Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Cachexia Sarcopenia Muscle. 2020 Dec;11(6):1487-1500. doi: 10.1002/jcsm.12621. Epub 2020 Oct 2.
Cachexia is a major cause of morbidity in pancreatic ductal adenocarcinoma (PDAC) patients. Our purpose was to understand the impact of PDAC-induced cachexia on brain metabolism in PDAC xenograft studies, to gain new insights into the causes of cachexia-induced morbidity. Changes in mouse and human plasma metabolites were characterized to identify underlying causes of brain metabolic changes.
We quantified metabolites, detected with high-resolution H magnetic resonance spectroscopy, in the brain and plasma of normal mice (n = 10) and mice bearing cachexia (n = 10) or non-cachexia (n = 9) inducing PDAC xenografts as well as in human plasma obtained from normal individuals (n = 24) and from individuals with benign pancreatic disease (n = 20) and PDAC (n = 20). Statistical significance was defined as a P value ≤0.05.
The brain metabolic signature of cachexia-inducing PDAC was characterized by a significant depletion of choline of -27% and -21% as well as increases of glutamine of 13% and 9% and formate of 21% and 14%, relative to normal controls and non-cachectic tumour-bearing mice, respectively. Good to moderate correlations with percent weight change were found for choline (r = 0.70), glutamine (r = -0.58), and formate (r = -0.43). Significant choline depletion of -38% and -30%, relative to normal controls and non-cachectic tumour-bearing mice, respectively, detected in the plasma of cachectic mice likely contributed to decreased brain choline in cachectic mice. Similarly, relative to normal controls and patients with benign disease, choline levels in human plasma samples of PDAC patients were significantly lower by -12% and -20% respectively. A comparison of plasma metabolites from PDAC patients with and without weight loss identified significant changes in glutamine metabolism.
Disturbances in metabolites of the choline/cholinergic and glutamine/glutamate/glutamatergic neurotransmitter pathways may contribute to morbidity. Metabolic normalization may provide strategies to reduce morbidity. The human plasma metabolite changes observed may lead to the development of companion diagnostic markers to detect PDAC and PDAC-induced cachexia.
恶病质是胰腺导管腺癌 (PDAC) 患者发病和致残的主要原因。我们的目的是了解 PDAC 诱导的恶病质对 PDAC 异种移植研究中大脑代谢的影响，以期深入了解恶病质导致发病的原因。本研究通过检测高分辨率 1 H 磁共振波谱，对正常小鼠 (n = 10)、患有恶病质 (n = 10) 或非恶病质 (n = 9) PDAC 异种移植的小鼠以及来自正常个体 (n = 24)、良性胰腺疾病个体 (n = 20) 和 PDAC 个体 (n = 20) 的血浆代谢物进行了定量分析，以确定大脑代谢变化的潜在原因。统计显著性定义为 P 值 ≤0.05。
诱导恶病质的 PDAC 导致大脑代谢特征发生变化，与正常对照和非恶病质荷瘤小鼠相比，胆碱降低 -27%和 -21%，谷氨酰胺增加 13%和 9%，甲酸盐增加 21%和 14%。与体重变化百分比的相关性良好到中度，胆碱 (r = 0.70)、谷氨酰胺 (r = -0.58) 和甲酸盐 (r = -0.43)。与正常对照和非恶病质荷瘤小鼠相比，恶病质小鼠的血浆中胆碱降低了 -38%和 -30%，可能导致恶病质小鼠大脑中胆碱的减少。同样，与正常对照和良性疾病患者相比，PDAC 患者的血浆样本中胆碱水平分别降低了 -12%和 -20%。对 PDAC 患者和体重减轻患者的血浆代谢物进行比较，发现谷氨酰胺代谢发生了显著变化。
胆碱/胆碱能和谷氨酰胺/谷氨酸/谷氨酰胺能神经递质途径的代谢物紊乱可能导致发病。代谢正常化可能为减少发病提供策略。观察到的人类血浆代谢物变化可能导致开发出用于检测 PDAC 和 PDAC 诱导恶病质的伴随诊断标志物。
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