Macrophage activation increases the invasive properties of hepatoma cells by destabilization of the adherens junction

FEBS Lett. 2006 May 29;580(13):3042-50. doi: 10.1016/j.febslet.2006.04.049. Epub 2006 Apr 27.


Tumor-associated macrophages play an important role in tumor progression, but whether they exert a tumor-progressive effect remains controversial. Here, we demonstrated that activated macrophage-conditioned medium (AMCM) obtained from RAW macrophages (RAW/AMCM) induced epithelial-mesenchymal transition (EMT) and stimulated the migratory and invasive activities of HepG2 cells, whereas control conditioned media had no effect. Epithelial-cadherin (E-cadherin) and beta-catenin staining patterns were altered at the adherens junctions by RAW/AMCM treatment, with an approximately 50% decrease in E-cadherin and beta-catenin in the cell membrane. Importantly, levels of beta-catenin-associated E-cadherin were also decreased. Following RAW/AMCM treatment, enhanced activation of c-Src was seen prior to increased tyrosine phosphorylation of beta-catenin, and this led to the destabilization of adherens junctions. Pretreatment of HepG2 cells with the Src kinase inhibitor, PP2, completely abolished the effects of RAW/AMCM on the EMT, migration, invasion, and expression and association of E-cadherin and beta-catenin. AMCMs obtained from human THP-1 monocytes and mouse peritoneal macrophages also caused disassembly of the adherens junctions and migration of HepG2 cells. Furthermore, inhibition of the epidermal growth factor receptor (EGFR) with gefitinib partially prevented the downregulation of E-cadherin and beta-catenin at the adherens junctions and migration behavior induced by RAW/AMCM. Our results suggest that activated macrophages have a tumor-progressive effect on HepG2 cells which involves the c-Src- and EGFR-dependent signaling cascades.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adherens Junctions / drug effects
  • Adherens Junctions / immunology*
  • Animals
  • Cadherins / metabolism
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / pathology*
  • Cell Movement* / drug effects
  • Culture Media, Conditioned / pharmacology
  • Down-Regulation
  • ErbB Receptors / antagonists & inhibitors
  • Humans
  • Interleukins / pharmacology
  • Liver Neoplasms / immunology
  • Liver Neoplasms / pathology*
  • Macrophage Activation*
  • Macrophages, Peritoneal / immunology*
  • Mice
  • Neoplasm Invasiveness
  • Phosphorylation
  • Pyrimidines / pharmacology
  • Tyrosine / metabolism
  • beta Catenin / metabolism
  • src-Family Kinases / antagonists & inhibitors


  • AG 1879
  • Cadherins
  • Culture Media, Conditioned
  • Interleukins
  • Pyrimidines
  • beta Catenin
  • Tyrosine
  • ErbB Receptors
  • src-Family Kinases