Extracellular-Regulated Protein Kinase 5-Mediated Control of p21 Expression Promotes Macrophage Proliferation Associated with Tumor Growth and Metastasis.
Extracellular-Regulated Protein Kinase 5-Mediated Control of p21 Expression Promotes Macrophage Proliferation Associated with Tumor Growth and Metastasis.
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DOI：
10.1158/0008-5472.can-19-2416
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发表时间：
2020-08-15
期刊：
影响因子：
11.2
通讯作者：
Tournier C
中科院分区：
文献类型：
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作者：
Giurisato E;Lonardi S;Telfer B;Lussoso S;Risa-Ebrí B;Zhang J;Russo I;Wang J;Santucci A;Finegan KG;Gray NS;Vermi W;Tournier C
在肿瘤微环境中被激活的免疫抑制巨噬细胞的存在是肿瘤生长和恶性的主要因素。根据这些知识，我们在这里报道巨噬细胞增殖是晚期癌症的一个重要特征。此外，我们还发现人类肿瘤中有高比例的增殖巨噬细胞表达细胞外调节蛋白激酶5 （ERK5）。ERK5是支持小鼠肿瘤移植物中巨噬细胞增殖所必需的。此外，髓系ERK5缺乏对转移性肺结节中常驻和浸润性巨噬细胞的增殖均有负面影响。ERK5通过抑制p21的表达来阻止巨噬细胞的分化程序，从而维持巨噬细胞的增殖能力。总的来说，这些数据提供了巨噬细胞增殖支持恶性肿瘤发展的机制，从而增强了erk5靶向治疗的价值，通过阻断致瘤前巨噬细胞激活来恢复抗肿瘤免疫。
The presence of immunosuppressive macrophages that become activated in the tumor microenvironment constitutes a major factor responsible for tumor growth and malignancy. In line with this knowledge, we report here that macrophage proliferation is a significant feature of advanced stages of cancer. Moreover, we have found that a high proportion of proliferating macrophages in human tumors express extracellular-regulated protein kinase 5 (ERK5). ERK5 was required for supporting the proliferation of macrophages in tumor grafts in mice. Furthermore, myeloid ERK5 deficiency negatively impacted the proliferation of both resident and infiltrated macrophages in metastatic lung nodules. ERK5 maintained the capacity of macrophages to proliferate by suppressing p21 expression to halt their differentiation program. Collectively, these data provide insight into the mechanism underpinning macrophage proliferation to support malignant tumor development, thereby strengthening the value of ERK5-targeted therapies to restore anti-tumor immunity through the blockade of pro-tumorigenic macrophage activation.