TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development
Anne Grosse-Wilde, … , Christopher J. Kemp, Henning Walczak
Anne Grosse-Wilde, … , Christopher J. Kemp, Henning Walczak
Published December 13, 2007
Citation Information: J Clin Invest. 2008;118(1):100-110. https://doi.org/10.1172/JCI33061.
View: Text | PDF
Research Article Article has an altmetric score of 3

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

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.

Authors

Anne Grosse-Wilde, Oksana Voloshanenko, S. Lawrence Bailey, Gary M. Longton, Uta Schaefer, Andreea I. Csernok, Günther Schütz, Erich F. Greiner, Christopher J. Kemp, Henning Walczak

×

Figure 1

Generation of Trail-r–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Generation of Trail-r–/– mice. (A) Strategy to target ex...
(A) Strategy to target exon 2 of the Trail-r gene. (i) Functional protein domains of TRAIL-R encoded by the Trail-r WT allele (ii). SP, signal peptide; CRD, cysteine-rich domain; TM, transmembrane domain; DD, death domain. Locations of the external (ext) 3′ and 5′ and the internal (int) probes and of genotyping primers mTR-a (a), mTR-b (b), and mTR-d (d) are indicated. (iii) Targeting construct. Open triangle, FRT sites; gray triangles, loxP sites; tkneo, selection cassette; DTA, diphtheria-toxin A-cassette. (iv) Null allele. (B) Southern blot analysis of targeted G418-selected ES cell clone after correct homologous recombination. (C) Constitutive deletion of exon 2 of Trail-r in different tissues. PCR analysis of genomic DNA of tail, lymph node, kidney, lung, heart, and brain of Trail-r–/–, Trail-r+/–, and Trail-r+/+ mice using primers a, b, and d is shown. The primers a and b amplified a 300-bp fragment of the Trail-r WT allele, and primers a and d amplified a 235-bp fragment of the Trail-r–null allele.