Sharma Raj Kumar, Winnard Paul T, Bharti Santosh Kumar, Krishnamachary Balaji, Mironchik Yelena, Penet Marie-France, Bhujwalla Zaver M
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Int J Cancer. 2025 Jun 2. doi: 10.1002/ijc.35487.
Pancreatic cancer patients with cachexia experience functional changes in visceral organs. To further understand these functional changes, here, for the first time, we characterized metabolic changes in the spleen, liver, pancreas, lungs, heart, and kidneys induced by human pancreatic cancer xenografts. These studies identify the commonality and consequences of cachexia-induced visceral organ metabolic dysregulation. The heart, kidneys, liver, lungs, pancreas, and spleen from euthanized non-tumor-bearing control mice and from cachexia-inducing Pa04C and non-cachexia-inducing Panc1 tumor-bearing mice (n = 8-10 per group) were metabolically characterized with 1H magnetic resonance spectroscopy. All visceral organs, with the exception of lungs, exhibited significant weight reduction in cachectic Pa04C mice relative to normal and non-cachectic Panc1 mice. A significant reduction (p ≤ .0166) of organ metabolites ranging from the amino acids leucine, isoleucine, valine, alanine, lysine, arginine, asparagine, glutamate, glutamine, aspartate, glycine, tyrosine, and phenylalanine, along with glucose, lactate, creatine, choline, and fumarate, depending upon the visceral organ, was observed in cachectic Pa04C mice compared to normal mice. The highest number of metabolites was reduced in the spleen, followed by the kidneys, lungs, and liver. The metabolic changes identified can lead to negative consequences in organ function by impacting pathways involved in tissue regeneration and resolving inflammation at the cellular level in cachectic mice. These results highlight the visceral organ metabolic reprogramming that can occur with cancer-induced cachexia, an understanding of which can identify noninvasive biomarkers and metabolic interventions to reduce morbidity and mortality from pancreatic cancer.
患有恶病质的胰腺癌患者会出现内脏器官功能改变。为了进一步了解这些功能变化，在此我们首次对人胰腺癌异种移植诱导的脾脏、肝脏、胰腺、肺、心脏和肾脏的代谢变化进行了表征。这些研究确定了恶病质诱导的内脏器官代谢失调的共性和后果。对安乐死的无肿瘤对照小鼠以及诱导恶病质的Pa04C和不诱导恶病质的Panc1荷瘤小鼠（每组n = 8 - 10只）的心脏、肾脏、肝脏、肺、胰腺和脾脏进行了1H磁共振波谱代谢表征。除肺部外，所有内脏器官在恶病质的Pa04C小鼠中相对于正常和非恶病质的Panc1小鼠均表现出显著体重减轻。与正常小鼠相比，在恶病质的Pa04C小鼠中观察到器官代谢物显著减少（p≤0.0166），这些代谢物包括亮氨酸、异亮氨酸、缬氨酸、丙氨酸、赖氨酸、精氨酸、天冬酰胺、谷氨酸、谷氨酰胺、天冬氨酸、甘氨酸、酪氨酸和苯丙氨酸等氨基酸，以及葡萄糖、乳酸、肌酸、胆碱和富马酸，具体取决于内脏器官。脾脏中代谢物减少的数量最多，其次是肾脏、肺和肝脏。所确定的代谢变化可通过影响恶病质小鼠细胞水平上参与组织再生和炎症消退的途径，对器官功能产生负面影响。这些结果突出了癌症诱导的恶病质可能发生的内脏器官代谢重编程，了解这一点可以识别出非侵入性生物标志物和代谢干预措施，以降低胰腺癌的发病率和死亡率。
