尽管治疗取得了进步，但大约 25% 的乳腺癌患者患有长期骨骼肌萎缩 (SMW)，这限制了活动能力，降低了药物耐受性并对生存产生了不利影响。通过了解 SMW 的潜在分子机制，我们可以开发新的策略来缓解这种情况并改善乳腺癌患者的生活。趋化因子是一种小的可溶性因子，在炎症过程中调节免疫细胞向组织的归巢。在乳腺癌中，C-C 趋化因子配体 2 (CCL2) 的过度表达与不良预后相关。外周血中 CCL2 水平升高表明该趋化因子可能对乳腺癌患者产生全身影响。在这里，我们研究了 CCL2 信号传导对肿瘤和非肿瘤环境中 SMW 的作用。在体外，增加 CCL2 浓度可通过涉及 JNK、SMAD3 和 AMPK 信号传导的 C-C 趋化因子受体 2 (CCR2) 依赖性机制抑制成肌细胞和肌管功能。在健康小鼠中，重组 CCL2 蛋白的递送以剂量依赖性方式促进 SMW。体内敲除乳腺肿瘤来源的 CCL2 可以部分防止 SMW。总体而言，慢性、上调的 CCL2/CCR2 信号传导可积极调节 SMW，对治疗靶向产生影响。© 2024。由 The Company of Biologies Ltd 出版。

Despite advancements in treatment, approximately 25% of breast cancer patients experience long-term skeletal muscle wasting (SMW), which limits mobility, reduces drug tolerance and adversely impacts survival. By understanding the underlying molecular mechanisms of SMW, we may develop new strategies to alleviate this condition and improve the lives of breast cancer patients. Chemokines are small soluble factors that regulate homing of immune cells to tissues during inflammation. In breast cancers, overexpression of the C-C chemokine ligand 2 (CCL2) correlates with unfavorable prognosis. Elevated levels of CCL2 in peripheral blood indicate possible systemic effects of this chemokine in breast cancer patients. Here, we investigated the role of CCL2 signaling on SMW in a tumor and non-tumor context. In vitro, increasing concentrations of CCL2 inhibits myoblast and myotube function through C-C chemokine receptor 2 (CCR2) dependent mechanisms involving JNK, SMAD3 and AMPK signaling. In healthy mice, delivery of recombinant CCL2 protein promotes SMW in a dose dependent manner. In vivo knockdown of breast tumor derived CCL2 partially protects against SMW. Overall, chronic, upregulated CCL2/CCR2 signaling positively regulates SMW, with implications on therapeutic targeting.© 2024. Published by The Company of Biologists Ltd.