STAT蛋白
贾纳斯激酶
癌症研究
车站3
斯达
JAK-STAT信号通路
肿瘤微环境
体内
生物
癌变
STAT1
巨噬细胞
Janus激酶1
状态5
信号转导
细胞因子
鲁索利替尼
细胞生物学
免疫系统
转录因子
免疫学
体外
癌症
骨髓
肿瘤细胞
酪氨酸激酶
生物技术
生物化学
遗传学
骨髓纤维化
作者
Emily A. Irey,Chelsea M. Lassiter,Nicholas J. Brady,Pavlina Chuntova,Ying Wang,Todd P. Knutson,Christine Henzler,Thomas S. Chaffee,Rachel Isaksson Vogel,Andrew C. Nelson,Michael A. Farrar,Kathryn L. Schwertfeger
标识
DOI:10.1073/pnas.1816410116
摘要
Tumor-associated macrophages contribute to tumor progression and therapeutic resistance in breast cancer. Within the tumor microenvironment, tumor-derived factors activate pathways that modulate macrophage function. Using in vitro and in vivo models, we find that tumor-derived factors induce activation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in macrophages. We also demonstrate that loss of STAT3 in myeloid cells leads to enhanced mammary tumorigenesis. Further studies show that macrophages contribute to resistance of mammary tumors to the JAK/STAT inhibitor ruxolitinib in vivo and that ruxolitinib-treated macrophages produce soluble factors that promote resistance of tumor cells to JAK inhibition in vitro. Finally, we demonstrate that STAT3 deletion and JAK/STAT inhibition in macrophages increases expression of the protumorigenic factor cyclooxygenase-2 (COX-2), and that COX-2 inhibition enhances responsiveness of tumors to ruxolitinib. These findings define a mechanism through which macrophages promote therapeutic resistance and highlight the importance of understanding the impact of targeted therapies on the tumor microenvironment.
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