Crosstalk between hepatic tumor cells and macrophages via Wnt/β-catenin signaling promotes M2-like macrophage polarization and reinforces tumor malignant behaviors

• Published in: Cell death & disease Vol. 9; no. 8; pp. 793 - 14
• Main Authors: Yang, Yang, Ye, Yu-Chen, Chen, Yan, Zhao, Jun-Long, Gao, Chun-Chen, Han, Hua, Liu, Wen-Chao, Qin, Hong-Yan
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 18.07.2018; Nature Publishing Group UK
• Subjects: Animals; beta Catenin - antagonists & inhibitors; beta Catenin - genetics; beta Catenin - metabolism; Bone Marrow Cells - cytology; c-Myc protein; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell activation; Cell Differentiation; Cell Line, Tumor; Coculture Techniques; Hepatocellular carcinoma; Humans; Immunosuppression; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Leukocyte migration; Ligands; Liver cancer; Liver Neoplasms - immunology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Macrophages; Macrophages - cytology; Macrophages - immunology; Macrophages - metabolism; Metastases; Mice; Mice, Inbred C57BL; Monocytes; Monocytes - cytology; Monocytes - metabolism; Myc protein; Paracrine Communication; Phenotypes; Polarization; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Tumor cells; Tumor Microenvironment; Tumorigenesis; Wnt protein; Wnt Signaling Pathway; Wnt3A Protein - genetics; Wnt3A Protein - metabolism; β-Catenin
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-0818-0

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.