Kim Young-Mee, Sanborn Mark A, Vijeth Shaluah, Gajwani Priyanka, Wang Xinge, Jung Dahee, Valyi-Nagy Tibor, Chakraborty Sreeparna, Mancinelli Georgina, Toth Peter T, Phillips Evan H, Grippo Paul, Salahudeen Ameen A, Park Jooman, Yeon Su Yeon, Ananthanarayanan Vijayalakshmi, Jiang Yuwei, Lee Steve Seung-Young, Valyi-Nagy Klara, Rehman Jalees
Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine, Chicago, IL, USA.
University of Illinois Cancer Center, Chicago, IL, USA.
Nat Cancer. 2025 May 26. doi: 10.1038/s43018-025-00975-6.
Cachexia is the wasting of skeletal muscle in cancer and is a major complication that impacts a person's quality of life. We hypothesized that cachexia is mediated by dysfunction of the vascular system, which is essential for maintaining perfusion and tempering inappropriate immune responses. Using transparent tissue topography, we discovered that loss of muscle vascular density precedes muscle wasting in multiple complementary tumor models, including pancreatic adenocarcinoma, colon carcinoma, lung adenocarcinoma and melanoma models. We also observed that persons suffering from cancer cachexia exhibit substantial loss of muscle vascular density. As tumors progress, increased circulating activin A remotely suppresses the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) in the muscle endothelium, thus inducing vascular leakage. Restoring endothelial PGC1α activity preserved vascular density and muscle mass in tumor-bearing mice. Our study suggests that restoring muscle endothelial function could be a valuable therapeutic approach for cancer cachexia.
恶病质是癌症患者骨骼肌的消耗，是影响患者生活质量的主要并发症。我们假设恶病质是由血管系统功能障碍介导的，而血管系统对于维持灌注和调节不适当的免疫反应至关重要。利用透明组织地形图，我们发现在多种互补肿瘤模型中，包括胰腺腺癌、结肠癌、肺腺癌和黑色素瘤模型，肌肉血管密度的丧失先于肌肉消耗。我们还观察到，患有癌症恶病质的人肌肉血管密度大幅降低。随着肿瘤进展，循环中激活素A增加会远程抑制肌肉内皮细胞中过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC1α）的表达，从而导致血管渗漏。恢复内皮细胞PGC1α活性可保留荷瘤小鼠的血管密度和肌肉质量。我们的研究表明，恢复肌肉内皮功能可能是治疗癌症恶病质的一种有价值的方法。
