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TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development
Anne Grosse-Wilde1, Oksana Voloshanenko, S Lawrence Bailey
1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
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.
Insights
The tumor suppressor TRAIL receptor (TRAIL-R) inhibits cancer metastasis. Detached cancer cells become sensitive to TRAIL, suggesting a mechanism to reduce metastasis incidence in patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells.
- The physiological role of TRAIL and its receptor (TRAIL-R) in tumorigenesis remains unclear.
- Conflicting results exist regarding TRAIL's role in tumor growth and development.
Purpose of the Study:
- To investigate the role of TRAIL-R in all stages of squamous cell carcinoma development.
- To determine if TRAIL-R acts as a metastasis suppressor.
- To elucidate the mechanism by which TRAIL-R might inhibit metastasis.
Main Methods:
- Utilized a multistage mouse model of squamous cell carcinoma.
- Examined tumor development and metastasis in TRAIL-R-deficient mice.
- Assessed TRAIL sensitivity of adherent and detached skin carcinoma cells in vitro.
- Investigated the role of the ERK signaling pathway in TRAIL resistance.
Main Results:
- TRAIL-R deficiency did not affect benign papilloma formation or progression to squamous cell carcinoma.
- Metastasis to lymph nodes was significantly increased in TRAIL-R-deficient mice.
- Adherent TRAIL-R-expressing cells were TRAIL resistant but sensitized upon detachment via ERK pathway inactivation.
Conclusions:
- TRAIL-R functions as a metastasis suppressor, not affecting primary tumor growth.
- TRAIL-R inactivation enhances lymph node metastasis.
- Detachment-induced sensitization to TRAIL, mediated by ERK pathway inactivation, provides a mechanism for metastasis suppression.
- Targeting TRAIL receptors with agonists may reduce metastasis in cancer patients.
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