Dantzer Robert, Chelette Brandon, Vichaya Elisabeth G, West A Phillip, Grossberg Aaron
Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Neurosci Biobehav Rev. 2025 Feb;169:106035. doi: 10.1016/j.neubiorev.2025.106035. Epub 2025 Jan 30.
Although we are all familiar with the sensation of fatigue, there are still profound divergences on what it represents and its mechanisms. Fatigue can take various forms depending on the condition in which it develops. Cancer-related fatigue is considered a symptom of exhaustion that is often present at the time of diagnosis, increases in intensity during cancer therapy, and does not always recede after completion of treatment. It is usually attributed to the inflammation induced by damage-associated molecular patterns released by tumor cells during cancer progression and in response to its treatment. In this review, we argue that it is necessary to go beyond the symptoms of fatigue to understand its nature and mechanisms. We propose to consider fatigue as a psychobiological process that regulates the behavioral activities an organism engages in to satisfy its needs, according to its physical ability to do so and to the capacity of its intermediary metabolism to exploit the resources procured by these activities. This last aspect is critical as it implies that these metabolic aspects need to be considered to understand fatigue. Based on the findings we have accumulated over several years of studying fatigue in diverse murine models of cancer, we show that energy metabolism plays a key role in the development and persistence of this condition. Cancer-related fatigue is dependent on the energy requirements of the tumor and the negative impact of cancer therapy on the mitochondrial function of the host. When inflammation is present, it adds to the organism's energy expenses. The organism needs to adjust its metabolism to the different forms of cellular stress it experiences thanks to specialized communication factors known as mitokines that act locally and at a distance from the cells in which they are produced. They induce the subjective, behavioral, and metabolic components of fatigue by acting in the brain. Therefore, the targeting of mitokines and their brain receptors offers a window of opportunity to treat fatigue when it is no longer adaptive but an obstacle to the quality of life of cancer survivors.
尽管我们都熟悉疲劳的感觉，但对于疲劳的本质及其机制仍存在深刻的分歧。疲劳会根据其产生的情况呈现出多种形式。癌症相关疲劳被认为是一种疲惫症状，通常在诊断时就已出现，在癌症治疗期间强度会增加，并且在治疗结束后并不总是会消退。它通常归因于肿瘤细胞在癌症进展过程中以及对其治疗的反应中释放的损伤相关分子模式所引发的炎症。在本综述中，我们认为有必要超越疲劳的症状来理解其本质和机制。我们建议将疲劳视为一种心理生物学过程，该过程根据生物体满足自身需求的身体能力以及中间代谢利用这些活动获取资源的能力，来调节生物体参与的行为活动。最后这一方面至关重要，因为这意味着需要考虑这些代谢方面来理解疲劳。基于我们在多种癌症小鼠模型中对疲劳进行数年研究积累的发现，我们表明能量代谢在这种情况的发生和持续中起着关键作用。癌症相关疲劳取决于肿瘤的能量需求以及癌症治疗对宿主线粒体功能的负面影响。当存在炎症时，它会增加生物体的能量消耗。生物体需要借助被称为线粒体因子的特殊通讯因子，将其新陈代谢调整到所经历的不同形式的细胞应激状态，这些因子在局部以及远离其产生细胞的位置发挥作用。它们通过作用于大脑来诱发疲劳的主观、行为和代谢成分。因此，当疲劳不再具有适应性而是成为癌症幸存者生活质量的障碍时，针对线粒体因子及其脑受体提供了一个治疗疲劳的机会窗口。
