Identification of key tumor cell-released factors that induce cachexia

项目总结 癌症恶病质，以肌肉萎缩为特征，见于约60%的癌症患者，也是主要原因之一 与癌症相关的发病率和死亡率。因此，恶病质是1/3的直接原因。 与癌症相关的死亡。我们必须控制恶病质，因为保护肌肉和身体质量可以促进 响应癌症治疗，改善患者身体状况，以承受癌症治疗，并延长 生死存亡。然而，由于癌症恶病质，目前还没有标准化的评估或既定的治疗方法。 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，其中许多因素已被提出，但恶病质的关键介体仍然存在 难以捉摸。在R01 AR063786的支持下，我们最近发现了不同类型的恶病质诱发肿瘤 释放高水平的细胞外Hsp70和Hsp90，与细胞外小泡(EV)相关，这是 是小鼠由于激活Toll样蛋白而导致的肌肉萎缩的必要条件和充分条件 肌细胞上的受体4(TLR4)，激活蛋白质降解途径。此外，血清的升高 荷瘤小鼠热休克蛋白70和90与炎性细胞因子(肿瘤坏死因子、α和IL-6)的升高有关 促进肌肉萎缩的物质。这些数据表明，升高的循环Hsp70和Hsp90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性疾病。 癌症恶病质的靶标。这些发现为基于病因学的诊断和干预提供了机会 癌症恶病质。然而，动物模型并不总是概括癌症中发生的复杂事件。 人类恶病质，重要的是进一步验证循环中Hsp70和Hsp90的重要性 人类癌症恶病质。尽管多项临床研究发现肿瘤患者血清Hsp70和Hsp90水平 患者随着病理分级和临床分期的发展而增加，且这种增加与 死亡率，血清HSP70和HSP90升高是否与癌症恶病质相关并导致癌症恶病质 未知。因此，我们建议检验这样的假设，即肿瘤释放的细胞外Hsp70和Hsp90是 人类癌症恶病质的生物标志物和治疗靶点。我们将进行一项纵向患者研究，以 确定血清Hsp70和Hsp90升高是否是与癌症恶病质相关的生物标志物 晚期恶性肿瘤的自然病史和临床结果。此外，我们将确定人类是否 癌细胞释放胞外囊泡相关的Hsp70和Hsp90导致肌肉萎缩和 通过研究患者来源的原代癌细胞和携带患者来源的小鼠的体外实验来缩短生存期 体内肿瘤的异种移植(PDX)最后，我们将对携带PDX的患者进行恶病质的实验性治疗。 通过使用药理学策略阻断Hsp70和Hsp90的释放。

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.