Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Solid Tumor Program, Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cell Rep. 2023 Jan 31;42(1):111934. doi: 10.1016/j.celrep.2022.111934. Epub 2022 Dec 29.
Cachexia is a systemic wasting syndrome that increases cancer-associated mortality. How cachexia progressively and differentially impacts distinct tissues is largely unknown. Here, we find that the heart and skeletal muscle undergo wasting at early stages and are the tissues transcriptionally most impacted by cachexia. We also identify general and organ-specific transcriptional changes that indicate functional derangement by cachexia even in tissues that do not undergo wasting, such as the brain. Secreted factors constitute a top category of cancer-regulated genes in host tissues, and these changes include upregulation of the angiotensin-converting enzyme (ACE). ACE inhibition with the drug lisinopril improves muscle force and partially impedes cachexia-induced transcriptional changes, although wasting is not prevented, suggesting that cancer-induced host-secreted factors can regulate tissue function during cachexia. Altogether, by defining prevalent and temporal and tissue-specific responses to cachexia, this resource highlights biomarkers and possible targets for general and tissue-tailored anti-cachexia therapies.
恶病质是一种全身性消耗综合征，会增加癌症相关死亡率。恶病质如何逐渐且差异化地影响不同组织在很大程度上尚不清楚。在这里，我们发现心脏和骨骼肌在早期就会出现消耗，并且是受恶病质影响最大的组织。我们还确定了一般和器官特异性转录变化，这些变化表明即使在不发生消耗的组织（如大脑）中，恶病质也会导致功能紊乱。分泌因子构成宿主组织中受癌症调控基因的首要类别，这些变化包括血管紧张素转换酶 (ACE) 的上调。用药物赖诺普利抑制 ACE 可改善肌肉力量，并部分阻止恶病质引起的转录变化，尽管不能阻止消耗，但这表明癌症诱导的宿主分泌因子可在恶病质期间调节组织功能。总的来说，通过定义对恶病质的普遍、时间和组织特异性反应，该资源突出了标志物和可能的通用和组织针对性抗恶病质治疗的靶点。
