title: Metabolic reprogramming and validation of hyperpolarized 13C lactate as a prostate cancer biomarker using a human prostate tissue slice culture bioreactor.
abstract: BACKGROUND
  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) (13) C 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 (13) C pyruvate MR in a patient-derived prostate tissue slice culture (TSC) model.
  
  
  METHODS
  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 (31) P and HP (13) C MR, respectively.
  
  
  RESULTS
  The prostate TSCs demonstrated steady-state glycolytic and phospholipid metabolism, and bioenergetics that recapitulate features of prostate cancer in vivo. (13) C spectra following injection of HP (13) C 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).
  
  
  CONCLUSIONS
  We provide the first mechanistic evidence for HP (13) C 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.
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
authors.forename: Kayvan R
authors.initials: KR
authors.lastname: Keshari
authors.forename: Renuka
authors.initials: R
authors.lastname: Sriram
authors.forename: Mark
authors.initials: M
authors.lastname: Van Criekinge
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.forename: Zhen J
authors.initials: ZJ
authors.lastname: Wang
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Vigneron
authors.forename: Donna M
authors.initials: DM
authors.lastname: Peehl
authors.forename: John
authors.initials: J
authors.lastname: Kurhanewicz
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D019149:Bioreactors; D002247:Carbon Isotopes; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000502:physiology; D009924:Organ Culture Techniques; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D002247:Carbon Isotopes; D019344:Lactic Acid