The Complement System and Cancer Cachexia

补体系统和癌症恶病质

• 批准号: 10537488
• 负责人: Carl Atkinson
• 金额: $ 47.71万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537488
• 关键词: Address; Adenocarcinoma; Affect; Atrophic; Body Weight decreased; C3AR1 gene; Cachexia; Calcium; Cancer Patient; Cell Nucleus; Cells; Chimeric Proteins; Collagen; Complement; Complement 3a; Complement 3d Receptors; Complement 5a; Complement Activation; Complement Inactivators; Complement Membrane Attack Complex; Data; Deposition; Development; Disease; Event; Fatty acid glycerol esters; Foundations; Functional disorder; Goals; Health; Homeostasis; Immune; Impairment; Infiltration; Inflammation; Injections; KPC model; Knock-out; Knowledge; Lead; Lectin; Leukocytes; Link; Liver; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Atrophy; Natural regeneration; Nutritional Support; Opsonin; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathologic; Pathology; Pathway interactions; Patients; Persons; Pharmacology; Phenotype; Physical Function; Proteins; Proteomics; Quality of life; Role; Site; Skeletal Muscle; Source; Stimulus; Syndrome; Testing; Therapeutic; Tissues; Transcript; Translating; Tumor Burden; Work; base; cancer cachexia; cancer surgery; cancer survival; cancer therapy; cell type; clinically relevant; complement pathway; complement system; conventional therapy; improved; insight; mortality; mouse model; muscle form; muscle regeneration; novel; pancreatic cancer model; pancreatic cancer patients; pancreatic neoplasm; preservation; prevent; response; skeletal muscle wasting; therapeutically effective; therapy development; transcriptome sequencing; translational potential; treatment strategy; tumor; tumor progression

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.

项目摘要/摘要 恶病质的特征是进行性骨骼肌和体重减轻，并影响多达80％的癌症 患者。由于肌肉质量的损失导致弱点，因此对常规治疗的耐受性降低，因此 并增加死亡率，了解驱动肌肉浪费的机制对于发展至关重要 治疗以改善生活质量并增强癌症患者的存活率。但是，在探索 可能驱动癌症引起的肌纤维萎缩的机制，重要的是在 我们和其他人在缓存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，非溶质炎症，再生受损以及脂肪增加，胶原蛋白和增加 钙沉积。从缓存的骨骼肌肉中收集的我们实验室的未发表的蛋白质组学数据 胰腺癌患者，随后是伴有胰腺肿瘤的缓存小鼠，释放 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 揭示了CP系统，C3和端子的中心部分的沉积增加 患有胰腺肿瘤的人和小鼠肌肉组织中的途径/膜攻击复合物（MAC）， 与对照组相比。基于这些发现以及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）细胞注入C3敲除胰腺（C3 - / - ） 小鼠并发现了针对KPC引起的肌肉浪费和无力的明显保护，这进一步联系起来 为了减少白细胞浸润到肌肉中并减少纤维化重塑。这些总体发现确定了 CP激活对恶病质开发的需求，具有很强的翻译相关性。目标1意志 基于这些基本发现并确定特定的CP激活途径和效应器机制 肿瘤诱导的肌肉病理和恶病质的发展所必需的。这将揭示最佳点 在CP途径中进行药理学封锁。 AIM 2将利用在不同功能的鼠标CP抑制剂 CP途径中的点，针对CP沉积部位，以确定最有效的治疗策略 使用KPC模型和C26腺癌模型，预防和反向肿瘤中的恶病质。 AIM 3将确定胰腺癌引起的局部肌纤维衍生的C3的充分性和需求 免疫细胞渗入肌肉，肌肉损伤，萎缩和无力。这个机械目标很重要 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是完全未知的。 因此，我们在这里的发现将提供机械见解，使我们能够优化和发展新颖 CP抑制性策略用于治疗广泛的肌肉条件。