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Cancers 2017, 9(12), 168; https://doi.org/10.3390/cancers9120168

Tracking Functional Tumor Cell Subpopulations of Malignant Glioma by Phasor Fluorescence Lifetime Imaging Microscopy of NADH

1
Laboratory for Fluorescence Dynamics and Department of Biomedical Engineering, University of California, Irvine, CA 92697, USA
2
UC Irvine Diabetes Center and Department of Medicine, University of California, Irvine, CA 92697, USA
3
UC Irvine Brain Tumor Laboratory and Department of Surgery, University of California, Irvine, CA 92697, USA
4
Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
*
Authors to whom correspondence should be addressed.
Received: 8 November 2017 / Revised: 27 November 2017 / Accepted: 1 December 2017 / Published: 6 December 2017
(This article belongs to the Special Issue Chromosomal Instability and Cancers)
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Abstract

Intra-tumoral heterogeneity is associated with therapeutic resistance of cancer and there exists a need to non-invasively identify functional tumor subpopulations responsible for tumor recurrence. Reduced nicotinamide adenine dinucleotide (NADH) is a metabolic coenzyme essential in cellular respiration. Fluorescence lifetime imaging microscopy (FLIM) of NADH has been demonstrated to be a powerful label-free indicator for inferring metabolic states of living cells. Using FLIM, we identified a significant shift towards longer NADH fluorescence lifetimes, suggesting an increase in the fraction of protein-bound NADH, in the invasive stem-like tumor-initiating cell (STIC) subpopulation relative to the tumor mass-forming cell (TMC) subpopulation of malignant gliomas. By applying our previously studied model to transition glioma from a majority of STIC to a majority of TMC in serum-adherent culture conditions following serial passages, we compared changes in NADH states, cellular respirations (oxidative phosphorylation and glycolysis), EGFR expression, and cell-growth speed over passages. We identified a significant positive correlation between free-NADH fraction and cell growth, which was related to an increase of TMC fraction. In comparison, the increase of EGFR and cellular respirations preceded all these changes. In conclusion, FLIM of NADH provides a non-invasive method to monitor the dynamics of tumor heterogeneity before and after treatment. View Full-Text
Keywords: Reduced nicotinamide adenine dinucleotide (NADH); cellular bioenergetics; malignant glioma; tumor cell subpopulation; fluorescence lifetime imaging microscopy (FLIM); stem-like tumor-initiating cells; tumor mass cells; intra-tumoral heterogeneity Reduced nicotinamide adenine dinucleotide (NADH); cellular bioenergetics; malignant glioma; tumor cell subpopulation; fluorescence lifetime imaging microscopy (FLIM); stem-like tumor-initiating cells; tumor mass cells; intra-tumoral heterogeneity
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Trinh, A.L.; Chen, H.; Chen, Y.; Hu, Y.; Li, Z.; Siegel, E.R.; Linskey, M.E.; Wang, P.H.; Digman, M.A.; Zhou, Y.-H. Tracking Functional Tumor Cell Subpopulations of Malignant Glioma by Phasor Fluorescence Lifetime Imaging Microscopy of NADH. Cancers 2017, 9, 168.

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