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：
10382247
负责人：
Syed H Jafri
金额：
$ 53.64万
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/10382247
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 of activation protein Metabolic syndrome Morbidity - disease rate Mus Muscle Muscle Cells Muscle Development Muscle Fibers Muscular Atrophy Natural History Newly Diagnosed Omeprazole Outcome Pathologic Patients Pharmacology Research Personnel Serum Standardization TLR4 gene TNF gene Testing Time Universities base 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 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.

项目摘要癌症恶病质（以肌肉浪费为特征）在约60％的癌症患者和主要贡献者中可见与癌症相关的病态和死亡率。与癌症有关的死亡。对癌症治疗的反应，改善有收费的癌症裤子并延长然而，生存没有标准化的评估或对CACHEXIA的既定治疗方法。对病因的不良理解。癌症环境，其中许多促成因素被支撑了，但是卡赫西亚的介体仍然存在难以捉摸。在R01 AR063786的支持下，我们最近发现释放与外囊泡（EVS）相关的高水平的外部HSP70和HSP90 由于它们的激活类似于Toll样，因此必要和足够受体4（TLR4）在激活蛋白质降解途径的肌肉细胞上。炎性细胞因子升高需要耐肿瘤小鼠的Hsp70＆Hsp90（TNFα和IL-6）需要促进肌肉浪费。癌症引起的肌肉浪费和全身性炎症的力可以治疗这些发现的癌症靶标为基于病因的诊断提供了机会但是，Cachexia。在人类中的恶病质，验证循环HSP70＆HSP90的重要性将非常重要在人类癌症中患者随着病理年级和临床阶段的发展而增加，增加与死亡率，升高的血清HSP70和HSP90是否与人类癌症相关并引起人类癌症恶病质因此。人类癌症患者的生物标志物和治疗靶标我们将进行纵向患者研究。确定血清HSP70和HSP90是否是与人类癌症患者的生物标志物，与晚期恶性肿瘤和临床结果的自然历史。癌细胞释放与囊泡相关的HSP70和HSP90是必不可少的。通过研究体外研究患者来源的原发性癌细胞和带有患者衍生的小鼠来缩短存活率癌症的异种（PDX）在体内。通过使用药理策略阻止HSP70和HSP90释放的小鼠。