Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90

Guohua Zhang, Zhelong Liu, Hui Ding, Yong Zhou, Hoang Anh Doan, Ka Wai Thomas Sin, Zhiren J. Zhu, Rene Flores, Yefei Wen, Xing Gong, Qingyun Liu and Yi-Ping Li ()
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Guohua Zhang: University of Texas Health Science Center at Houston (UTHealth)
Zhelong Liu: University of Texas Health Science Center at Houston (UTHealth)
Hui Ding: University of Texas Health Science Center at Houston (UTHealth)
Yong Zhou: University of Texas Health Science Center at Houston (UTHealth)
Hoang Anh Doan: University of Texas Health Science Center at Houston (UTHealth)
Ka Wai Thomas Sin: University of Texas Health Science Center at Houston (UTHealth)
Zhiren J. Zhu: University of Texas Health Science Center at Houston (UTHealth)
Rene Flores: University of Texas Health Science Center at Houston (UTHealth)
Yefei Wen: University of Texas Health Science Center at Houston (UTHealth)
Xing Gong: University of Texas Health Science Center at Houston (UTHealth)
Qingyun Liu: University of Texas Health Science Center at Houston (UTHealth)
Yi-Ping Li: University of Texas Health Science Center at Houston (UTHealth)

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract Cachexia, characterized by muscle wasting, is a major contributor to cancer-related mortality. However, the key cachexins that mediate cancer-induced muscle wasting remain elusive. Here, we show that tumor-released extracellular Hsp70 and Hsp90 are responsible for tumor’s capacity to induce muscle wasting. We detected high-level constitutive release of Hsp70 and Hsp90 associated with extracellular vesicles (EVs) from diverse cachexia-inducing tumor cells, resulting in elevated serum levels in mice. Neutralizing extracellular Hsp70/90 or silencing Hsp70/90 expression in tumor cells abrogates tumor-induced muscle catabolism and wasting in cultured myotubes and in mice. Conversely, administration of recombinant Hsp70 and Hsp90 recapitulates the catabolic effects of tumor. In addition, tumor-released Hsp70/90-expressing EVs are necessary and sufficient for tumor-induced muscle wasting. Further, Hsp70 and Hsp90 induce muscle catabolism by activating TLR4, and are responsible for elevation of circulating cytokines. These findings identify tumor-released circulating Hsp70 and Hsp90 as key cachexins causing muscle wasting in mice.

Date: 2017
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DOI: 10.1038/s41467-017-00726-x

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