Korenchan David E, Bok Robert, Sriram Renuka, Liu Kristina, Santos Romelyn Delos, Qin Hecong, Lobach Iryna, Korn Natalie, Wilson David M, Kurhanewicz John, Flavell Robert R
Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
Department of Physical Chemistry, Technical University of Munich, Munich, Germany.
Oncotarget. 2019 Oct 22;10(58):6096-6110. doi: 10.18632/oncotarget.27225.
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 (pH) can potentially be used to identify aggressive phenotypes. In this study, we employ an optimized, high signal-to-noise ratio hyperpolarized (HP) C pH 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 [C] bicarbonate MRI for pH, with H apparent diffusion coefficient (ADC) mapping and HP [1-C] 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 pH between low- and high-grade tumor regions, with high-grade tumors demonstrating a lower pH. The pH also correlated strongly with monocarboxylate transporter 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 pH imaging to detect high-grade, clinically significant disease in men as part of a multiparametric MRI examination.
对于区分惰性与侵袭性前列腺癌的新型且可靠的成像生物标志物，存在未满足的临床需求。侵袭性肿瘤的特征，如细胞外pH值（pH）降低，有可能用于识别侵袭性表型。在本研究中，我们采用一种优化的、高信噪比的超极化（HP）¹³C pH成像方法，在前列腺癌小鼠模型中区分惰性和侵袭性疾病。小鼠前列腺转基因腺癌（TRAMP）小鼠接受了多参数磁共振成像检查，包括用于pH值的HP [¹³C]碳酸氢盐MRI、氢表观扩散系数（ADC）图谱以及HP [¹³C]丙酮酸MRI以研究乳酸代谢。切除肿瘤组织进行组织学染色和定量逆转录聚合酶链反应（qRT-PCR），以量化相关糖酵解酶和转运蛋白的mRNA表达。我们观察到低级别和高级别肿瘤区域之间在pH值上有良好的区分，高级别肿瘤的pH值较低。在所有肿瘤中，pH值也与单羧酸转运蛋白基因表达密切相关，这表明在该模型中通过MCT4输出乳酸与酸化有关。我们的结果表明细胞外酸化是前列腺癌从惰性向侵袭性转变的一个指标，并表明HP pH成像作为多参数MRI检查的一部分，在检测男性高级别、具有临床意义的疾病方面具有可行性。
