Hyperpolarized in vivo pH imaging reveals grade-dependent acidification in prostate cancer
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David E. Korenchan1, Robert Bok1, Renuka Sriram1, Kristina Liu5, Romelyn Delos Santos1, Hecong Qin1, Iryna Lobach2, Natalie Korn1, David M. Wilson1, John Kurhanewicz1,3,4 and Robert R. Flavell1,3
1 Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA
2 Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
3 Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA
4 Department of Urology, University of California, San Francisco, CA, USA
5 Department of Physical Chemistry, Technical University of Munich, Munich, Germany
|Robert R. Flavell,||email:||[email protected]|
Keywords: prostate cancer; extracellular pH; hyperpolarization; MRI; metabolism
Received: August 01, 2019 Accepted: September 10, 2019 Published: October 22, 2019
There is an unmet clinical need for new and robust imaging biomarkers to distinguish indolent from aggressive prostate cancer. Hallmarks of aggressive tumors such as a decrease in extracellular pH (pHe) can potentially be used to identify aggressive phenotypes. In this study, we employ an optimized, high signal-to-noise ratio hyperpolarized (HP) 13C pHe imaging method to discriminate between indolent and aggressive disease in a murine model of prostate cancer. Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice underwent a multiparametric MR imaging exam, including HP [13C] bicarbonate MRI for pHe, with 1H apparent diffusion coefficient (ADC) mapping and HP [1-13C] pyruvate MRI to study lactate metabolism. Tumor tissue was excised for histological staining and qRT-PCR to quantify mRNA expression for relevant glycolytic enzymes and transporters. We observed good separation in pHe between low- and high-grade tumor regions, with high-grade tumors demonstrating a lower pHe. The pHe also correlated strongly with monocarboxylate transporter Mct4 gene expression across all tumors, suggesting that lactate export via MCT4 is associated with acidification in this model. Our results implicate extracellular acidification as an indicator of indolent-to-aggressive transition in prostate cancer and suggest feasibility of HP pHe imaging to detect high-grade, clinically significant disease in men as part of a multiparametric MRI examination.
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