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

David E Korenchan,Renuka Sriram,Natalie Korn,Hecong Qin,Kristina Liu,Romelyn Delos Santos,Iryna Lobach,Robert Bok,David M Wilson,Robert R Flavell,John Kurhanewicz

doi:10.18632/oncotarget.27225

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.

Highlights

Current clinical management of prostate cancer is lacking in the ability to confidently distinguish indolent from aggressive tumors
We developed and implemented a new multiparametric magnetic resonance (MR) protocol to study extracellular acidification, glycolytic metabolism, and tumor cellularity in a single imaging exam (Figure 1)
We chose to use the genetically engineered Transgenic adenocarcinoma of the mouse prostate (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, with regards to lactate metabolism [8, 14, 30], and progresses through low- and high-grade stages analogous to human prostate cancer [31]

Summary

Introduction

Current clinical management of prostate cancer is lacking in the ability to confidently distinguish indolent from aggressive tumors. For patients with prostate tumors that are likely indolent, typically having less than 0.5 cc of volume and a Gleason grade below 3+3, active surveillance represents a clinical standard for detecting indolent-to-aggressive transition [3]. In particular multiparametric 1H MRI, plays a prominent role in active surveillance because of its ability to localize aggressive focal lesions within the prostate for focal therapy [4]. Prostate MRI still suffers from a high incidence of both false positive [5] and false negative [6] events, requiring other biomarkers and associated imaging techniques for delineation of focal lesions

Methods

Results

Conclusion