Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various tumor cells in vitro, but its physiological role in tumor surveillance remains unknown. Here, we report that TRAIL is constitutively expressed on murine natural killer (NK) cells in the liver and plays a substantial role in suppressing tumor metastasis. Freshly isolated NK cells, but not natural killer T cells or ordinary T cells, from the liver expressed cell surface TRAIL, which was responsible for spontaneous cytotoxicity against TRAIL-sensitive tumor cells in vitro along with perforin and Fas ligand (FasL). Administration of neutralizing monoclonal antibody against TRAIL significantly increased experimental liver metastases of several TRAIL-sensitive tumor cell lines. Such an anti-metastatic effect of TRAIL was not observed in NK cell–depleted mice or interferon-γ–deficient mice, the latter of which lacked TRAIL on liver NK cells. These findings provide the first evidence for the physiological function of TRAIL as a tumor suppressor.
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Acknowledgements
This work was supported by grant-in-aids for Scientific Research from the Princess Takamatsu Cancer Research Fund (99-23110) and the Ministry of Education, Science, and Culture, Japan. M.J.S. was supported by the National Health and Medical Research Council of Australia.We thank T. Sayers and R. Wiltrout for Renca cells and advice, and H. Akiba, H. Matsuda and E. Cretney for technical assistance.
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Takeda, K., Hayakawa, Y., Smyth, M. et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 7, 94–100 (2001). https://doi.org/10.1038/83416
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DOI: https://doi.org/10.1038/83416
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