Metabolic Reprogramming and Validation of Hyperpolarized¹³C 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) 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. 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 31P and HP 13C MR, respectively. RESULTS 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). CONCLUSIONS 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.

Metabolic Imaging of Patients with Prostate Cancer Using Hyperpolarized [1- 13 C]Pyruvate

“…The [1- 13 C]lactate signal was low or undetectable in slices from regions of the prostate that did not include tumor. This agrees with previous patient prostate biopsy studies, which demonstrated very low lactate concentrations (30), and with preclinical studies, which demonstrated a low flux of hyperpolarized [1- 13 C]pyruvate to lactate in normal prostate (17). The 2D dynamic MRSI data were able to distinguish signals from tumor and vessels, with the rate of [1- 13 C]pyruvate to [1- 13 C]lactate conversion being four to five times higher in tumor.…”

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…Consistently, lactate dehydrogenase B, which catalyzes the lactate to pyruvate conversion, is suppressed [131,134]. This is further functionally supported by experiments with hyperpolarized pyruvate, where in situ tumors convert pyruvate into lactate [135][136][137]. Thus, it is questionable whether cells in vivo exchange lactate or rather other substrates (e.g.…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…re lease large amounts of lac tate in vivo [259][260][261]. Al though stud ies on cell cul tures showed that mi to chon dr ial res pi ra tion is lim ited in sev eral can cer cell lines [262][263][264], in vivo data showed that mi to chon dr ial oxy gen con sump tion is not im paired in tu mors and that ox ida tive glu cose me tab o lism is re quired for tu mor growth [265].…”