TCF4 enhances hepatic metastasis of colorectal cancer by regulating tumor-associated macrophage via CCL2/CCR2 signaling

Wei Tu,Wei Tu,Zhenzhen Zhou,Jin Gong,Jin Gong,Dean Tian,Dean Tian,Zhijun Wang,Zhijun Wang

doi:10.1038/s41419-021-04166-w

Abstract

Colorectal cancer (CRC) liver metastasis is a significant clinical problem for which better therapies are urgently needed. Tumor-associated macrophage, a major cell population in the tumor microenvironment, is a known contributor to primary cancer progression and cancer metastasis. Here, we found TAM recruitment and M2 polarization were increased in the hepatic metastatic lesion compared with the primary site of human CRC tissues. Moreover, Pearson correlation analysis showed that TAM recruitment and polarization were closely correlated with the elevated TCF4 expression in the metastatic site. To investigate the role of TCF4 in CRC liver metastasis, we generated a syngeneic mouse model using MC38 cells splenic injection. Results from in vivo experiments and mouse models revealed that TCF4 deficiency in MC38 cells does not affect their proliferation and invasion; however, it reduces TAM infiltration and M2 polarization in the metastasis site. Further studies indicated that these effects are mediated by the TCF4 regulated CCL2 and CCR2 expression. TCF4 or CCL2 silencing in the tumor cells prevent CRC liver metastasis in the mouse model. Altogether, these findings suggest that the TCF4-CCL2-CCR2 axis plays an essential role in CRC liver metastasis by enhancing TAMs recruitment and M2 polarization.

Highlights

Colorectal cancer(CRC) is the third diagnosed cancer and one of the leading causes of cancer-related deaths worldwide [1]
TCF4 expression is correlated with Tumor-associated macrophages (TAMs) recruitment and M2 phenotype in human CRC tissues To investigate the role of TCF4 in colorectal cancer liver metastasis, we compared TCF4 expression in human primary colorectal cancer and hepatic metastasis samples
Immunohistochemistry staining showed that TCF4 nuclear staining cells were significantly higher in hepatic metastasis samples than in primary sites (Fig. 1A)

Summary

Introduction

Colorectal cancer(CRC) is the third diagnosed cancer and one of the leading causes of cancer-related deaths worldwide [1]. Metastasis is the major cause that determines the prognosis of CRC in patients. The liver is the dominant metastatic site for CRC. To improve CRC patients’ overall survival, we need to further investigate the mechanism of CRC liver metastases and develop novel targets for the clinic therapeutic approaches. Emerging evidence demonstrated that the tumor microenvironment plays an essential role in tumor liver metastasis, including CRC [5,6,7,8]. Tumor-associated macrophages (TAMs) represent the majority of immune cells in the tumor microenvironment. The macrophage was believed to exert anti-tumor function previously [9, 10], increasing experimental evidence and abundant clinical data suggest that TAMs enhance tumor growth and metastasis [11,12,13,14]

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Results

Conclusion