Physiological impact of in vivo stable isotope tracing on cancer metabolism

• Published in: Molecular metabolism (Germany) Vol. 53; p. 101294
• Main Authors: Grima-Reyes, Manuel, Martinez-Turtos, Adriana, Abramovich, Ifat, Gottlieb, Eyal, Chiche, Johanna, Ricci, Jean-Ehrland
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01-11-2021; Elsevier
• Subjects: Animals; Fasting; Humans; Interorgan exchange; Isotope Labeling; Life Sciences; Neoplasms - metabolism; Review; Stable isotope tracing; Tracer administration; Tumor metabolism; Stable isotope tracing; Tumor metabolism; Fasting; Tracer administration; Interorgan exchange; Inter-organ exchange
• DOI: 10.1016/j.molmet.2021.101294
• EISSN: 2212-8778

There is growing interest in the analysis of tumor metabolism to identify cancer-specific metabolic vulnerabilities and therapeutic targets. Finding of such candidate metabolic pathways mainly relies on the highly sensitive identification and quantitation of numerous metabolites and metabolic fluxes using metabolomics and isotope tracing analyses. However, nutritional requirements and metabolic routes used by cancer cells cultivated in vitro do not always reflect the metabolic demands of malignant cells within the tumor milieu. Therefore, to understand how the metabolism of tumor cells in its physiological environment differs from that of normal cells, these analyses must be performed in vivo.
This review covers the physiological impact of the exogenous administration of a stable isotope tracer into cancer animal models. We discuss specific aspects of in vivo isotope tracing protocols based on discrete bolus injections of a labeled metabolite: the tracer administration per se and the fasting period prior to it. In addition, we illustrate the complex physiological scenarios that arise when studying tumor metabolism – by isotopic labeling in animal models fed with a specific amino acid restricted diet. Finally, we provide strategies to minimize these limitations.
There is growing evidence that metabolic dependencies in cancers are influenced by tissue environment, cancer lineage, and genetic events. An increasing number of studies describe discrepancies in tumor metabolic dependencies when studied in in vitro settings or in vivo models, including cancer patients. Therefore, in-depth in vivo profiling of tumor metabolic routes within the appropriate pathophysiological environment will be key to identify relevant alterations that contribute to cancer onset and progression.
•In vivo isotope tracing is the state-of-the-art approach to study tumor metabolism.•In vivo tracer administration challenges the physiological metabolism of mice.•Interorgan conversion of the tracer might confound tumor labeling patterns.•Mouse fasting before in vivo tracing impacts on systemic and tumor metabolism.•Optimization is key to minimize physiological alterations linked to in vivo tracing.