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

被引:159
作者
Grosse-Wilde, Anne [1 ,2 ,3 ]
Voloshanenko, Oksana [2 ,3 ]
Bailey, S. Lawrence [1 ]
Longton, Gary M. [4 ]
Schaefer, Uta [2 ,3 ]
Csernok, Andreea I. [2 ,3 ]
Schuetz, Guenter [5 ]
Greiner, Erich F. [5 ]
Kemp, Christopher J. [1 ]
Walczak, Henning [2 ,3 ]
机构
[1] Fred Hutchinson Canc Res Ctr, Human Biol Div, Seattle, WA 98109 USA
[2] Univ London Imperial Coll Sci Technol & Med, Dept Immunol, Tumour Immunol Unit, Div Med, London W12 ONN, England
[3] German Canc Res Ctr, Div Apoptosis Regulat, D-6900 Heidelberg, Germany
[4] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA
[5] German Canc Res Ctr, Div Mol Biol Cell 1, D-6900 Heidelberg, Germany
关键词
D O I
10.1172/JCI33061
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:100 / 110
页数:11
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