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Breast Cancer Redox Heterogeneity Detectable with Chemical Exchange Saturation Transfer (CEST) MRI

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Abstract

Purpose

Tissue redox state is an important mediator of various biological processes in health and diseases such as cancer. Previously, we discovered that the mitochondrial redox state of ex vivo tissues detected by redox scanning (an optical imaging method) revealed interesting tumor redox state heterogeneity that could differentiate tumor aggressiveness. Because the noninvasive chemical exchange saturation transfer (CEST) MRI can probe the proton transfer and generate contrasts from endogenous metabolites, we aim to investigate if the in vivo CEST contrast is sensitive to proton transfer of the redox reactions so as to reveal the tissue redox states in breast cancer animal models.

Procedures

CEST MRI has been employed to characterize tumor metabolic heterogeneity and correlated with the redox states measured by the redox scanning in two human breast cancer mouse xenograft models, MDA-MB-231 and MCF-7. The possible biological mechanism on the correlation between the two imaging modalities was further investigated by phantom studies where the reductants and the oxidants of the representative redox reactions were measured.

Results

The CEST contrast is found linearly correlated with NADH concentration and the NADH redox ratio with high statistical significance, where NADH is the reduced form of nicotinamide adenine dinucleotide. The phantom studies showed that the reductants of the redox reactions have more CEST contrast than the corresponding oxidants, indicating that higher CEST effect corresponds to the more reduced redox state.

Conclusions

This preliminary study suggests that CEST MRI, once calibrated, might provide a novel noninvasive imaging surrogate for the tissue redox state and a possible diagnostic biomarker for breast cancer in the clinic.

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Acknowledgments

The authors thank Drs. Steve Pickup and Weixia Liu for their technical assistance with animal MRI scanners. This work was supported by the National Center for Research Resources and the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health through grant number P41 EB015893 and NIH grants R21-DA032256, R01-CA155348, and 2U24-CA083105. The work was also supported by a grant from Susan G. Komen Research Foundation (KG081069).

Conflict of Interest

The authors disclose no potential conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Radiology, University of Illinois College of Medicine, Chicago, IL, USA

    Kejia Cai

  2. Center for Magnetic Resonance and Optical Imaging (CMROI), Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA

    Kejia Cai, Anup Singh, Mohammad Haris & Ravinder Reddy

  3. Molecular Imaging Section, Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA

    He N. Xu, Lily Moon & Lin Z. Li

  4. Britton Chance Laboratory of Redox Imaging, Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA

    He N. Xu, Lily Moon & Lin Z. Li

  5. Research Branch Sidra Medical and Research Center, Doha, Qatar

    Mohammad Haris

  6. Center for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi, India

    Anup Singh

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  1. Kejia Cai
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Correspondence to Kejia Cai.

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Cai, K., Xu, H.N., Singh, A. et al. Breast Cancer Redox Heterogeneity Detectable with Chemical Exchange Saturation Transfer (CEST) MRI. Mol Imaging Biol 16, 670–679 (2014). https://doi.org/10.1007/s11307-014-0739-y

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