Abstract
BackgroundCancer stem cells (CSCs) are highly tumorigenic and are responsible for tumor progression and chemoresistance. Noninvasive imaging methods for the visualization of CSC populations within tumors in vivo will have a considerable impact on the development of new CSC-targeting therapeutics.Methodology/Principal FindingsIn this study, human breast cancer stem cells (BCSCs) transduced with dual reporter genes (human ferritin heavy chain [FTH] and enhanced green fluorescence protein [EGFP]) were transplanted into NOD/SCID mice to allow noninvasive tracking of BCSC-derived populations. No changes in the properties of the BCSCs were observed due to ferritin overexpression. Magnetic resonance imaging (MRI) revealed significantly different signal intensities (R2* values) between BCSCs and FTH-BCSCs in vitro and in vivo. In addition, distinct populations of pixels with high R2* values were detected in docetaxel-treated FTH-BCSC tumors compared with control tumors, even before the tumor sizes changed. Histological analysis revealed that areas showing high R2* values in docetaxel-treated FTH-BCSC tumors by MRI contained EGFP+/FTH+ viable cell populations with high percentages of CD44+/CD24− cells.Conclusions/SignificanceThese findings suggest that ferritin-based MRI, which provides high spatial resolution and tissue contrast, can be used as a reliable method to identify viable cell populations derived from BCSCs after chemotherapy and may serve as a new tool to monitor the efficacy of CSC-targeting therapies in vivo.
Highlights
Since the first identification of breast cancer stem cells (BCSCs) from human tumor samples using CD44+/CD242 markers by Al-Hajj et al, the role of BCSCs in tumor progression and therapeutic resistance has been actively investigated to develop better anti-cancer treatment strategies [1,2]
Conclusions/Significance: These findings suggest that ferritin-based Magnetic resonance imaging (MRI), which provides high spatial resolution and tissue contrast, can be used as a reliable method to identify viable cell populations derived from BCSCs after chemotherapy and may serve as a new tool to monitor the efficacy of CSC-targeting therapies in vivo
The cellular iron levels of both groups increased in a dose-dependent manner, but the FTH-BCSCs had significantly higher iron levels compared with the BCSCs (Figure 1E; P,0.05 in 25 and 50 mM of ferric ammonium citrate (FAC))
Summary
Since the first identification of breast cancer stem cells (BCSCs) from human tumor samples using CD44+/CD242 markers by Al-Hajj et al, the role of BCSCs in tumor progression and therapeutic resistance has been actively investigated to develop better anti-cancer treatment strategies [1,2]. Monitoring the efficacy of cancer stem cell (CSC) therapeutics in vivo, is challenging because the conventional method of measuring tumor size is inadequate as an endpoint [7]. In vivo identification of BCSCs using cellular imaging techniques will be extremely useful for this purpose because the efficacy of treatment depends more on the fraction of viable cancer cells in the tumor [8,9]. Noninvasive imaging methods for the visualization of CSC populations within tumors in vivo will have a considerable impact on the development of new CSC-targeting therapeutics
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