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In Vivo Electron Paramagnetic Resonance Molecular Profiling of Tumor Microenvironment upon Tumor Progression to Malignancy in an Animal Model of Breast Cancer

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Abstract

Purpose

Hypoxia and acidosis are recognized tumor microenvironment (TME) biomarkers of cancer progression. Alterations in cancer redox status and metabolism are also associated with elevated levels of intracellular glutathione (GSH) and interstitial inorganic phosphate (Pi). This study aims to evaluate the capability of these biomarkers to discriminate between stages and inform on a switch to malignancy.

Procedures

These studies were performed using MMTV-PyMT( +) female transgenic mice that spontaneously develop breast cancer and emulate human tumor staging. In vivo assessment of oxygen concentration (pO2), extracellular acidity (pHe), Pi, and GSH was performed using L-band electron paramagnetic resonance spectroscopy and multifunctional trityl and GSH-sensitive nitroxide probes.

Results

Profiling of the TME showed significant deviation of measured biomarkers upon tumor progression from pre-malignancy (pre-S4) to the malignant stage (S4). For the combined marker, HOP: (pHe × pO2)/Pi, a value > 186 indicated that the tumors were pre-malignant in 85% of the mammary glands analyzed, and when < 186, they were malignant 42% of the time. For GSH, a value < 3 mM indicated that the tumors were pre-malignant 74% of the time, and when > 3 mM, they were malignant 80% of the time. The only marker that markedly deviated as early as stage 1 (S1) from its value in pre-S1 was elevated Pi, followed by a decrease of pHe and pO2 and increase in GSH at later stages.

Conclusion

Molecular TME profiling informs on alteration of tumor redox and metabolism during tumor staging. Early elevation of interstitial Pi at S1 may reflect tumor metabolic alterations that demand elevated phosphorus supply in accordance with the high rate growth hypothesis. These metabolic changes are supported by the following decrease of pHe due to a high tumor reliance on glycolysis and increase of intracellular GSH, a major intracellular redox buffer. The appreciable decrease in TME pO2 was observed only at malignant S4, apparently as a consequence of tumor mass growth and corresponding decrease in perfusion efficacy and increase in oxygen consumption as the tumor cells proliferate.

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Funding

This work was partially supported by NIH grants CA194013, CA192064, EB028553, EB023990, and U54GM104942.

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Authors and Affiliations

  1. In Vivo Multifunctional Magnetic Resonance Center, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV, 26506, USA

    Timothy D. Eubank, Andrey A. Bobko, E. Hannah Hoblitzell, Marieta Gencheva, Benoit Driesschaert & Valery V. Khramtsov

  2. Department of Microbiology, Immunology, and Cell Biology, School of Medicine, West Virginia University, Morgantown, WV, 26506, USA

    Timothy D. Eubank & E. Hannah Hoblitzell

  3. Department of Biochemistry and Molecular Medicine, School of Medicine, West Virginia University, Morgantown, WV, 26506, USA

    Andrey A. Bobko, Marieta Gencheva & Valery V. Khramtsov

  4. Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, 26506, USA

    Benoit Driesschaert

  5. C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV, 26506, USA

    Benoit Driesschaert

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Eubank, T.D., Bobko, A.A., Hoblitzell, E.H. et al. In Vivo Electron Paramagnetic Resonance Molecular Profiling of Tumor Microenvironment upon Tumor Progression to Malignancy in an Animal Model of Breast Cancer. Mol Imaging Biol (2023). https://doi.org/10.1007/s11307-023-01847-0

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