Abstract
Oncogenetic events and unique phenomena of the tumor microenvironment together induce adaptive metabolic responses that may offer new diagnostic tools and therapeutic targets of cancer. Hypoxia, or low oxygen tension, represents a well-established and universal feature of the tumor microenvironment and has been linked to increased tumor aggressiveness as well as resistance to conventional oncological treatments. Previous studies have provided important insights into hypoxia induced changes of the transcriptome and proteome; however, how this translates into changes at the metabolite level remains to be defined. Here, we have investigated dynamic, time-dependent effects of hypoxia on the cancer cell metabolome across all families of macromolecules, i.e., carbohydrate, protein, lipid and nucleic acid, in human glioblastoma cells. Using GC/MS and LC/MS/MS, 345 and 126 metabolites were identified and quantified in cells and corresponding media, respectively, at short (6 h), intermediate (24 h), and prolonged (48 h) incubation at normoxic or hypoxic (1% O2) conditions. In conjunction, we performed gene array studies with hypoxic and normoxic cells following short and prolonged incubation. We found that levels of several key metabolites varied with the duration of hypoxic stress. In some cases, metabolic changes corresponded with hypoxic regulation of key pathways at the transcriptional level. Our results provide new insights into the metabolic response of glioblastoma cells to hypoxia, which should stimulate further work aimed at targeting cancer cell adaptive mechanisms to microenvironmental stress.
Highlights
Glioblastoma (GBM) constitutes the most common type of primary tumors of the brain, and is characterized by severe hypoxia, vascular hyperproliferation and therapy resistance
Quantitative analysis of compounds upor down-regulated in hypoxic compared with normoxic GBM cells indicated that significant metabolic changes were mainly observed at prolonged exposure to hypoxia (Fig. 1D and S1 Table)
Transcriptional activation of enzymes involved in cystathionine-betasynthase (CBS), cystathionine gamma-lyase (CTH), and glutamate-cysteine ligase (GCLC) (Fig. 7M), may support increased synthesis of cysteine and glutathione in hypoxic GBM cells. It is well-established that hypoxia and down-stream features of the tumor microenvironment, e.g. acidosis correlate with GBM tumor aggressiveness and patient outcome
Summary
Glioblastoma (GBM) constitutes the most common type of primary tumors of the brain, and is characterized by severe hypoxia, vascular hyperproliferation and therapy resistance. Radiochemotherapy and adjuvant chemotherapy the median overall survival of GBM patients is only approx. Hypoxia is primarily a pathophysiologic consequence of uncontrolled tumor growth, resulting in structurally and functionally disturbed microcirculation [2, 3]. It is a major driver of cancer progression as it provides a strong selective pressure resulting in the survival and propagation of the most aggressive malignant.
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