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

Abstract

Background: Tumor-associated macrophages (TAMs) in the tumor microenvironment influence tumor initiation, invasion and metastasis. Several studies have shown that Wnt5a is mainly expressed in the tumor stroma, especially in TAMs. However, whether Wnt5a regulates the polarization and biological function of TAMs in colorectal cancer (CRC) is incompletely understood. Methods: Immunofluorescence staining was performed to detect CD68 and Wnt5a expression in colorectal tissues from patients (63 CRC specimens VS 20 normal tissues). RT-qPCR, flow cytometry, ELISA and inhibitors were carried out to explore the role of Wnt5a in the polarization of TAMs. Clone formation and transwell assays were performed to determine the effects of Wnt5a-treated macrophages on tumor proliferation, migration and invasion in vitro. Finally, a xenograft model was applied to confirm the effects of Wnt5a + TAMs on CRC tumorigenesis. Results: We found that high Wnt5a + CD68 + /CD68 + TAMs ratio was significantly associated with poor prognosis in CRC patients and Wnt5a + TAM was an M2-like TAM subtype. Subsequently, we found that Wnt5a induced macrophages to secrete IL-10, which then acted as an autocrine cytokine to induce M2 polarization of these macrophages. IL-10 neutralizing antibody completely reversed the pro-M2 effect of Wnt5a. Mechanistically, the CaKMII-ERK1/2-STAT3 pathway was required for Wnt5a-mediated IL-10 expression in macrophages. Furthermore, Wnt5a-induced M2 macrophages promoted CRC cells proliferation, migration and invasion; knockdown of Wnt5a in TAMs significantly impaired the pro-tumor functions of TAMs. Conclusions: Our data indicate that Wnt5a could induce M2 polarization of TAMs by regulating CaKMII-ERK1/2-STAT3 pathway-mediated IL-10 secretion, ultimately promoting tumor growth and metastasis of CRC.

PAFAH1B3 Expression Is Correlated With Gastric Cancer Cell Proliferation and Immune Infiltration

“…Accumulating evidence has elucidated their clinicopathological significance in predicting the outcomes and therapeutic efficacy in cancer patients (18,19). The infiltration of CD8positive T cells and tumor-associated macrophages was reported to facilitate the progression of epithelial gastric cancer (20)(21)(22). In the present study, infiltration levels of CD8-positive T cells and M1 macrophages were significantly higher in the gastric cancer group with high PAFAH1B3 expression.…”

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

“…Liu et al showed that a high Wnt5a+CD68+/CD68+ TAMs ratio can be associated with poor prognosis in colorectal cancer patients. Moreover, they revealed that Wnt5a could induce an M2-like polarization of TAMs, promoting tumor growth and metastasis [ 84 ]. It was also demonstrated that TAMs in colorectal cancer are able to promote angiogenesis and metastasis through the secretion of VEGF [ 102 ].…”

Polarization of intestinal tumour-associated macrophages regulates the development of schistosomal colorectal cancer

“…Schistosomiasis may alter the mechanism underlying the development and progression of CRC, leading to changes in its clinicopathological features and prognosis [37]. TAMs may play an important role in this process [38][39][40][41][42]. In this study, we found that the number of TAMs and the proportion of M2 TAMs in schistosomal CRC tissues were much higher than that in non-schistosomal CRC tissues; both differences were significant.…”