C-C 趋化因子配体 2 信号传导促进了非肿瘤和乳腺肿瘤小鼠模型中骨骼肌的萎缩。

IF 4 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2024-08-01 Epub Date: 2024-09-09 DOI:10.1242/dmm.050398
Nadia Alissa, Wei Bin Fang, Marcela Medrano, Nick Bergeron, Yuuka Kozai, Qingting Hu, Chloe Redding, John Thyfault, Jill Hamilton-Reeves, Cory Berkland, Nikki Cheng
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引用次数: 0

摘要

尽管治疗手段不断进步,但仍有约 25% 的乳腺癌患者会出现长期骨骼肌萎缩 (SMW),这限制了患者的活动能力,降低了患者对药物的耐受性,并对患者的生存产生不利影响。通过了解骨骼肌萎缩的潜在分子机制,我们可能会开发出缓解这一症状的新策略,改善乳腺癌患者的生活。趋化因子是一种小型可溶性因子,可在炎症期间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)的过度表达与预后不良有关。外周血中 CCL2 水平的升高表明这种趋化因子可能对乳腺癌患者产生全身性影响。在此,我们研究了 CCL2 信号在肿瘤和非肿瘤情况下对 SMW 的作用。在体外,通过涉及 JNK、SMAD3 和 AMPK 信号转导的 C-C 趋化因子受体 2(CCR2)依赖性机制,增加 CCL2 的浓度可抑制成肌细胞和肌管的功能。在健康小鼠体内,给药重组 CCL2 蛋白会以剂量依赖的方式促进 SMW。体内敲除乳腺肿瘤衍生的 CCL2 可部分抵御 SMW。总之,长期上调的 CCL2/CCR2 信号对 SMW 有积极的调节作用,这对靶向治疗具有重要意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
CCL2 signaling promotes skeletal muscle wasting in non-tumor and breast tumor models.

Despite advancements in treatment, approximately 25% of patients with breast cancer 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 be able to develop new strategies to alleviate this condition and improve the lives of patients with breast cancer. Chemokines are small soluble factors that regulate homing of immune cells to tissues during inflammation. In breast cancers, overexpression of 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 patients with breast cancer. Here, we investigated the role of CCL2 signaling on SMW in tumor and non-tumor contexts. In vitro, increasing concentrations of CCL2 inhibited 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 promoted SMW in a dose-dependent manner. In vivo knockdown of breast tumor-derived CCL2 partially protected against SMW. Overall, chronic, upregulated CCL2-CCR2 signaling positively regulates SMW, with implications for therapeutic targeting.

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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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