The Complement System and Cancer Cachexia

项目摘要/摘要 恶病质的特征是进行性的骨骼肌和体重减轻，影响高达80%的癌症 病人。由于这种肌肉质量的丧失会导致虚弱，对常规治疗的耐受性降低， 和死亡率的增加，了解导致肌肉萎缩的机制对发展至关重要 改善癌症患者生活质量和提高存活率的治疗方法。然而，在探索 可能导致癌症引起的肌纤维萎缩的机制，重要的是在 我们和其他人在恶病质肿瘤宿主的肌肉中表现出的更广泛的肌肉病理， 包括组织损伤，顽固性炎症，再生障碍，脂肪，胶原和 钙沉积。来自我们实验室的未发表的蛋白质组学数据收集在恶病质的骨骼肌中 胰腺癌患者以及随后携带胰腺肿瘤的恶病质小鼠释放出一种 补体(CP)系统的多个途径的丰富。进一步的免疫组织化学分析 显示CP系统的中心组件C3和终端的沉积增加 胰腺癌患者和小鼠肌肉组织中的途径/膜攻击复合体(MAC)， 与对照组相比。根据这些发现和CP蛋白在引起炎症中的既定作用 和组织损伤，我们将小鼠胰腺癌(KPC)细胞注射到C3基因敲除(C3-/-)的胰腺中。 发现对KPC诱导的肌肉萎缩和虚弱有显著的保护作用，这进一步联系到 减少白细胞渗入肌肉，减少纤维化重塑。这些总体调查结果确立了 恶病质的发展需要CP的激活，具有很强的翻译相关性。目标1将 在这些基础发现的基础上，确定特定的CP激活途径和效应机制(S) 对于肿瘤引起的肌肉病理和恶病质的发展是必需的。这将揭示最佳点 在CP通路中起药理阻断作用。Aim 2将利用小鼠CP抑制剂，这些抑制剂在不同的 CP通路中的点，针对CP沉积的位置，以确定最有效的治疗策略 使用KPC模型和C26腺癌模型预防和逆转荷瘤小鼠的恶病质。 目标3将确定局部肌纤维来源的C3在胰腺癌诱导中的充分性和必要性 免疫细胞渗入肌肉，肌肉受损、萎缩和虚弱。这个机械性的目标很重要 因为局部肌纤维衍生的CP在肌肉健康和疾病中的作用几乎完全未知。 因此，我们在这里的发现将提供机械性的见解，使我们能够优化和开发新的 CP抑制策略可用于治疗多种肌肉疾病。

Project Summary/Abstract Cachexia is characterized by progressive skeletal muscle and body weight loss and affects up to 80% of cancer patients. Since this loss of muscle mass contributes to weakness, reduced tolerance to conventional treatments, and increased mortality, understanding the mechanisms that drive muscle wasting is critical to the development of treatments to improve quality of life and enhance survival of cancer patients. However, in exploring the mechanisms that may drive cancer-induced atrophy of myofibers, it is important to do so in the context of the broader muscle pathologies that we and others have shown in the muscle of cachectic tumor bearing hosts, including tissue damage, non-resolute inflammation, impaired regeneration, and increased fat, collagen and calcium deposition. Unpublished proteomics data from our lab collected in the skeletal muscle of cachectic pancreatic cancer patients and, subsequently, cachectic mice bearing pancreatic tumors, releaved an enrichment of multiple pathways of the complement (Cp) system. Further immunohistochemical analyses revealed increased deposition of the central component of the Cp system, C3, and the terminal pathway/membrane attack complex (MAC) within muscle tissues of people and mice with pancreatic tumors, compared to controls. Based on these findings and the established roles of Cp proteins in causing inflammation and tissue damage, we injected mouse pancreatic cancer (KPC) cells into the pancreas of C3 knockout (C3-/-) mice and found significant protection against KPC-induced muscle wasting and weakness, that was further linked to reduced leukocyte infiltration into muscle and reduced fibrotic remodeling. These overall findings establish the requirement of Cp activation for the development of cachexia, with strong translational relevance. Aim 1 will build on these foundational findings and identify the specific Cp activation pathway and effector mechanism(s) required for the development of tumor-induced muscle pathologies and cachexia. This will reveal optimum points in the Cp pathway for pharmacological blockade. Aim 2 will utilize mouse Cp inhibitors that function at different points in the Cp pathway, targeted to sites of Cp deposition, to identify the most effective therapeutic strategy to prevent and reverse cachexia in tumor bearing mice using both the KPC model and C26 adenocarcinoma model. Aim 3 will determine the sufficiency and requirement of local myofiber-derived C3 in pancreatic cancer-induced immune cell infiltration into muscle, muscle damage, atrophy and weakness. This mechanistic aim is important because the role of local myofiber-derived Cp in muscle health and disease is almost completely unknown. Therefore, our findings here will provide mechanistic insights that will enable us to optimize and develop novel Cp inhibitory strategies for the treatment of a broad range of muscle conditions.