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

Abstract

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.

Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights

“…In the absence of death/apoptotic signal to VECs, this provided a mechanism for the stimulation of VECs via macrophages and tumor angiogenesis (68). Also, Wnt ligands secreted by tumor cells could stimulate the polarization of TAMs to M2 subtype via the canonical Wnt signaling pathway, resulting in tumor growth and migration (69). Moreover, macrophage-derived soluble factors also induced canonical Wnt signaling pathway and promoted tumor growth and metastasis.…”

Wnt Signaling Cascade in Dendritic Cells and Regulation of Anti-tumor Immunity

“…Wnt-β-catenin signaling regulates macrophages functions, such as adhesion, migration and tissue recruitment (35,36) Wnt-b-catenin signaling promotes M2-like polarization of TAMs resulting in tumor growth, migration, metastasis, and immunosuppression (35,37,38) Wnts produced by macrophages drive contribute to tumor cell invasiveness and tumor growth (35,37,38)…”

“…Tumorassociated macrophages (TAMs) play an important role in tumor progression and immune suppression (76)(77)(78). Wnts regulate macrophage functions, such as adhesion, migration, and tissue recruitment (35). In addition, it is well-documented that Wnts produced by macrophages is critical for tissue development and repair (35).…”

“…Wnts regulate macrophage functions, such as adhesion, migration, and tissue recruitment (35). In addition, it is well-documented that Wnts produced by macrophages is critical for tissue development and repair (35). Emerging studies have shown that Wnts produced by macrophages contribute to tumor cell invasiveness and tumor growth (36,37).…”

Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression

“…M2 polarization of TAMs is a multi-factor, multi-step and complex pathological process (13). Recent studies have shown that Wnt signaling plays a major role in M2-like TAMs polarization (14,15). Wnt5a, a member of Wnt family, binds to the frizzled receptor and LRP5/6 co-receptors to regulate multiple signaling pathways (16), thereby altering TME by inducing adipocytes to dedifferentiate into fibroblastlike cells or mesenchymal cells (17).…”