Although cancer and its therapy are well known to be associated with fatigue, the exact nature of cancer-related fatigue remains ill-defined. We previously reported that fatigue-like behavior induced independently by tumor growth and by the chemotherapeutic agent cisplatin is characterized by reduced voluntary wheel running and an intact motivation to expand effort for food rewards. The present set of experiments was initiated to characterize the functional consequences of fatigue induced by chemoradiotherapy in tumor-bearing mice and relate them to changes in the expression of genes coding for inflammation, mitochondria dynamics and metabolism. Two syngeneic murine models of cancer were selected for this purpose, a model of human papilloma virus-related head and neck cancer and a model of lung cancer. In both models, tumor-bearing mice were submitted to chemoradiotherapy to limit tumor progression. Two dimensions of fatigue were assessed, the physical dimension by changes in physical activity in mice trained to run in wheels and the motivational dimension by changes in the performance of mice trained to nose poke to obtain a food reward in a progressive ratio schedule of food reinforcement. Chemoradiotherapy reliably decreased wheel running activity but had no effect on performance in the progressive ratio in both murine models of cancer. These effects were the same for the two murine models of cancer and did not differ according to sex. Livers and brains were collected at the end of the experiments for qRT-PCR analysis of expression of genes coding for inflammation, mitochondria dynamics, and metabolism. The observed changes were mainly apparent in the liver and typical of activation of type I interferon and NF-κB-dependent signaling, with alterations in mitochondrial dynamics and a shift toward glycolysis. Although the importance of these alterations for the pathophysiology of cancer-related fatigue remains to be explored, the present findings indicate that fatigue brought on by cancer therapy in tumor-bearing mice is more physical than motivational.

尽管众所周知癌症及其治疗与疲劳有关，但与癌症相关的疲劳的确切性质仍然不明确。我们之前报道过，由肿瘤生长和化疗药物顺铂独立诱导的疲劳样行为的特点是自愿轮动减少和为食物奖励而努力的完整动机。本组实验的目的是表征荷瘤小鼠放化疗引起的疲劳的功能后果，并将其与编码炎症、线粒体动力学和代谢的基因表达的变化联系起来。为此目的，选择了两种同基因小鼠癌症模型，一种是人乳头瘤病毒相关的头颈癌模型，另一种是肺癌模型。在这两种模型中，荷瘤小鼠均接受放化疗以限制肿瘤进展。评估了疲劳的两个维度，身体维度通过训练在轮子上跑步的小鼠的身体活动变化来评估，动机维度通过训练小鼠戳鼻子以获得食物强化的渐进比例计划中的食物奖励的表现变化来评估。在两种小鼠癌症模型中，放化疗确实降低了轮跑活动，但对进展率没有影响。这些效果对于两种小鼠癌症模型是相同的，并且没有因性别而异。实验结束时收集肝脏和大脑，用于 qRT-PCR 分析编码炎症、线粒体动力学和代谢的基因表达。观察到的变化主要在肝脏中明显，典型的是I 型干扰素和 NF-κB 依赖性信号传导的激活，以及线粒体动力学的改变和糖酵解的转变。尽管这些改变对于癌症相关疲劳的病理生理学的重要性仍有待探索，但目前的研究结果表明，癌症治疗给荷瘤小鼠带来的疲劳更多是身体上的，而不是动机上的。