Characterization of the host proinflammatory response to tumor cells during the initial stages of liver metastasis.
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.
Khatib
Abdel-Majid
AM
Department of Surgery, Royal Victoria Hospital, Room H6.25, 687 Pine Ave., W. Montreal, Quebec, Canada H3A 1A1.
Auguste
Patrick
P
Fallavollita
Lucia
L
Wang
Ni
N
Samani
Amir
A
Kontogiannea
Maria
M
Meterissian
Sarkis
S
Brodt
Pnina
P
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000378:metabolism* / Q000556:secondary*; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000556:secondary*; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D016207:Cytokines; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1