Alternatively Activated (m2) Macrophages Promote Tumour Growth And Invasiveness In Hepatocellular Carcinoma

Abstract

Background and Aim: The roles of alternatively activated (M2) macrophages on pro-tumor phenotypes have been well documented in many cancers except hepatocellular carcinoma (HCC). Considering their close relationship with chronic tissue injuries as well as enhanced tumor invasiveness and growth, we aimed to investigate the direct effects of M2 macrophages on HCC. Materials and Methods: M2 macrophages in 95 HCC clinical specimens were quantified using immunohistochemistry and quantitative PCR. The protumor functions and the underlying molecular mechanisms of M2 macrophages in HCC were investigated in vivo and in vitro co-culture system. Results: In the clinical study, high level M2 specific CD163 (hazard ratio=2.693; p = 0.043) and scavenger receptor A (hazard ratio=3.563; p = 0.044) indicated poor prognosis and correlated with increased tumor nodules and venous infiltration in HCC patients. In an orthotopic model, the liver tumor volume was increased 3.26-fold (1.27cm3±0.36) after M2 macrophages injection compared with the control (0.39cm3±0.05)(p = 0.032). An increased rate of lung metastasis was also found in the treatment group. In vitro, co-cultivation with M2 macrophages elevated the number of HCC cells (MHCC97L) and migration events by 1.3-fold and 3.2-fold, respectively (p <0.05). Strongly induced by MHCC97L, M2 macrophage-derived CCL22 was proven to enhance tumor migration capacities and correlate with venous infiltration in HCC patients. Increased epithelial-mesenchymal transition (EMT) via Snail activation in MHCC97L was found to be promoted by M2 macrophages and CCL22. Conclusions: M2 macrophages contributed to poor prognosis in HCC and promoted tumor invasiveness through CCL22 induced EMT.