Abstract
BackgroundCancer metabolism is emerging as an important focus area in cancer research. However, the in vitro cell culture conditions under which much cellular metabolism research is performed differ drastically from in vivo tumor conditions, which are characterized by variations in the levels of oxygen, nutrients like glucose, and other molecules like chemotherapeutics. Moreover, it is important to know how the diverse cell types in a tumor, including cancer stem cells that are believed to be a major cause of cancer recurrence, respond to these variations. Here, in vitro environmental perturbations designed to mimic different aspects of the in vivo environment were used to characterize how an ovarian cancer cell line and its derived, isogenic cancer stem cells metabolically respond to environmental cues.ResultsMass spectrometry was used to profile metabolite levels in response to in vitro environmental perturbations. Docetaxel, the chemotherapeutic used for this experiment, caused significant metabolic changes in amino acid and carbohydrate metabolism in ovarian cancer cells, but had virtually no metabolic effect on isogenic ovarian cancer stem cells. Glucose deprivation, hypoxia, and the combination thereof altered ovarian cancer cell and cancer stem cell metabolism to varying extents for the two cell types. Hypoxia had a much larger effect on ovarian cancer cell metabolism, while glucose deprivation had a greater effect on ovarian cancer stem cell metabolism. Core metabolites and pathways affected by these perturbations were identified, along with pathways that were unique to cell types or perturbations.ConclusionsThe metabolic responses of an ovarian cancer cell line and its derived isogenic cancer stem cells differ greatly under most conditions, suggesting that these two cell types may behave quite differently in an in vivo tumor microenvironment. While cancer metabolism and cancer stem cells are each promising potential therapeutic targets, such varied behaviors in vivo would need to be considered in the design and early testing of such treatments.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-014-0134-y) contains supplementary material, which is available to authorized users.
Highlights
Cancer metabolism is emerging as an important focus area in cancer research
Lists of annotated metabolites in this work come from unique matches to known human metabolites in either the Kyoto Encyclopedia of Genes and Genomes (KEGG) or the Human Metabolome Database (HMDB), followed by a manual confirmation of similarity between the annotated peak spectrum and the library spectrum
In this study, ovarian cancer cells (OCCs) and ovarian cancer stem cells (OCSCs) from our model system were for the first time shown to have different metabolic responses to biologically-based perturbations applied in vitro to mimic in vivo tumor conditions
Summary
The in vitro cell culture conditions under which much cellular metabolism research is performed differ drastically from in vivo tumor conditions, which are characterized by variations in the levels of oxygen, nutrients like glucose, and other molecules like chemotherapeutics. In vitro environmental perturbations designed to mimic different aspects of the in vivo environment were used to characterize how an ovarian cancer cell line and its derived, isogenic cancer stem cells metabolically respond to environmental cues. Along with poor cellular growth conditions, most tumors are treated with chemotherapeutics to attempt to eradicate the tumor. These differences in environmental conditions can be critical in correctly understanding and treating cancer cells. It is critical to attempt to study cancer cells grown in vitro under conditions relevant to their natural tumor environment
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