Notch Signaling Mediates Skeletal Muscle Atrophy in Cancer Cachexia Caused by Osteosarcoma.
Notch Signaling Mediates Skeletal Muscle Atrophy in Cancer Cachexia Caused by Osteosarcoma.
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作者：
Mu X;Agarwal R;March D;Rothenberg A;Voigt C;Tebbets J;Huard J;Weiss K
癌症恶病质中骨骼肌萎缩是由肌肉干细胞和各种肿瘤因子之间的相互作用介导的。虽然Notch信号传导已被认为是癌症发展和肌肉干细胞活性的关键调节因子，但Notch信号传导在癌症恶病质和伴随的肌肉萎缩中的潜在参与尚未阐明。鼠K7M2骨肉瘤细胞系用于产生肉瘤相关恶病质的原位模型，并评估Notch信号传导的作用。在荷瘤小鼠中观察到骨骼肌萎缩，并且Notch信号在肿瘤组织和萎缩的骨骼肌中都高度活跃。Notch信号传导的全身性抑制减少了肌肉萎缩。骨肉瘤细胞与从正常小鼠分离的肌源性干细胞（MDSC）体外共培养导致MDSC的成肌潜能降低，而Notch抑制剂的应用能够拯救这种被抑制的成肌潜能。我们进一步观察到Notch激活因子存在于骨肉瘤细胞的外泌体中，其激活MDSC中的Notch信号传导并随后抑制肌生成。我们的结果表明，肿瘤和肌肉之间通过Notch途径的信号传导可能在介导癌症恶病质中出现的骨骼肌萎缩中发挥重要作用。
Skeletal muscle atrophy in cancer cachexia is mediated by the interaction between muscle stem cells and various tumor factors. Although Notch signaling has been known as a key regulator of both cancer development and muscle stem cell activity, the potential involvement of Notch signaling in cancer cachexia and concomitant muscle atrophy has yet to be elucidated. The murine K7M2 osteosarcoma cell line was used to generate an orthotopic model of sarcoma-associated cachexia, and the role of Notch signaling was evaluated. Skeletal muscle atrophy was observed in the sarcoma-bearing mice, and Notch signaling was highly active in both tumor tissues and the atrophic skeletal muscles. Systemic inhibition of Notch signaling reduced muscle atrophy. In vitro coculture of osteosarcoma cells with muscle-derived stem cells (MDSCs) isolated from normal mice resulted in decreased myogenic potential of MDSCs, while the application of Notch inhibitor was able to rescue this repressed myogenic potential. We further observed that Notch-activating factors reside in the exosomes of osteosarcoma cells, which activate Notch signaling in MDSCs and subsequently repress myogenesis. Our results revealed that signaling between tumor and muscle via the Notch pathway may play an important role in mediating the skeletal muscle atrophy seen in cancer cachexia.