趋化因子
CCR2型
癌症研究
四氯化碳
乳腺癌
肿瘤微环境
骨骼肌
炎症
医学
生物
免疫学
趋化因子受体
内科学
癌症
免疫系统
作者
NULL AUTHOR_ID,NULL AUTHOR_ID,NULL AUTHOR_ID,NULL AUTHOR_ID,NULL AUTHOR_ID,NULL AUTHOR_ID,NULL AUTHOR_ID,John P. Thyfault,NULL AUTHOR_ID,NULL AUTHOR_ID,Nikki Cheng
摘要
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.
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