MAPKAP Kinase-2 Drives Expression of Angiogenic Factors by Tumor-Associated Macrophages in a Model of Inflammation-Induced Colon Cancer.
MAPKAP Kinase-2 Drives Expression of Angiogenic Factors by Tumor-Associated Macrophages in a Model of Inflammation-Induced Colon Cancer.
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MAPKAP激酶-2驱动炎症诱导结肠癌模型中肿瘤相关巨噬细胞表达血管生成因子
DOI：
10.3389/fimmu.2020.607891
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发表时间：
2020
影响因子：
7.3
通讯作者：
Yaffe MB
中科院分区：
文献类型：
--
作者：
Suarez-Lopez L;Kong YW;Sriram G;Patterson JC;Rosenberg S;Morandell S;Haigis KM;Yaffe MB
慢性炎症通过与肿瘤微环境相关的多种机制增加结直肠癌的风险。MAPK激活的蛋白激酶2(MK2)是p38MAPK应激和DNA损伤反应信号通路的主要效应者，也是促炎细胞因子产生的关键调节因子，已被认为是慢性炎症条件下结肠肿瘤发生的关键因素。我们之前已经描述了结肠癌炎症模型中MK2的基因失活如何导致肿瘤进展延迟，肿瘤血管生成减少，并损害巨噬细胞向促肿瘤M2样状态的分化。然而，导致血管生成受损和肿瘤进展的分子机制仍然存在争议和模糊。在这里，通过RNA表达分析、血管生成因子的分析、遗传模型、体内巨噬细胞的耗竭和通过过继细胞转移重建巨噬细胞MK2的功能，我们证明了在炎症诱导的肿瘤进展过程中，巨噬细胞中的MK2活性是肿瘤血管生成的必要条件和充分条件。我们发现，除了MK2依赖于肿瘤微环境中几种细胞对Serpin-E1/PAI-1的调节外，MK2对肿瘤相关巨噬细胞分泌的众所周知的促血管生成因子CXCL-12/SDF-1的调节也具有关键的、以前未被认识到的作用。
Chronic inflammation increases the risk for colorectal cancer through a variety of mechanisms involving the tumor microenvironment. MAPK-activated protein kinase 2 (MK2), a major effector of the p38 MAPK stress and DNA damage response signaling pathway, and a critical regulator of pro-inflammatory cytokine production, has been identified as a key contributor to colon tumorigenesis under conditions of chronic inflammation. We have previously described how genetic inactivation of MK2 in an inflammatory model of colon cancer results in delayed tumor progression, decreased tumor angiogenesis, and impaired macrophage differentiation into a pro-tumorigenic M2-like state. The molecular mechanism responsible for the impaired angiogenesis and tumor progression, however, has remained contentious and poorly defined. Here, using RNA expression analysis, assays of angiogenesis factors, genetic models, in vivo macrophage depletion and reconstitution of macrophage MK2 function using adoptive cell transfer, we demonstrate that MK2 activity in macrophages is necessary and sufficient for tumor angiogenesis during inflammation-induced cancer progression. We identify a critical and previously unappreciated role for MK2-dependent regulation of the well-known pro-angiogenesis factor CXCL-12/SDF-1 secreted by tumor associated-macrophages, in addition to MK2-dependent regulation of Serpin-E1/PAI-1 by several cell types within the tumor microenvironment.
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影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
7.3
作者：
Albini A;Bruno A;Noonan DM;Mortara L
通讯作者：
Mortara L
影响因子：
5.5
作者：
Gaestel M
通讯作者：
Gaestel M
影响因子：
4.8
作者：
Enslen, H;Raingeaud, J;Davis, RJ
通讯作者：
Davis, RJ
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I