Schmidt Manuel, Poser Christine, von Maltzahn Julia
Leibniz Institute on Aging, Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany.
Mol Ther Oncolytics. 2020 Jan 11;16:134-146. doi: 10.1016/j.omto.2019.12.011. eCollection 2020 Mar 27.
Cancer cachexia is a complex metabolic disease so far lacking effective therapy, and it accounts for approximately one third of all cancer-related deaths worldwide. The extracellular ligand Wnt7a has a dual function in skeletal muscle, inducing the anabolic AKT/mammalian target of rapamycin (mTOR) pathway in myofibers and driving muscle stem cell expansion in skeletal muscle, making it a promising candidate for treatment of muscle wasting diseases. In murine and human myotubes, Wnt7a activates the anabolic AKT/mTOR pathway, thereby preventing cachexia-induced atrophy with a single application being sufficient to prevent atrophy independently of the tumor cell type causing cachexia. Addition of Wnt7a also improved activation and differentiation of muscle stem cells in cancer cachexia, a condition under which skeletal muscle regeneration is severely impaired due to stalled muscle stem cell differentiation. Finally, we show that Wnt7a prevents cancer cachexia in an mouse model based on C26 colon carcinoma cells. Wnt7a has a dual role in cachectic skeletal muscle; that is, it effectively counteracts muscle wasting through activation of the anabolic AKT/mTOR pathway and, furthermore, reverts the loss of muscle stem cell functionality due to cancer cachexia, making Wnt7a a promising candidate for an ameliorative treatment of cancer cachexia.
癌症恶病质是一种复杂的代谢性疾病，目前缺乏有效的治疗方法，在全球所有癌症相关死亡中约占三分之一。细胞外配体Wnt7a在骨骼肌中具有双重功能，可诱导肌纤维中的合成代谢AKT/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路，并驱动骨骼肌中肌肉干细胞的扩增，使其成为治疗肌肉萎缩性疾病的有希望的候选药物。在小鼠和人类肌管中，Wnt7a激活合成代谢AKT/mTOR信号通路，从而预防恶病质诱导的萎缩，单次应用就足以独立于导致恶病质的肿瘤细胞类型预防萎缩。添加Wnt7a还改善了癌症恶病质中肌肉干细胞的激活和分化，在这种情况下，由于肌肉干细胞分化停滞，骨骼肌再生严重受损。最后，我们表明Wnt7a在基于C26结肠癌细胞的小鼠模型中可预防癌症恶病质。Wnt7a在恶病质骨骼肌中具有双重作用；也就是说，它通过激活合成代谢AKT/mTOR信号通路有效对抗肌肉萎缩，此外，还能逆转癌症恶病质导致的肌肉干细胞功能丧失，使Wnt7a成为改善癌症恶病质治疗的有希望的候选药物。
