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Identification of key tumor cell-released factors that induce cachexia

诱导恶病质的关键肿瘤细胞释放因子的鉴定

基本信息

批准号：
10599093
负责人：
Syed H Jafri
金额：
$ 54.53万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599093
关键词：
Animal Model Biological Markers Cachexia Cancer Etiology Cancer Intervention Cancer Patient Catabolism Cessation of life Clinical Clinical Research Complex Data Degradation Pathway Development Diagnosis Diagnosis Clinical Trials Disease Etiology Event Florida Human Implant In Vitro Inflammatory Interleukin-6 Investigational Therapies Longitudinal Studies Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediator Metabolic syndrome Morbidity - disease rate Mus Muscle Muscle Cells Muscle Development Muscle Fibers Muscular Atrophy Natural History Newly Diagnosed Omeprazole Outcome Pathologic Patients Research Personnel Serum Standardization TLR4 gene TNF gene Testing Time Universities cancer cachexia cancer cell cancer therapy cancer type cytokine design driving force extracellular extracellular vesicles gene therapy improved in vivo inhibitor knock-down member mortality mouse model neoplastic cell neutralizing antibody pancreatic PDX models pancreatic cancer cells patient derived xenograft model pharmacologic preservation protein degradation recruit release factor response success systemic inflammatory response therapeutic target tumor vesicular release

项目摘要

Project summary Cancer cachexia, characterized by muscle wasting, is seen in ~60% of cancer patients and a major contributor to the morbidity and mortality associated with cancer. Consequently, cachexia is the direct cause of ~1/3 of cancer-related deaths. We must manage cachexia because preserving muscle and body mass could promote response to cancer treatment, improve patient physical condition to withstand cancer treatment, and prolong survival. However, there is no standardized assessment or established treatment for cancer cachexia due to the poor understanding of its etiology. A major difficulty in understanding cachexia is the high complexity of cancer milieu, in which many contributing factors have been proposed, but the key mediators of cachexia remain elusive. Supported by R01 AR063786, we discovered recently that diverse types of cachexia-inducing tumors release high levels of extracellular Hsp70 & Hsp90 that are associated with extracellular vesicles (EVs), which is necessary and sufficient for the development of muscle wasting in mice due to their activation of Toll-like receptor 4 (TLR4) on muscle cells that activates protein degradation pathways. In addition, elevation of serum Hsp70 & Hsp90 in tumor-bearing mice is required for the elevation of inflammatory cytokines (TNFα and IL-6) that promote muscle wasting. These data indicate that elevated circulating Hsp70 & Hsp90 are the key driving force of cancer-induced muscle wasting and systemic inflammation, thus, could be biomarkers and therapeutic targets of cancer cachexia. These findings provide an opportunity for etiology-based diagnosis and intervention of cancer cachexia. However, animal models do not always recapitulate complex events that occur in cancer cachexia in humans, it will be important moving forward to validate the importance of circulating Hsp70 & Hsp90 in human cancer cachexia. Although multiple clinical studies found that serum Hsp70 & Hsp90 levels in cancer patients increase with the development of pathological grade and clinical stage, and the increase correlates with mortality, whether elevated serum Hsp70 & Hsp90 correlate with and cause human cancer cachexia are unknown. Therefore, we propose to test the hypothesis that tumor-released extracellular Hsp70 & Hsp90 are biomarkers and therapeutic targets of human cancer cachexia. We will conduct a longitudinal patient study to determine whether elevated serum Hsp70 & Hsp90 are biomarkers of human cancer cachexia that correlate with natural history of advanced malignancies and clinical outcome. In addition, we will determine whether human cancer cell release of extracellular vesicle-associated Hsp70 & Hsp90 are causal to muscle wasting and shortened survival by studying patient-derived primary cancer cells in vitro, and mice bearing patient-derived xenografts (PDX) of cancer in vivo. Finally, we will conduct experimental therapy of cachexia in PDX-bearing mice by blocking Hsp70 & Hsp90 release using a pharmacological strategy.

项目总结