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(American Journal of Pathology. 2005;167:749-759.)
© 2005 American Society for Investigative Pathology

Characterization of the Host Proinflammatory Response to Tumor Cells during the Initial Stages of Liver Metastasis

Abdel-Majid Khatib^*, Patrick Auguste^*,, Lucia Fallavollita^*, Ni Wang^*, Amir Samani^*, Maria Kontogiannea^*, Sarkis Meterissian^* and Pnina Brodt^*,

From the Departments of Surgery^* and Medicine, McGill University and the Royal Victoria Hospital, Quebec, Canada; and the Molecular Angiogenesis Laboratory, Institut National de la Santé et de la Recherche Médicale EMI 0113, Université Bordeaux 1, Talence, France

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)- 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-⁺ 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- 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- production as an early, tumor-selective host inflammatory response to liver-invading tumor cells that may influence the course of metastasis.

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