Department of Medical Laboratory Technology, Faculty of Natural Sciences, NTNU - Norwegian University of Science and Technology, 7491, Trondheim, Norway.
Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine, NTNU - Norwegian University of Science and Technology, 7030, Trondheim, Norway.
Sci Rep. 2017 May 17;7(1):2046. doi: 10.1038/s41598-017-02088-2.
The majority of cancer patients with advanced disease experience weight loss, including loss of lean body mass. Severe weight loss is characteristic for cancer cachexia, a condition that significantly impairs functional status and survival. The underlying causes of cachexia are incompletely understood, and currently no therapeutic approach can completely reverse the condition. Autophagy coordinates lysosomal destruction of cytosolic constituents and is systemically induced by starvation. We hypothesized that starvation-mimicking signaling compounds secreted from tumor cells may cause a systemic acceleration of autophagy during cachexia. We found that IL-6 secreted by tumor cells accelerates autophagy in myotubes when complexed with soluble IL-6 receptor (trans-signaling). In lung cancer patients, were cachexia is prevalent, there was a significant correlation between elevated IL-6 expression in the tumor and poor prognosis of the patients. We found evidence for an autophagy-inducing bioactivity in serum from cancer patients and that this is clearly associated with weight loss. Importantly, the autophagy-inducing bioactivity was reduced by interference with IL-6 trans-signaling. Together, our findings suggest that IL-6 trans-signaling may be targeted in cancer cachexia.
大多数晚期癌症患者会经历体重下降，包括去脂体重的减少。严重的体重下降是癌症恶病质的特征，这会显著损害功能状态和生存。恶病质的根本原因尚不完全清楚，目前没有任何治疗方法可以完全逆转这种情况。自噬协调溶酶体对细胞溶质成分的破坏，并被饥饿系统性地诱导。我们假设来自肿瘤细胞的模拟饥饿信号化合物可能会在恶病质期间导致全身自噬加速。我们发现，肿瘤细胞分泌的 IL-6 与可溶性 IL-6 受体（转信号）结合时，可加速肌管中的自噬。在肺癌患者中，恶病质很普遍，肿瘤中 IL-6 表达升高与患者预后不良显著相关。我们在癌症患者的血清中发现了具有诱导自噬活性的物质，并且这与体重减轻明显相关。重要的是，IL-6 转信号的干扰会降低这种诱导自噬的生物活性。总之，我们的研究结果表明，IL-6 转信号可能是癌症恶病质的靶点。
