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

Abstract

There is an unmet clinical need for new and robust imaging biomarkers to distinguish indolent from aggressive prostate cancer. Hallmarks of aggressive tumors such as a decrease in extracellular pH (pHe) can potentially be used to identify aggressive phenotypes. In this study, we employ an optimized, high signal-to-noise ratio hyperpolarized (HP) 13C pHe imaging method to discriminate between indolent and aggressive disease in a murine model of prostate cancer. Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice underwent a multiparametric MR imaging exam, including HP [13C] bicarbonate MRI for pHe, with 1H apparent diffusion coefficient (ADC) mapping and HP [1-13C] pyruvate MRI to study lactate metabolism. Tumor tissue was excised for histological staining and qRT-PCR to quantify mRNA expression for relevant glycolytic enzymes and transporters. We observed good separation in pHe between low- and high-grade tumor regions, with high-grade tumors demonstrating a lower pHe. The pHe also correlated strongly with monocarboxylate transporter Mct4 gene expression across all tumors, suggesting that lactate export via MCT4 is associated with acidification in this model. Our results implicate extracellular acidification as an indicator of indolent-to-aggressive transition in prostate cancer and suggest feasibility of HP pHe imaging to detect high-grade, clinically significant disease in men as part of a multiparametric MRI examination.

Spatiotemporal pH Heterogeneity as a Promoter of Cancer Progression and Therapeutic Resistance

“…We hypothesized that pH e would decrease based on prior data indicating increased production of lactic acid in high-grade tumors [62], as well as the observation that treatment with sodium bicarbonate blocked tumorigenesis in this model [63]. Supporting the hypothesis, we found that there was a significant decrease in pH e in mice bearing high-grade tumors compared against low-grade counterparts [64]. Therefore, there is an accumulating body of both indirect and direct evidence supporting the hypothesis that a temporal decrease in pH e could represent a biomarker of tumor disease progression.…”

Sodium bicarbonate transporter NBCe1 regulates proliferation and viability of human prostate cancer cells LNCaP and PC3

“…As in other cancers, acidic microenvironments in prostate cancer are also considered to be an important prognostic factor (23). Acidic pH o can be used as a robust imaging biomarker for aggressive prostate cancer (24). Pharmacological inhibition or knockdown of several acid extrusion transporters, such as Na/H exchangers NHEs (25), V-ATPases (26,27) and monocarboxylate transporters MCTs (28), prevents prostate cancer progression in vivo and in vitro.…”

Cardiac pH-Imaging With Hyperpolarized MRI

“…But the technique may have even more to offer in prognostication, patient selection and early treatment evaluation. For example, from the field of oncology, metabolic assessment with hyperpolarized MRI is reported to correlate with tumor grade ( 36 , 51 , 52 ) and depict the early metabolic response to chemotherapy ( 32 , 53 , 54 ). In cardiology, hyperpolarized MRI could be useful for selecting patients for novel metabolic or pH-altering therapy in heart failure ( 1 ), or for detecting the severity, reversibility and localization of ischemia in coronary artery disease.…”