The Role of Lactate Metabolism in Prostate Cancer Progression and Metastases Revealed by Dual-Agent Hyperpolarized 13C MRSI

Abstract

This study applied a dual-agent, 13C-pyruvate and 13C-urea, hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) and multi-parametric (mp) 1H magnetic resonance imaging (MRI) approach in the transgenic adenocarcinoma of mouse prostate (TRAMP) model to investigate changes in tumor perfusion and lactate metabolism during prostate cancer development, progression and metastases, and after lactate dehydrogenase-A (LDHA) knock-out. An increased Warburg effect, as measured by an elevated hyperpolarized (HP) Lactate/Pyruvate (Lac/Pyr) ratio, and associated Ldha expression and LDH activity were significantly higher in high- versus low-grade TRAMP tumors and normal prostates. The hypoxic tumor microenvironment in high-grade tumors, as measured by significantly decreased HP 13C-urea perfusion and increased PIM staining, played a key role in increasing lactate production through increased Hif1α and then Ldha expression. Increased lactate induced Mct4 expression and an acidic tumor microenvironment that provided a potential mechanism for the observed high rate of lymph node (86%) and liver (33%) metastases. The Ldha knockdown in the triple-transgenic mouse model of prostate cancer resulted in a significant reduction in HP Lac/Pyr, which preceded a reduction in tumor volume or apparent water diffusion coefficient (ADC). The Ldha gene knockdown significantly reduced primary tumor growth and reduced lymph node and visceral metastases. These data suggested a metabolic transformation from low- to high-grade prostate cancer including an increased Warburg effect, decreased perfusion, and increased metastatic potential. Moreover, these data suggested that LDH activity and lactate are required for tumor progression. The lactate metabolism changes during prostate cancer provided the motivation for applying hyperpolarized 13C MRSI to detect aggressive disease at diagnosis and predict early therapeutic response.

Hyperpolarized 13C-pyruvate MRI detects real-time metabolic flux in prostate cancer metastases to bone and liver: a clinical feasibility study

“…c In addition, serum PSA decreased from 38-13.4 ng/ml also indicating therapeutic response. HA arterial phase, PV portal venous phase therapy [28][29][30]. The high Ldha expression relative to Pdha1 in this study was consistent with a larger published mCRPC cohort [6], reflective of enhanced aerobic glycolysis, whereas in normal prostate epithelial cells the glucose metabolism favors oxidative phosphorylation, and Pdha1 expression should predominate (Fig.…”

Hyperpolarized in vivo pH imaging reveals grade-dependent acidification in prostate cancer

“…We chose to use the genetically engineered TRAMP mouse model in order to study metabolic, morphologic, and microenvironmental changes. This mouse model is known to recapitulate the phenotype of human prostate cancer, particularly with regards to lactate metabolism [8, 14, 30], and progresses through low- and high-grade stages analogous to human prostate cancer [31]. We performed HP and conventional MR imaging on a total of 10 TRAMP mice.…”

“…In particular, increased lactic acid export via monocarboxylate transporter 4 (MCT4) overexpression has been observed in high-grade renal cell carcinoma cell lines [12] and patient-derived tissue slices [13]. The MCT4 transporter is overexpressed in aggressive murine prostate cancer [14] and patient-derived tissue slices [15]. Although this increase in lactic acid efflux can be measured in vivo using diffusion-weighted imaging [16], the inherent changes in cellularity with tumor grade in prostate cancer obfuscate the changes in the apparent diffusion coefficient and reduce the dynamic range between intracellular and extracellular compartments.…”

Elevated Tumor Lactate and Efflux in High-grade Prostate Cancer demonstrated by Hyperpolarized 13C Magnetic Resonance Spectroscopy of Prostate Tissue Slice Cultures

“…Specifically, there was a 1.6-fold increase in LDHA expression in high-versus low-grade PCa. LDHA expression levels have been previously correlated with prostate cancer progression, metastasis, and biochemical recurrence [41,42]. Unfortunately, the ability to detect tissue lactate in in vivo 1 H MRSI studies of PCa is inhibited by large contributions from lipids that surround the prostate and whose resonances overlap the lactate resonance chemical shift [20].…”