Liver endothelial cells participate in T-cell-dependent host resistance to lymphoma metastasis by production of nitric oxide in vivo.
Tumor growth and metastasis of lacZ-transduced murine lymphoma ESbL cells inoculated into syngeneic DBA/2 mice are characterized by a transient plateau phase with a constant tumor diameter and low metastatic load, indicating a host response against the tumor. Here we show that endothelial cells participate in a T-cell-dependent, anti-metastatic response by producing NO in situ. Liver endothelial cells were isolated and examined directly ex vivo without further manipulation. NO production in liver endothelial cells reached the highest level during the plateau phase but declined toward the end of it, followed by an overall breakdown of host response, leading to progressive tumor growth and high load of liver metastasis. Mice subjected to anti-tumor immunization and subsequent challenge with a tumorigenic dose of ESbL-lacZ cells showed, in comparison to non-immunized challenged controls, reduced liver metastasis and increased endothelial NO production. Adoptive transfer of anti-tumor immune spleen cells from semi-allogeneic B10.D2 mice into tumor-bearing animals during the plateau phase caused a regression of primary tumor and metastases, together with a preservation of the high level of NO synthesis in endothelial cells. In immuno-incompetent (SCID) mice, tumor growth and metastasis were progressive and there was no endothelial NO response. Pre-immunization of immuno-competent mice with both live and irradiated tumor cells at different sites of the body led to an induction of NO production by liver endothelial cells. These results reveal a novel role of endothelial cells in the suppression of lymphoma metastasis in the liver. The inducible endothelial cell NO response is apparently dependent and induced by mature T lymphocytes.
Rocha
M
M
Division of Cellular Immunology, German Cancer Research Center, Heidelberg, Germany.
Krüger
A
A
Van Rooijen
N
N
Schirrmacher
V
V
Umansky
V
V
D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism*; D016219:Immunotherapy, Adoptive; D007728:Kupffer Cells / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000556:secondary*; D008223:Lymphoma / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D009569:Nitric Oxide / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000276:immunology*
D009569:Nitric Oxide