Metabolic Reprogramming and Validation of Hyperpolarized 13C Lactate as a Prostate Cancer Biomarker Using a Human Prostate Tissue Slice Culture Bioreactor
Article first published online: 26 MAR 2013
Copyright © 2013 Wiley Periodicals, Inc.
Volume 73, Issue 11, pages 1171–1181, August 2013
How to Cite
Keshari, K. R., Sriram, R., Van Criekinge, M., Wilson, D. M., Wang, Z. J., Vigneron, D. B., Peehl, D. M. and Kurhanewicz, J. (2013), Metabolic Reprogramming and Validation of Hyperpolarized 13C Lactate as a Prostate Cancer Biomarker Using a Human Prostate Tissue Slice Culture Bioreactor. Prostate, 73: 1171–1181. doi: 10.1002/pros.22665
- Issue published online: 21 JUN 2013
- Article first published online: 26 MAR 2013
- Manuscript Accepted: 26 FEB 2013
- Manuscript Received: 11 JAN 2013
- Department of Defense Synergistic Idea Development Award. Grant Number: W81XWH-10-1-0334
- Postdoctoral Fellowship. Grant Number: W81XWH-12-1-0328
- Peer Reviewed Cancer Research Concept Award
- National Institute of Health. Grant Numbers: P41 EB013598, K99 EB014328, R01 CA166766
- translational biomarkers;
- metabolic flux;
- magnetic resonance spectroscopy
The treatment of prostate cancer has been impeded by the lack of both clinically relevant disease models and metabolic markers that track tumor progression. Hyperpolarized (HP) 13C MR spectroscopy has emerged as a new technology to investigate the metabolic shifts in prostate cancer. In this study, we investigate the glucose reprogramming using HP 13C pyruvate MR in a patient-derived prostate tissue slice culture (TSC) model.
The steady-state metabolite concentrations in freshly excised human prostate TSCs were assessed and compared to those from snap-frozen biopsy samples. The TSCs were then applied to a perfused cell (bioreactor) platform, and the bioenergetics and the dynamic pyruvate flux of the TSCs were investigated by 31P and HP 13C MR, respectively.
The prostate TSCs demonstrated steady-state glycolytic and phospholipid metabolism, and bioenergetics that recapitulate features of prostate cancer in vivo. 13C spectra following injection of HP 13C pyruvate showed significantly increased pyruvate to lactate flux in malignant as compared to the benign prostate TSCs. This increased flux in the malignant prostate TSCs correlated with both increased expression of monocarboxylate transporters (MCT) and activity of lactate dehydrogenase (LDH).
We provide the first mechanistic evidence for HP 13C lactate as a prostate cancer biomarker in living human tissues, critical for the interpretation of in vivo studies. More broadly, the clinically relevant metabolic model system in combination with HP MR can facilitate the identification of clinically translatable biomarkers of prostate cancer presence, aggressiveness, and treatment response. Prostate 73: 1171–1181, 2013. © 2013 Wiley Periodicals, Inc.