Neutrophils promote liver metastasis via Mac-1-mediated interactions with circulating tumor cells

Cancer Res. 2012 Aug 15;72(16):3919-27. doi: 10.1158/0008-5472.CAN-11-2393. Epub 2012 Jul 2.


Although circulating neutrophils are associated with distant metastasis and poor outcome in a number of epithelial malignancies, it remains unclear whether neutrophils play an active causal role in the metastatic cascade. Using in vivo models of metastasis, we found that neutrophils promote cancer cell adhesion within liver sinusoids and, thereby, influence metastasis. Neutrophil depletion before cancer cell inoculation resulted in a decreased number of gross metastases in an intrasplenic model of liver metastasis. This effect was reversed when inflamed neutrophils were co-inoculated with cancer cells. In addition, early adhesion within liver sinusoids was inhibited in the absence of neutrophils and partially restored with a short perfusion of isolated activated neutrophils. Intravital microscopy showed that cancer cells adhered directly on top of arrested neutrophils, indicating that neutrophils may act as a bridge to facilitate interactions between cancer cells and the liver parenchyma. The adhesion of lipopolysaccharide-activated neutrophils to cancer cells was mediated by neutrophil Mac-1/ICAM-1. Our findings, therefore, show a novel role for neutrophils in the early adhesive steps of liver metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Lewis Lung / blood
  • Carcinoma, Lewis Lung / immunology
  • Carcinoma, Lewis Lung / metabolism
  • Carcinoma, Lewis Lung / pathology
  • Cell Aggregation / physiology
  • Cell Communication / physiology
  • Cell Line, Tumor
  • Human Umbilical Vein Endothelial Cells / pathology
  • Humans
  • Lipopolysaccharides / pharmacology
  • Liver Neoplasms, Experimental / blood
  • Liver Neoplasms, Experimental / immunology
  • Liver Neoplasms, Experimental / metabolism
  • Liver Neoplasms, Experimental / secondary*
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Macrophage-1 Antigen / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Neoplastic Cells, Circulating / pathology*
  • Neutrophil Activation / drug effects
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Neutrophils / pathology*


  • Lipopolysaccharides
  • Macrophage-1 Antigen