D'Lugos Andrew C, Ducharme Jeremy B, Callaway Chandler S, Trevino Jose G, Atkinson Carl, Judge Sarah M, Judge Andrew R
Department of Physical Therapy and.
Myology Institute, University of Florida, Gainesville, Florida, USA.
J Clin Invest. 2025 Apr 8;135(12). doi: 10.1172/JCI178806. eCollection 2025 Jun 16.
Cancer cachexia is a multifactorial condition characterized by skeletal muscle wasting that impairs quality of life and longevity for many cancer patients. A greater understanding of the molecular etiology of this condition is needed for effective therapies to be developed. We performed a quantitative proteomic analysis of skeletal muscle from cachectic pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer controls, followed by immunohistochemical analyses of muscle cross sections. These data provide evidence of a local inflammatory response in muscles of cachectic PDAC patients, including an accumulation of plasma proteins and recruitment of immune cells into muscle that may promote the pathological remodeling of muscle. Our data further support the complement system as a potential mediator of these processes, which we tested by injecting murine pancreatic cancer cells into wild-type mice and mice with genetic deletion of the central complement component 3 (C3-/- mice). Compared with wild-type mice, C3-/- mice showed attenuated tumor-induced muscle wasting and dysfunction and reduced immune cell recruitment and fibrotic remodeling of muscle. These studies demonstrate that complement activation contributes to the skeletal muscle pathology and dysfunction in PDAC, suggesting that the complement system may possess therapeutic potential in preserving skeletal muscle mass and function.
癌症恶病质是一种多因素病症，其特征为骨骼肌消瘦，这会损害许多癌症患者的生活质量和寿命。要开发有效的治疗方法，需要更深入地了解这种病症的分子病因。我们对恶病质胰腺导管腺癌（PDAC）患者和非癌症对照者的骨骼肌进行了定量蛋白质组学分析，随后对肌肉横截面进行了免疫组织化学分析。这些数据证明恶病质PDAC患者的肌肉存在局部炎症反应，包括血浆蛋白的积累以及免疫细胞募集到肌肉中，这可能会促进肌肉的病理重塑。我们的数据进一步支持补体系统作为这些过程的潜在介质，我们通过将小鼠胰腺癌细胞注射到野生型小鼠和中央补体成分3基因缺失的小鼠（C3-/-小鼠）中来进行测试。与野生型小鼠相比，C3-/-小鼠的肿瘤诱导的肌肉消瘦和功能障碍有所减轻，免疫细胞募集和肌肉纤维化重塑减少。这些研究表明补体激活促成了PDAC中的骨骼肌病理和功能障碍，这表明补体系统在维持骨骼肌质量和功能方面可能具有治疗潜力。
