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The Complement System and Cancer Cachexia

补体系统和癌症恶病质

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘