Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma

J Hepatol. 2015 Mar;62(3):607-16. doi: 10.1016/j.jhep.2014.10.029. Epub 2014 Oct 30.


Background & aims: The roles of alternatively activated (M2) macrophages on pro-tumour phenotypes have been well documented in many cancers except hepatocellular carcinoma (HCC). Considering their close relationship with chronic tissue injuries as well as enhanced tumour invasiveness and growth, we aimed to investigate the direct effects of M2 macrophages on HCC.

Methods: M2 macrophages in 95 HCC clinical specimens were quantified using immunohistochemistry and quantitative PCR. The pro-tumour functions and the underlying molecular mechanisms of M2 macrophages in HCC were investigated in vivo and in an in vitro co-culture system.

Results: In the clinical study, high M2-specific CD163 (hazard ratio=2.693; p=0.043) and scavenger receptor A (hazard ratio=3.563; p=0.044) levels indicated poor prognosis and correlated with increased tumour nodules and venous infiltration in HCC patients. In an orthotopic model, the liver tumour volume was increased 3.26-fold (1.27 cm3±0.36) after M2 macrophage injection compared with the control (0.39 cm3±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 tumour 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 contribute to poor prognosis in HCC and promote tumour invasiveness through CCL22-induced EMT.

Keywords: Epithelial-mesenchymal transition; Hepatocellular carcinoma; Invasiveness; M2 macrophages; Prognostic predictor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / pathology*
  • Carcinoma, Hepatocellular / secondary
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • Chemokine CCL22 / metabolism
  • Coculture Techniques
  • Epithelial-Mesenchymal Transition / immunology
  • Female
  • Heterografts
  • Humans
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / pathology*
  • Macrophage Activation
  • Macrophages / classification
  • Macrophages / immunology*
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Neoplasm Invasiveness / immunology
  • Neoplasm Invasiveness / pathology
  • Prognosis
  • Receptors, CCR4 / metabolism
  • Receptors, Cell Surface / metabolism
  • Scavenger Receptors, Class A / metabolism
  • Young Adult


  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CCL22 protein, human
  • CCR4 protein, human
  • CD163 antigen
  • Chemokine CCL22
  • Receptors, CCR4
  • Receptors, Cell Surface
  • Scavenger Receptors, Class A