Abstract
Non-invasive assessment of the biological aggressiveness of prostate cancer (PCa) is needed for men with localized disease. Hyperpolarized (HP) 13C magnetic resonance (MR) spectroscopy is a powerful approach to image metabolism, specifically the conversion of HP [1-13C]pyruvate to [1-13C]lactate, catalyzed by lactate dehydrogenase (LDH). Significant increase in tumor lactate was measured in high-grade PCa relative to benign and low-grade cancer, suggesting that HP 13C MR could distinguish low-risk (Gleason score ≤3 + 4) from high-risk (Gleason score ≥4 + 3) PCa. To test this and the ability of HP 13C MR to detect these metabolic changes, we cultured prostate tissues in an MR-compatible bioreactor under continuous perfusion. 31P spectra demonstrated good viability and dynamic HP 13C-pyruvate MR demonstrated that high-grade PCa had significantly increased lactate efflux compared to low-grade PCa and benign prostate tissue. These metabolic differences are attributed to significantly increased LDHA expression and LDH activity, as well as significantly increased monocarboxylate transporter 4 (MCT4) expression in high- versus low- grade PCa. Moreover, lactate efflux, LDH activity, and MCT4 expression were not different between low-grade PCa and benign prostate tissues, indicating that these metabolic alterations are specific for high-grade disease. These distinctive metabolic alterations can be used to differentiate high-grade PCa from low-grade PCa and benign prostate tissues using clinically translatable HP [1-13C]pyruvate MR.
Highlights
A pressing need facing the clinical management of men with primary prostate cancer (PCa) is an accurate method for distinguishing indolent from aggressive, potentially lethal, cancer in individualCancers 2020, 12, 537; doi:10.3390/cancers12030537 www.mdpi.com/journal/cancersCancers 2020, 12, 537 patients [1]
To test the hypothesis that tumor tissue lactate concentrations increase in a Gleason grade-dependent fashion in PCa, lactate concentrations were measured in snap-frozen prostate biopsies using quantitative 1 H high resolution–magic angle spinning (HR–MAS) nuclear magnetic resonance (NMR) spectroscopy
Consistent with prior preclinical HP 13 C magnetic resonance (MR) publications involving murine models, the progression from low- to high-grade human PCa resulted in a significant increase in lactate and an associated increase in lactate dehydrogenase (LDH) activity in living prostate tissue cultures
Summary
A pressing need facing the clinical management of men with primary prostate cancer (PCa) is an accurate method for distinguishing indolent from aggressive, potentially lethal, cancer in individualCancers 2020, 12, 537; doi:10.3390/cancers12030537 www.mdpi.com/journal/cancersCancers 2020, 12, 537 patients [1]. Screening for PCa with a serum prostate-specific antigen (PSA) test has reduced mortality through identification and treatment of high-risk cancer at an earlier time-point, but at the cost of over-diagnosis and over-treatment of low-risk tumors with questionable benefit for many patients [3,4,5,6] This dilemma reflects the biological heterogeneity of PCa and incites efforts to distinguish the small number of patients having aggressive PCa who will benefit from therapeutic intervention and the larger proportion of patients whose tumors are unlikely to progress [1,7,8,9,10,11]. The current state-of-the-art for imaging localized PCa, multiparametric 1 H magnetic resonance imaging (MRI), has demonstrated the ability to localize tumors for subsequent biopsy and treatment, but cannot consistently grade tumor aggressiveness accurately in individual patients [16]
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