Crosstalk between hepatic tumor cells and macrophages via Wnt/β-catenin signaling promotes M2-like macrophage polarization and reinforces tumor malignant behaviors.
Crosstalk between hepatic tumor cells and macrophages via Wnt/β-catenin signaling promotes M2-like macrophage polarization and reinforces tumor malignant behaviors.
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肝肿瘤细胞和巨噬细胞之间通过 Wnt/β-catenin 信号传导促进 M2 样巨噬细胞极化并强化肿瘤恶性行为
DOI：
10.1038/s41419-018-0818-0
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发表时间：
2018-07-18
影响因子：
9
通讯作者：
Qin HY
中科院分区：
文献类型：
--
作者：
Yang Y;Ye YC;Chen Y;Zhao JL;Gao CC;Han H;Liu WC;Qin HY
肿瘤相关巨噬细胞（Tumor-associated macrophages，TAMs）是肿瘤微环境（tumor microenvironment，TME）的重要组成部分，在肝细胞癌（hepatocellular carcinoma，HCC）的发生、发展中起着重要作用。Wnt信号转导在进化上是保守的，并参与肝脏肿瘤的发生。一些研究表明，巨噬细胞衍生的Wnt配体可以激活肿瘤细胞中的Wnt信号传导。然而，肿瘤细胞分泌的Wnt配体是否可以触发巨噬细胞中的Wnt信号转导仍然是难以捉摸的。在这项研究中，我们首先验证了经典Wnt/β-catenin信号传导在单核细胞向巨噬细胞分化期间和在M2极化的巨噬细胞中被激活。在一系列实验中，M2巨噬细胞中β-catenin的敲低在与Hepa 1 -6肝癌细胞共培养时表现出更强的抗肿瘤特性。Wnt信号的激活通过c-Myc促进M2巨噬细胞极化。此外，将幼稚巨噬细胞与通过敲低Wntless阻断Wnt配体分泌的Hepa 1 -6 HCC细胞共培养在体外抑制了M2极化。一致地，原位接种Wnt沉默的Hepa 1 -6细胞的HCC肿瘤的生长受到阻碍，并且由于TAM中的Wnt/β-连环蛋白信号转导减弱，M2样TAM的表型被废除，导致破坏的免疫抑制性TME。最后，我们证实了M2巨噬细胞极化和人HCC活检中CD 68+巨噬细胞核β-连环蛋白积累之间的相关性。总之，我们的研究表明，肿瘤细胞来源的Wnt配体通过经典的Wnt/β-catenin信号传导刺激TAM的M2样极化，这导致HCC中的肿瘤生长、迁移、转移和免疫抑制。阻断肿瘤细胞分泌Wnt和/或TAMs中Wnt/β-catenin信号通路可能是未来肝癌治疗的潜在策略。
Tumor-associated macrophages (TAMs) are a major component of tumor microenvironment (TME) and play pivotal roles in the progression of hepatocellular carcinoma (HCC). Wnt signaling is evolutionarily conserved and participates in liver tumorigenesis. Several studies have shown that macrophage-derived Wnt ligands can activate Wnt signaling in tumor cells. However, whether Wnt ligands secreted by tumor cells can trigger Wnt signaling in macrophages is still elusive. In this study, we first verified that canonical Wnt/β-catenin signaling was activated during monocyte-to-macrophage differentiation and in M2-polarized macrophages. Knockdown of β-catenin in M2 macrophages exhibited stronger antitumor characteristics when cocultured with Hepa1-6 HCC cells in a series of experiments. Activation of Wnt signaling promoted M2 macrophage polarization through c-Myc. Moreover, co-culturing naïve macrophages with Hepa1-6 HCC cells in which Wnt ligands secretion was blocked by knockdown of Wntless inhibited M2 polarization in vitro. Consistently, the growth of HCC tumor orthotopically inoculated with Wntless-silenced Hepa1-6 cells was impeded, and the phenotype of M2-like TAMs was abrogated due to attenuated Wnt/β-catenin signaling in TAMs, leading to subverted immunosuppressive TME. Finally, we confirmed the correlation between M2 macrophage polarization and nuclear β-catenin accumulation in CD68+macrophages in human HCC biopsies. Taken together, our study indicates that tumor cells-derived Wnt ligands stimulate M2-like polarization of TAMs via canonical Wnt/β-catenin signaling, which results in tumor growth, migration, metastasis, and immunosuppression in HCC. To block Wnts secretion from tumor cells and/or Wnt/β-catenin signal activation in TAMs may be potential strategy for HCC therapy in future.
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影响因子：
3.7
作者：
Cosín-Roger J;Ortiz-Masiá D;Calatayud S;Hernández C;Alvarez A;Hinojosa J;Esplugues JV;Barrachina MD
通讯作者：
Barrachina MD
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
2.9
作者：
Brown, Anna L.;Salerno, Diana G.;Sadras, Teresa;Engler, Grant A.;Kok, Chung H.;Wilkinson, Christopher R.;Samaraweera, Saumya E.;Sadlon, Timothy J.;Perugini, Michelle;Lewis, Ian D.;Gonda, Thomas J.;D'Andrea, Richard J.
通讯作者：
D'Andrea, Richard J.
影响因子：
15.9
作者：
Kim, Wantae;Khan, Sanjoy Kumar;Yang, Yingzi
通讯作者：
Yang, Yingzi
影响因子：
2.6
作者：
Baena, Esther;Ortiz, Maitane;de Alboran, Ignacio Moreno
通讯作者：
de Alboran, Ignacio Moreno