Tumors with high glycolytic or hypoxic properties must produce sufficient levels of acetyl-CoA to maintain cellular survival and proliferation under adverse nutrient conditions. Acetyl-CoA can be generated by oxidation of glucose, glutamine, or fatty acids. There are principal differences between the metabolism of normal, well-fed cells and tumor cells, especially under nutrientdeprived conditions. Whereas the former consume glucose/ pyruvate/acetyl-CoA-derived citrate to synthesize acetyl-CoA, which is then used for fatty acid and cholesterol synthesis, generation of nucleotides and amino acids, and histone acetylation, the latter divert the main metabolite of glucose into aerobic glycolysis from pyruvate-derived mitochondrial acetylCoA to lactate. The “bioenergetic substrate gap” develops when under oxygen-limiting conditions the ability of a cell to make acetyl-CoA is impaired, and the question arises how sufficient amounts of citrate via ATP citrate lyase are produced. In the brain, glial cells are capable of oxidizing acetate. In an extremely elegant study, integrating observations from clinical experiments, ex vivo data, and preclinical mouse and cell culture studies, Mashimo and Pichumani et al from the Bachoo and Maher laboratories showed that primary and metastatic tumors growing in the brain have the capacity to oxidize acetate while simultaneously oxidizing glucose, providing an explanation for the yet unknown carbon source for the generation of the critical metabolite acetyl-CoA. Previously, C-nuclear magnetic resonance analysis showed that upon infusion of C-glucose during surgery for primary or metastatic brain tumors, ,50% of carbon in the acetyl-CoA pool was derived from glucose. The principal hypothesis by Mashimo and Pichumani et al is that glioma cells retain the acetatemetabolizing ability of the “healthy” glial cells. For metastases, it had been speculated that the microenvironment provokes a change in cells from non-acetate-metabolizing organs, like lung and breast, to allow them to metabolize acetate. In their work, relevant human orthotopic tumor mouse models of glioblastoma and brain metastases with remarkable preservation of the hallmark histopathological and molecular features (ER-/PR-negative/Her2-positive breast cancer, EGFR/ALK/KRAS wild-type non-small cell lung cancer, VHL-nil clear cell renal carcinoma, or BRAF melanoma) were used in C-NMR tissue examinations with very clear co-infusion experiments of C-glucose and C-acetate. Each of the metastatic cell lines oxidized glucose but showed a relevant bioenergetics carbon substrate gap. In co-infusion experiments with C-glucose and C-acetate, which produce distinct labeling patterns in the citric acid cycle intermediates, in six glioblastoma human orthotopic lines derived from patients prior to treatment and one line derived from the progression of one initial line a considerable, tumor-specific and variable consumption of acetate was demonstrated. The finding that the human tumors oxidize acetate was validated in the clinical setting by infusing C-acetate during glioblastoma and brain metastases operations. In contrast, glutamine is taken up by primary and metastatic brain tumors but not metabolized in the citric acid cycle in vivo. In a study published back-to-back with the Mashimo and Pichumani et al paper, Comerford and colleagues demonstrate that the nucleocytosolic acetyl-CoA synthetase enzyme (ACSS2) is expressed and has a critical role in hepatocellular carcinoma, gliomas, and breast and lung cancer for acetate utilization. Immunoreactivity to ACSS2 is correlated with glioma WHO grade (II-IV) and reduced survival in grade II/III gliomas. ACSS2 expression was also correlated with accumulation of mutation in diverse genetic mouse glioma models. Reintroduction of ACSS2 in ACSS2-knockout mouse embryonic fibroblasts enabled these cells to increase acetate incorporation into glutamate. The authors conclude that despite extensive molecular alterations in glioblastoma the ability to oxidize acetate, which is typical for glial cells, is at least maintained. The unexpected finding that metastases to the CNS can metabolize acetate may be discussed as an adaptation to the brain microenvironment or rather a more general property of tumor cells. ACSS2 upregulation is a prerequisite for the tumor cell to convert actetate to acetyl-CoA. Therefore, ACSS2 might be a vulnerability specific to the tumor metabolism. Further, the studies summarized provide nice examples of the relevance of in vivo models for research in cancer metabolism and also the strength of clinical cross-validation.
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Aug 7, 2017
Angad Singh + 4
Open Access