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.

项目概要/摘要 恶病质的特点是进行性骨骼肌和体重减轻，影响高达 80% 的癌症 患者。由于肌肉质量的损失会导致虚弱，降低对传统治疗的耐受性， 和死亡率增加，了解导致肌肉萎缩的机制对于发展至关重要 改善生活质量并提高癌症患者生存率的治疗方法。然而，在探索 可能驱动癌症引起的肌纤维萎缩的机制，因此在以下背景下这样做很重要 我们和其他人在恶病质肿瘤宿主的肌肉中展示了更广泛的肌肉病理， 包括组织损伤、非彻底的炎症、再生受损以及脂肪、胶原蛋白和 钙沉积。我们实验室在恶病质骨骼肌中收集的未发表的蛋白质组学数据 胰腺癌患者以及随后携带胰腺肿瘤的恶病质小鼠，释放了 补体（Cp）系统多种途径的富集。进一步的免疫组织化学分析 揭示了 Cp 系统的中心成分 C3 和末端的沉积增加 患有胰腺肿瘤的人和小鼠的肌肉组织内的通路/膜攻击复合物（MAC）， 与对照相比。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）细胞注射到C3敲除（C3-/-）的胰腺中 小鼠，发现对 KPC 引起的肌肉萎缩和无力有显着的保护作用，这进一步相关 减少白细胞浸润到肌肉并减少纤维化重塑。这些总体发现确定了 Cp 激活是恶病质发生的必要条件，具有很强的转化相关性。目标1将 以这些基础发现为基础，确定特定的 Cp 激活途径和效应机制 肿瘤引起的肌肉病理学和恶病质的发展所必需的。这将揭示最佳点 在 Cp 途径中进行药理学阻断。目标 2 将利用小鼠 Cp 抑制剂，其作用于不同的 Cp 通路中的点，针对 Cp 沉积位点，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 将确定局部肌纤维衍生的 C3 在胰腺癌诱发中的充足性和需求 免疫细胞渗入肌肉，使肌肉受损、萎缩和无力。 This mechanistic aim is important 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，我们的研究结果将提供机制见解，使我们能够优化和开发新颖的 用于治疗多种肌肉疾病的 Cp 抑制策略。