육종 대사체학

2021

https://www.mdpi.com/2073-4409/10/6/1432/htm

Sarcoma Metabolomics: Current Horizons and Future Perspectives

Sarcoma Metabolomics: Current Horizons and Future Perspectives

able 1. Cancer metabolic adaptations and acquired phenotypes.

Metabolic HallmarkAlterations and Adaptations in CancerOutcome/Acquired Phenotype

Deregulated uptake of glucose and amino acids [5]	(1) Mutations of the oncogenes c-MYC, KRAS and YAP [8] (2) Overexpression of YAP and loss-of-function mutations in p53 [8] (3) Phosphoinositide 3-kinase (PI3K)/Akt pathway hyperactivation [5,8] (4) C-MYC, n-MYC, mTORC1, IL-4 and lactate modulation [8] (5) RAS mutations [8]	(1) Upregulate glucose transporter (GLUT) 1 expression [8] (2) Augments GLUT3 expression [8] (1) and (2) Increase entrance of glucose into the cell [8] (3) Promotes GLUT1 mRNA expression and GLUT1 protein translocation from the inner membranes to the cell surface [5] and hexokinase (HK)2 activity upregulation, trapping glucose inside the cell [8] (4) Upregulates ASCT2 glutamine transporter expression increasing entrance of glutamine into the cell [8] (5) Increases glutamine uptake by micropinocytosis [8]
Use of opportunistic modes of nutrient acquisition [5]	(1) Hypoxia triggers the expression of transcription factors called hypoxia-inducible factors (HIF) [9] (2) Cholesterol depletion induces activation of sterol regulatory element-binding proteins [9] (3) Amino acid deprivation leads to activation of the GCN2 kinase [9] (4) Ras or c-Src mutations [5] (5) Prolonged periods of extracellular nutrients absence lead to macroautophagy [9]	(1) Stimulates glucose uptake, lactate export, glycolysis and angiogenesis (by induction of VEGF expression) [9] (2) Stimulates the expression of enzymes required for de novo synthesis of fatty acid and sterol lipids, increases LDL receptors expression and enhances NADPH production [9] (3) Promotes selective translation of mRNAs like ATF4, promoting the transcription of amino acids transporters and enzymes involved in the generation of non-essential amino acids [9] (4) Enhances the recovery of free amino acids by lysosomal digestion of extracellular proteins by several processes including micropinocytosis, degradation of entire living cells (entosis) and digestion of apoptotic cellular corpses [5] (5) Sequestrates and promotes lysosomal digestion of cytosolic macromolecules and organelles, allowing the recycling of these cellular components into nutrients [9]
Use of glycolysis/TCA cycle intermediates for biosynthesis and NADPH production [5]	(1) C-MYC and β-catenin/TCF signaling hyperactivation [5]	(1) Leads to overexpression of multiple key enzymes for generation of diverse glycolytic and TCA cycle intermediates that are biosynthetic precursors [5]
Increased demand for nitrogen [5]	(1) C-MYC signaling hyperactivation [5] (2) Asparagine synthetase upregulation [5] (3) Glutamine synthetase upregulation [5]	(1) Promotes celular glutamine uptake, upregulates the expression of different enzymes with roles in nucleotide biosynthesis and upregulates glutaminase [5] (2) Increases asparagine synthesis (crucial in glutamine deprived conditions) [5] (3) Augments intracelular de novo glutamine production (fundamental in glutamine deprived conditions) [5]
Alterations in metabolite-driven gene regulation [5]	(1) Diverse oncogenic pathways hyperactivation [10] (2) Loss-of-function SDH and FH mutations [10] (3) Gain-of-function IDH1 and IDH2 mutations [10]	(1) Enhances total histone acetylation, leading to increased and broader oncogene expression [10] (2) Succinate and fumarate accumulation leads to inhibition of demethylases (JmJC and TET), increase of genome wide DNA and histone hypermethylation, enabling oncogenic promoter-enhancer interactions, inducing epithelial-to-mesenchymal transition, and disrupting DNA repair mechanisms [10] (3) Catalyzes the conversion of α-ketoglutarate to 2-HG, leading to 2-HG accumulation, DNA and histone hypermethylation with downregulation of genes associated with tumor-suppression and cellular differentiation blockade [10]
Metabolic interactions with the microenvironment [5]	(1) Low glucose and aminoacids (glutamine, L-arginine, methionine) extracellular availability and extracellular lactate accumulation [11] (2) Increased CAF glycolytic and glutamine anabolic metabolism [11] (3) CAF-derived exosomes proliferation [11] (4) Metabolic plasticity (glycolysis vs. mitochondrial metabolism) relative to local oxygen availability [11]	(1) Decreases mTOR activity leading to an impairment of T cell (CD8+) and NK cell function and proliferation and promotes a macrophage M2 polarization [11] (2) Leads to use of resultant metabolites from CAF glycolysis and glutamine metabolism to fuel cancer cells [11] (3) Supplies cancer cells with amino acids, lipids and TCA intermediates [11] (4) Sustains glucose consumption, glycolysis and OXPHOS in cancer cells located in well perfused areas, while cells in poorly perfused areas depend on other carbon sources [11]

GLUT1—Glucose Transporter 1; GLUT3—Glucose Transporter 3; PI3K/Akt—Phosphoinositide 3-kinase/Protein kinase B; HK2 Hexokinase 2; ASCT2—Alanine, Serine, Cysteine Transporter 2; HIF—Hypoxia inducible-factors; VEGF—Vascular Endothelial Growth Factor; LDL—Low-density lipoprotein; NADPH—Nicotinamide adenine dinucleotide phosphate; GCN2—General control nonderepressible 2; ATF4—Activating transcription factor 4; SDH—Succinate dehydrogenase; FH—Fumarate hydratase; JmJC—Jumonji C; TET—Ten eleven translocation methylcytosine dioxygenases; IDH—Isocitrate dehydrogenase; 2-HG—2-hydroxyglutarate; mTOR—Mechanistic target of rapamycin; NK—Natural killer; CAF—Cancer associated fibroblasts; TCA—Tricarboxylic acid cycle; OXPHOS—Oxidative phosphorylation.

 

 

Figure 2. Soft tissue sarcoma metabolic hallmarks.