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 (TNF? 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.
Cancer-induced cachexia, or cancer cachexia, is a complex metabolic syndrome that significantly increases the morbidity and mortality of cancer patients. However, understanding of the underlying mechanism of cancer cachexia is limited and hence there is no standardized assessment or established treatment. The current project is designed to evaluate whether cancer-released circulating Hsp70 and Hsp90 are biomarkers and therapeutic targets of human cancer cachexia based on previous findings in mouse models of cancer cachexia.
| Ding, Hui; Zhang, Guohua; Sin, Ka Wai Thomas et al. (2017) Activin A induces skeletal muscle catabolism via p38? mitogen-activated protein kinase. J Cachexia Sarcopenia Muscle 8:202-212 |
| Zhang, Guohua; Liu, Zhelong; Ding, Hui et al. (2017) Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90. Nat Commun 8:589 |
| Ennequin, Gaël; Boisseau, Nathalie; Caillaud, Kevin et al. (2015) Exercise training and return to a well-balanced diet activate the neuregulin 1/ErbB pathway in skeletal muscle of obese rats. J Physiol 593:2665-77 |
| Chen, Ji-An; Splenser, Andres; Guillory, Bobby et al. (2015) Ghrelin prevents tumour- and cisplatin-induced muscle wasting: characterization of multiple mechanisms involved. J Cachexia Sarcopenia Muscle 6:132-43 |
| Li, Yi-Ping; Niu, Airu; Wen, Yefei (2014) Regulation of myogenic activation of p38 MAPK by TACE-mediated TNF? release. Front Cell Dev Biol 2:21 |
