi=myelin inclusion, N=nucleus, VW=vessel wall.

Figure 3

Lipids in IDH1-mt astrocytoma tumors. A-C, lipid droplets (LDs) inside tumor cells, B, LDs at a higher magnification inside the cytoplasm, C, LDs that were formed by filling up the degenerate mitochondria, notice the remaining mitochondrial membrane, a LD present inside the nucleus. D-F, an overview of lipids interspersed between tumor cells in addition to LDs inside tumor cells. G & H, lipid inside mitochondria that are in different degrees of degeneration, arrows point to the degenerate mitochondria, the cytoplasm is packed with intermediate filaments. I, lipids within the vessel lumen. Abbreviations: IM=intermediate filaments, L=lipid, N=nucleus, RBC=red blood cell.

Figure 4

Extranuclear DNA (enDNA) fragments (black arrows) embedded in the lipid deposits of IDH1-mt astrocytoma tumor cells. A, a large chromatin circle (~750 nm in diameter) and two small chromatin clumps (the smallest 125 nm in the largest dimension). B, two large chromatin clumps in the lipid deposits, the large clump is ~1.75 μm, and the small one ~750 nm. Abbreviations: L=lipid.