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By Jamshed Arslan Pharm.D.
Muscle atrophy is a common feature of many tumors. Cancer-induced muscle wasting, or cancer cachexia, results from pro-inflammatory cytokines (TNFα and IL-6) and/or agonists of type IIB activin receptors (ActRIIB), but the key humoral factors have remained elusive. Animal studies have implicated systemic inflammation-induced activation of p38β MAPK-C/EBPβ signaling, but the etiology of cancer cachexia was unclear until recently. A team led by researchers at the University of Texas Health Science Center (UTHealth), Texas, found that conditioned medium of Lewis lung carcinoma (LLC) cells has catabolic activity related to high levels of two heat shock proteins, Hsp70 and Hsp90. By neutralizing these two proteins and silencing their genes, the team was also able to treat cancer cachexia in mice.[1]
Cachectic cancers release high amounts of EV-associated Hsp70/90
The team compared the conditioned media of cachexic cancer cells with the conditioned media of non-cachexic cancer and non-tumorigenic cells, in order to investigate if all cachexic cancers release Hsp70/90. ELISA showed that cachexic cancer cells, such as LLC (lung) and C26 (colon), release about ten-fold higher levels of Hsp70 and Hsp90α. Moreover, increased Hsp70 and Hsp90α in the sera of mice models led investigators to think that tumor cells release these two proteins extracellularly through extracellular vesicles (EVs). Western blotting and immunoprecipitation of isolated EVs revealed that the release of Hsp70/90 was associated with CD9/TSG101/acetylcholinesterase-positive EVs.
However, investigators made the important observation that "elevated serum Hsp70 has been reported in patients with CHF and COPD.[2,3] These conditions are known to induce muscle atrophy, too."
Professor Yi-Ping Li, PhD., Department of Integrative Biology and Pharmacology, UTHealth
Cancer cachexia depends on Hsp70/90
In order to know if elevated levels of circulating Hsp70/90 induce muscle catabolism, the team exposed primary rat and C2C12 myotubes to the conditioned media of LLC and C26 cells in the presence/absence of antibodies against Hsp70 and/or Hsp90. Only blocking of both Hsp70 and Hsp90 led to complete abolishment of the upregulation of E3 ligases atrogin1 and UBR2, suppression of p38 MAPK activation, and prevention of myotube atrophy and myosin heavy chain loss. The results in mice cancer models validated the cachexia-inducing impact of Hsp70/90.
The team then used small interfering RNAs and short hairpin RNAs against Hsp70/90 in LLC cells to answer the next logical question: is the cachexia-inducing ability of tumors dependent on Hsp70/90? As expected, Hsp70/90-deficient tumors did not lead to muscle catabolism and Hsp70/90-deficient mice did not exhibit increased serum Hsp70/90 levels. Intriguingly, blocking the GTPases that control EV release (Rab27a and Rab27b) in LLC and C26 cells stalled the release of EVs, and consequently blocked Hsp70/90 and muscle catabolism. Furthermore, exposing myotubes to cancer-generated EVs revealed that catabolic response to Hsp70/90 was dependent on TLR4, but not on TLR2.
Significance
The findings from these UTHealth investigators and their collaborators let us appreciate the nuances in some widely held notions. For example, they did not find any abnormal PTHrP release in serum or from cancer cells, and IL-1β was found to be not associated with tumor cachexia. They are the first ones to associate serum Hsp70/90 to cachexia in an in vivo (mice) model, and demonstrate that Hsp70/90 drive inflammation and cachexia in cancer. They found that increase in cytokines (TNF-α and IL-6) in cachectic tumor-bearing mice was an immune response to TLR4 activation by Hsp70/90, indicating that effective therapeutic strategies should target upstream activation of TLR4, not the cytokines per se. Likewise, now we know the major humoral factors (Hsp70/90) that initiate cancer cachexia, and hope that targeting them will improve patients' quality of life.
University of Alabama at Birmingham, School of Medicine
Dr. Arslan studies cell signaling in mitochondrial defects in C. elegans and transgenic mice.
References
- Zhang, Guohua, et al. "Tumor Induces Muscle Wasting in Mice through Releasing Extracellular Hsp70 and Hsp90." Nature Communications, vol. 8, no. 1, 2017, n.pag. doi: 10.1038/s41467-017-00726-x.
- Genth-Zotz, Sabine, et al. "Heat Shock Protein 70 in Patients with Chronic Heart Failure: Relation to Disease Severity and Survival." International Journal of Cardiology, vol. 96, no. 3, 2004, pp. 397–401. http://ift.tt/2AXSWev
- Hacker, S, et al. "Elevated HSP27, HSP70 and HSP90 Alpha in Chronic Obstructive Pulmonary Disease: Markers for Immune Activation and Tissue Destruction." Clinical Laboratory, vol. 55, no. 1-2, 2009, pp. 31–40. doi: 10.1515/9783110213072.1.31
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