TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development

• Published in: The Journal of clinical investigation 2008-01, Vol.118 (1), p.100-110
• Main Authors: Grosse-Wilde, Anne, Voloshanenko, Oksana, Bailey, S Lawrence, Longton, Gary M, Schaefer, Uta, Csernok, Andreea I, Schütz, Günther, Greiner, Erich F, Kemp, Christopher J, Walczak, Henning
• Format: Article
• Language: English
• Subjects: Agonists (Biochemistry); Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biomedical research; Cancer; Carcinogens; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Care and treatment; Cell Adhesion; Dosage and administration; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Female; Health aspects; Ligands; Lymph Nodes - metabolism; Lymph Nodes - pathology; Lymphatic Metastasis; Lymphatic system; Male; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; Metastasis; Mice; Neoplasm Transplantation; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Papilloma - drug therapy; Papilloma - genetics; Papilloma - metabolism; Papilloma - pathology; Physiology; Receptors, TNF-Related Apoptosis-Inducing Ligand - biosynthesis; Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; TNF-Related Apoptosis-Inducing Ligand - genetics; TNF-Related Apoptosis-Inducing Ligand - metabolism; TNF-Related Apoptosis-Inducing Ligand - pharmacology; Tumor necrosis factor; Tumorigenesis; Tumors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI33061

TRAIL is a promising anticancer agent due to its ability to selectively induce apoptosis in established tumor cell lines but not nontransformed cells. Herein, we demonstrate a role for the apoptosis-inducing TRAIL receptor (TRAIL-R) as a metastasis suppressor. Although mouse models employing tumor transplantation have shown that TRAIL can reduce tumor growth, autochthonous tumor models have generated conflicting results with respect to the physiological role of the TRAIL system during tumorigenesis. We used a multistage model of squamous cell carcinoma to examine the role of TRAIL-R throughout all steps of tumor development. DMBA/TPA-treated TRAIL-R-deficient mice showed neither an increase in number or growth rate of benign papillomas nor an increase in the rate of progression to squamous cell carcinoma. However, metastasis to lymph nodes was significantly enhanced, indicating a role for TRAIL-R specifically in the suppression of metastasis. We also found that adherent TRAIL-R-expressing skin carcinoma cells were TRAIL resistant in vitro but were sensitized to TRAIL upon detachment by inactivation of the ERK signaling pathway. As detachment from the primary tumor is an obligatory step in metastasis, this provides a possible mechanism by which TRAIL-R could inhibit metastasis. Hence, treatment of cancer patients with agonists of the apoptosis-inducing receptors for TRAIL may prove useful in reducing the incidence of metastasis.