Identification of key tumor cell-released factors that induce cachexia

项目摘要 以肌肉萎缩为特征的癌症恶病质见于约60%的癌症患者， 与癌症相关的发病率和死亡率。因此，恶病质是约1/3的 与癌症有关的死亡我们必须控制恶病质，因为保持肌肉和身体质量可以促进 对癌症治疗的反应，改善患者的身体状况，以承受癌症治疗，并延长 生存然而，对于癌症恶病质没有标准化的评估或既定的治疗， 对其病因的认识不足。理解恶病质的一个主要困难是 癌症环境，其中许多促成因素已被提出，但恶病质的关键介质仍然存在 难以捉摸。在R 01 AR 063786的支持下，我们最近发现不同类型的恶病质诱导肿瘤 释放高水平的细胞外Hsp 70和Hsp 90，其与细胞外囊泡（EV）相关， 是必要的和足够的发展肌肉萎缩的小鼠由于其激活Toll样 受体4（TLR 4）在肌肉细胞上激活蛋白质降解途径。此外，血清中 Hsp 70和Hsp 90在荷瘤小鼠中是升高炎性细胞因子（TNFα和IL-6）所必需的 促进肌肉萎缩这些数据表明循环中Hsp 70和Hsp 90的升高是关键驱动因素 因此，癌症引起的肌肉萎缩和全身炎症的力量可能是生物标志物和治疗方法。 癌症恶病质的靶点。这些发现为基于病因的诊断和干预提供了机会 癌症恶病质然而，动物模型并不总是重述发生在癌症中的复杂事件 在人类恶病质中，重要的是要向前迈进，以验证循环Hsp 70和Hsp 90的重要性， 在人类癌症恶病质中。虽然多项临床研究发现，癌症患者血清Hsp 70和Hsp 90水平 随着病理分级和临床分期的发展，患者的增加， 死亡率，血清Hsp 70和Hsp 90升高是否与人类癌症恶病质相关并引起人类癌症恶病质， 未知因此，我们建议验证肿瘤释放的细胞外Hsp 70和Hsp 90是肿瘤细胞的一部分的假设。 人类癌症恶病质的生物标志物和治疗靶点。我们将进行纵向患者研究， 确定升高的血清Hsp 70和Hsp 90是否是人类癌症恶病质的生物标志物， 晚期恶性肿瘤的自然史和临床结果。此外，我们将确定人类是否 癌细胞释放细胞外囊泡相关的Hsp 70和Hsp 90是肌肉萎缩的原因， 通过体外研究患者来源的原发性癌细胞，以及携带患者来源的 异种移植物（PDX）。最后，我们将对携带PDX的恶病质进行实验性治疗 小鼠通过使用药理学策略阻断Hsp 70和Hsp 90释放。

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.