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

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

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Figure 2

TRAIL-R does not influence primary skin tumorigenesis.

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TRAIL-R does not influence primary skin tumorigenesis. (A) Papilloma inc...
(A) Papilloma incidence rates. (B) Tumor initiation rates, as reflected in the average number of papillomas over time. (C) Tumor growth rates, represented by combined average papilloma area over time. (D) Carcinoma incidence rates. Vertical bars indicate deaths of mice with carcinomas. (E) Papilloma-to-carcinoma conversion rate per week of papilloma exposure. The 95% confidence intervals are displayed. (F) Cell surface–expressed TRAIL-R was examined using a TRAIL-R–specific antibody (MD5-1) on WT immortalized keratinocytes (cell line C-50), papilloma cells (cell line 308), and carcinoma cells (cell lines DT02 and DT12). Histological analysis (G–J) of tumor sections did not reveal any differences between the different Trail-r genotypes. Representative tissue sections (H&E staining and brown keratin staining) from Trail-r–/– mice are shown. (G) Keratin-positive papilloma. Among all genotypes, primary malignant tumors were (H) SCC, (I) spindle cell variant of SCC (SVSCC), or (J) fibrosarcomas, which is shown with keratin-positive hair follicles (HF). (K) Tissue sections of malignant carcinomas (fibrosarcoma or SCC) were stained with antibodies against active caspase-3 or Ki-67. Representative fields are shown (original magnification, ×400).