Characterization of the host proinflammatory response to tumor cells during the initial stages of liver metastasis

Am J Pathol. 2005 Sep;167(3):749-59. doi: 10.1016/S0002-9440(10)62048-2.


The influx of metastatic tumor cells into the liver triggers a rapid proinflammatory cytokine cascade. To further analyze this host response, we used intrasplenic/portal inoculation of green fluorescent protein-marked human and murine carcinoma cells and a combination of immunohistochemistry and confocal microscopy. The metastatic murine lung carcinoma H-59 or human colorectal carcinoma CX-1 cells triggered tumor necrosis factor (TNF)-alpha production by Kupffer cells located in sinusoidal vessels around the invading tumor cells. H-59 cells rapidly elicited a fourfold increase in the number of TNF-alpha(+) Kupffer cells relative to basal levels within 2 hours and this response declined gradually after 6 hours. Increased cytokine production in these mice was confirmed by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay performed on isolated Kupffer cells. CX-1 cells elicited a more gradual response that peaked at 10 to 16 hours, remained high up to 48 hours, and involved CX-1-Kupffer cell attachment. Furthermore, the rapidly induced production of TNF-alpha was followed by increased expression of the vascular adhesion receptors E-selectin P-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 on sinusoidal endothelial cells. This proinflammatory response was tumor-specific and was not observed with nonmetastatic murine M-27 or human MIP-101 carcinoma cells. These results identify Kupffer cell-mediated TNF-alpha production as an early, tumor-selective host inflammatory response to liver-invading tumor cells that may influence the course of metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Lewis Lung / metabolism*
  • Carcinoma, Lewis Lung / secondary*
  • Cells, Cultured
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / secondary*
  • Cytokines / metabolism*
  • Humans
  • Inflammation Mediators / metabolism*
  • Kupffer Cells / metabolism*
  • Macrophages / metabolism
  • Mice
  • Neoplasm Transplantation
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Up-Regulation
  • Vascular Cell Adhesion Molecule-1 / metabolism


  • Cytokines
  • Inflammation Mediators
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1