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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*,{dagger}, Lucia Fallavollita*, Ni Wang*, Amir Samani*, Maria Kontogiannea*, Sarkis Meterissian* and Pnina Brodt*,{ddagger}

From the Departments of Surgery* and Medicine,{ddagger} McGill University and the Royal Victoria Hospital, Quebec, Canada; and the Molecular Angiogenesis Laboratory,{dagger} 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)-{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.




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