Vermeersch Kathleen A, Wang Lijuan, McDonald John F, Styczynski Mark P
School of Chemical & Biomolecular Engineering and Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, 311 Ferst Dr, Atlanta, GA, 30332-0100, USA.
Ovarian Cancer Institute, School of Biology, and Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr, Atlanta, GA, 30332-0363, USA.
BMC Syst Biol. 2014 Dec 18;8:134. doi: 10.1186/s12918-014-0134-y.
Cancer 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.
Mass 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.
The 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.
癌症代谢正成为癌症研究中的一个重要重点领域。然而，许多细胞代谢研究在其中进行的体外细胞培养条件与体内肿瘤条件截然不同，体内肿瘤条件的特征是氧气水平、葡萄糖等营养物质以及化疗药物等其他分子存在差异。此外，了解肿瘤中的多种细胞类型，包括被认为是癌症复发主要原因的癌症干细胞，如何对这些差异做出反应也很重要。在此，通过设计旨在模拟体内环境不同方面的体外环境扰动，来表征一种卵巢癌细胞系及其衍生的同基因癌症干细胞如何对环境线索做出代谢反应。
使用质谱分析来描绘代谢物水平对体外环境扰动的反应。用于该实验的化疗药物多西他赛在卵巢癌细胞中引起了氨基酸和碳水化合物代谢的显著变化，但对同基因卵巢癌干细胞几乎没有代谢影响。葡萄糖剥夺、缺氧及其组合对这两种细胞类型的卵巢癌细胞和癌症干细胞代谢产生了不同程度的改变。缺氧对卵巢癌细胞代谢的影响更大，而葡萄糖剥夺对卵巢癌干细胞代谢的影响更大。确定了受这些扰动影响的核心代谢物和途径，以及细胞类型或扰动特有的途径。
在大多数情况下，卵巢癌细胞系及其衍生的同基因癌症干细胞的代谢反应差异很大，这表明这两种细胞类型在体内肿瘤微环境中的行为可能大不相同。虽然癌症代谢和癌症干细胞都是有前景的潜在治疗靶点，但在设计和早期测试此类治疗方法时，需要考虑它们在体内的这种不同行为。
