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Research Article Free access | 10.1172/JCI33061

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

Anne Grosse-Wilde,1,2 Oksana Voloshanenko,2 S. Lawrence Bailey,1 Gary M. Longton,3 Uta Schaefer,2 Andreea I. Csernok,2 Günther Schütz,4 Erich F. Greiner,4 Christopher J. Kemp,1 and Henning Walczak2,5

1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 2Division of Apoptosis Regulation, German Cancer Research Center, Heidelberg, Germany. 3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 4Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany 5Tumour Immunology Unit, Division of Medicine, Imperial College London, London, United Kingdom.

Address correspondence to: Henning Walczak, Tumour Immunology Unit, Department of Immunology, Imperial College London, Hammersmith Hospital Campus, 10N6-Commonwealth Building, Du Cane Road, London W12 ONN, United Kingdom. Phone: 44-208-38-32094; Fax: 44-208-38-32788; E-mail: h.walczak@imperial.ac.uk. Or to: Christopher J. Kemp, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. Phone: (206) 667-4252; Fax: (206) 667-5815; E-mail: cjkemp@fhcrc.org.

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1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 2Division of Apoptosis Regulation, German Cancer Research Center, Heidelberg, Germany. 3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 4Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany 5Tumour Immunology Unit, Division of Medicine, Imperial College London, London, United Kingdom.

Address correspondence to: Henning Walczak, Tumour Immunology Unit, Department of Immunology, Imperial College London, Hammersmith Hospital Campus, 10N6-Commonwealth Building, Du Cane Road, London W12 ONN, United Kingdom. Phone: 44-208-38-32094; Fax: 44-208-38-32788; E-mail: h.walczak@imperial.ac.uk. Or to: Christopher J. Kemp, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. Phone: (206) 667-4252; Fax: (206) 667-5815; E-mail: cjkemp@fhcrc.org.

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1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 2Division of Apoptosis Regulation, German Cancer Research Center, Heidelberg, Germany. 3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 4Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany 5Tumour Immunology Unit, Division of Medicine, Imperial College London, London, United Kingdom.

Address correspondence to: Henning Walczak, Tumour Immunology Unit, Department of Immunology, Imperial College London, Hammersmith Hospital Campus, 10N6-Commonwealth Building, Du Cane Road, London W12 ONN, United Kingdom. Phone: 44-208-38-32094; Fax: 44-208-38-32788; E-mail: h.walczak@imperial.ac.uk. Or to: Christopher J. Kemp, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. Phone: (206) 667-4252; Fax: (206) 667-5815; E-mail: cjkemp@fhcrc.org.

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1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 2Division of Apoptosis Regulation, German Cancer Research Center, Heidelberg, Germany. 3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 4Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany 5Tumour Immunology Unit, Division of Medicine, Imperial College London, London, United Kingdom.

Address correspondence to: Henning Walczak, Tumour Immunology Unit, Department of Immunology, Imperial College London, Hammersmith Hospital Campus, 10N6-Commonwealth Building, Du Cane Road, London W12 ONN, United Kingdom. Phone: 44-208-38-32094; Fax: 44-208-38-32788; E-mail: h.walczak@imperial.ac.uk. Or to: Christopher J. Kemp, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. Phone: (206) 667-4252; Fax: (206) 667-5815; E-mail: cjkemp@fhcrc.org.

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1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 2Division of Apoptosis Regulation, German Cancer Research Center, Heidelberg, Germany. 3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 4Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany 5Tumour Immunology Unit, Division of Medicine, Imperial College London, London, United Kingdom.

Address correspondence to: Henning Walczak, Tumour Immunology Unit, Department of Immunology, Imperial College London, Hammersmith Hospital Campus, 10N6-Commonwealth Building, Du Cane Road, London W12 ONN, United Kingdom. Phone: 44-208-38-32094; Fax: 44-208-38-32788; E-mail: h.walczak@imperial.ac.uk. Or to: Christopher J. Kemp, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. Phone: (206) 667-4252; Fax: (206) 667-5815; E-mail: cjkemp@fhcrc.org.

Find articles by Schaefer, U. in: PubMed | Google Scholar

1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 2Division of Apoptosis Regulation, German Cancer Research Center, Heidelberg, Germany. 3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 4Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany 5Tumour Immunology Unit, Division of Medicine, Imperial College London, London, United Kingdom.

Address correspondence to: Henning Walczak, Tumour Immunology Unit, Department of Immunology, Imperial College London, Hammersmith Hospital Campus, 10N6-Commonwealth Building, Du Cane Road, London W12 ONN, United Kingdom. Phone: 44-208-38-32094; Fax: 44-208-38-32788; E-mail: h.walczak@imperial.ac.uk. Or to: Christopher J. Kemp, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. Phone: (206) 667-4252; Fax: (206) 667-5815; E-mail: cjkemp@fhcrc.org.

Find articles by Csernok, A. in: PubMed | Google Scholar

1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 2Division of Apoptosis Regulation, German Cancer Research Center, Heidelberg, Germany. 3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 4Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany 5Tumour Immunology Unit, Division of Medicine, Imperial College London, London, United Kingdom.

Address correspondence to: Henning Walczak, Tumour Immunology Unit, Department of Immunology, Imperial College London, Hammersmith Hospital Campus, 10N6-Commonwealth Building, Du Cane Road, London W12 ONN, United Kingdom. Phone: 44-208-38-32094; Fax: 44-208-38-32788; E-mail: h.walczak@imperial.ac.uk. Or to: Christopher J. Kemp, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. Phone: (206) 667-4252; Fax: (206) 667-5815; E-mail: cjkemp@fhcrc.org.

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1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 2Division of Apoptosis Regulation, German Cancer Research Center, Heidelberg, Germany. 3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 4Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany 5Tumour Immunology Unit, Division of Medicine, Imperial College London, London, United Kingdom.

Address correspondence to: Henning Walczak, Tumour Immunology Unit, Department of Immunology, Imperial College London, Hammersmith Hospital Campus, 10N6-Commonwealth Building, Du Cane Road, London W12 ONN, United Kingdom. Phone: 44-208-38-32094; Fax: 44-208-38-32788; E-mail: h.walczak@imperial.ac.uk. Or to: Christopher J. Kemp, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. Phone: (206) 667-4252; Fax: (206) 667-5815; E-mail: cjkemp@fhcrc.org.

Find articles by Greiner, E. in: PubMed | Google Scholar

1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 2Division of Apoptosis Regulation, German Cancer Research Center, Heidelberg, Germany. 3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 4Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany 5Tumour Immunology Unit, Division of Medicine, Imperial College London, London, United Kingdom.

Address correspondence to: Henning Walczak, Tumour Immunology Unit, Department of Immunology, Imperial College London, Hammersmith Hospital Campus, 10N6-Commonwealth Building, Du Cane Road, London W12 ONN, United Kingdom. Phone: 44-208-38-32094; Fax: 44-208-38-32788; E-mail: h.walczak@imperial.ac.uk. Or to: Christopher J. Kemp, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. Phone: (206) 667-4252; Fax: (206) 667-5815; E-mail: cjkemp@fhcrc.org.

Find articles by Kemp, C. in: PubMed | Google Scholar

1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 2Division of Apoptosis Regulation, German Cancer Research Center, Heidelberg, Germany. 3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 4Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany 5Tumour Immunology Unit, Division of Medicine, Imperial College London, London, United Kingdom.

Address correspondence to: Henning Walczak, Tumour Immunology Unit, Department of Immunology, Imperial College London, Hammersmith Hospital Campus, 10N6-Commonwealth Building, Du Cane Road, London W12 ONN, United Kingdom. Phone: 44-208-38-32094; Fax: 44-208-38-32788; E-mail: h.walczak@imperial.ac.uk. Or to: Christopher J. Kemp, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. Phone: (206) 667-4252; Fax: (206) 667-5815; E-mail: cjkemp@fhcrc.org.

Find articles by Walczak, H. in: PubMed | Google Scholar

Published December 13, 2007 - More info

J Clin Invest. https://doi.org/10.1172/JCI33061.
© 2007 The American Society for Clinical Investigation
Published December 13, 2007 - Version history
Received: June 21, 2007; Accepted: October 24, 2007
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Abstract

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.

Version history
  • Version 1 (December 13, 2007): No description
  • Version 2 (January 2, 2008): No description
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