Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma

Abstract

Tumor-associated macrophages (TAMs), a crucial component of immune cells infiltrated in tumor microenvironment, have been found to be associated with progression and metastasis of hepatocellular carcinoma (HCC). In this study, we aimed to clarify the mechanism underlying the crosstalk between TAMs and cancer stem cells (CSCs) in HCC. Mouse macrophage cell line RAW264.7 cells were used to investigate the effects of TAMs on mouse hepatoma cell line Hepa1-6 cells in vivo and vitro. A total of 90 clinical samples had pathology-proven HCC were used to evaluate the distribution of TAMs and CSCs and analyze their value in predicting the prognosis. In the study, we have found that the number of TAMs has a positive correlation with the density of CSCs in the marginal of human HCC. Our results show that, cocultured with TAM-conditioned medium (CM) promoted CSC-like properties in Hepa1-6 cells, which underwent EMT and gained higher invasive capability. TAMs secreted more transforming growth factor- beta1 (TGF-beta1) than other phenotypes of macrophage. Furthermore, depletion of TGF-beta1 blocked acquisition of CSC-like properties by inhibition of TGF-beta1-induced EMT. High expression of CD68 in the EpCAM positive expression HCC tissues was strongly associated with both poor cancer-free survival and overall survival in patients. Our results indicate that the TAMs promote CSC-like properties via TGF-beta1-induced EMT and they may contribute to investigate the prognosis of HCC.

Keywords: Cancer stem cells; Epithelial to mesenchymal transition; Hepatocellular carcinoma; Transforming growth factor-beta1; Tumor-associated macrophages.