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Metastasis Suppressor Function of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand-R in Mice: Implications for TRAIL-Based Therapy in Humans?

Department of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington

Requests for reprints: Anne Grosse-Wilde, Institute for System Biology, Seattle, WA 98103. Phone: 1-206-732-1355; Fax: 1-206-732-1299; E-mail: agwilde{at}systemsbiology.org.

Key Words: metastasis suppressor • therapy • TRAIL

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy, as it can induce apoptosis specifically in tumor cells but not in normal cells. Although earlier mouse tumor studies revealed a strong tissue dependency of TRAIL and its death receptor in suppressing primary tumorigenesis or experimental metastases, we recently found that TRAIL-R inhibits lymph node metastases without affecting primary tumor formation in a mouse model of multistage skin tumorigenesis. This finding uncouples the role of TRAIL in primary tumorigenesis from metastasis formation, likely by sensitization of previously TRAIL-resistant tumor cells upon detachment, an early step required for metastasis formation. Therefore, TRAIL-R is a novel metastasis suppressor, suggesting that TRAIL-related tumor therapy might be most effective in primary tumors and early metastatic cancers, before selection for TRAIL resistance occurs. [Cancer Res 2008;68(15):6035–7]

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