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.

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

“…The following mouse lines were used in this study: AlfpCre, 31 NEMO floxed, 10 FADD floxed, 32 Tnf À / À , 23 33 TRAIL-R floxed, 34 Fas floxed 35 and Rag1 À / À . 36 All mice were maintained in C57BL/6 background.…”

New insights into apoptosis signaling by Apo2L/TRAIL

“…Apo2L/TRAIL-knockout mice did not spontaneously develop tumors and deletion of the gene in either p53 null or APC min mice did not affect tumorigenesis (Yue et al, 2005). Apo2L/TRAIL deficiency also did not affect the initiation of skin cancer in response to chemical carcinogen (Grosse-Wilde et al, 2008). On the other hand, loss of Apo2L/TRAIL promoted the development of methylcholanthreneinduced fibrosarcomas in mice (Cretney et al, 2002).…”

“…Recently, comparison of geneexpression profiles in a panel of 368 human breast tumor samples revealed that downregulation of Apo2L/ TRAIL correlates with breast cancer metastasis to the brain (Bos et al, 2009). Moreover, a significant increase in metastasis of lymphoma and skin carcinoma has been observed in mDR5-knockout mice (Finnberg et al, 2008;Grosse-Wilde et al, 2008). Although there is good evidence for antimetastatic activity of Apo2L/TRAIL, the importance of the endogenous ligand for controlling initiation and growth of primary tumors is still a matter of debate.…”

“…There is also evidence for a role of Apo2L/TRAIL signaling in radiosensitivity: mDR5-knockout mice were found to develop bronchopneumonia and lung cancers in response to sublethal doses of ionizing radiation (Grosse-Wilde et al, 2008). More recently, DR5 has been implicated in the regulation of detachment-induced cell death (anoikis) in colorectal carcinoma cell lines (Laguinge et al, 2008).…”

Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro

“…In mouse models, lymph node metastases were greatly enhanced upon removal of TRAIL-R, as the TRAIL was ordinarily responsible for both sensitizing the cells to apoptosis by loss of adhesion, then inducing apoptosis directly (Grosse-Wilde et al, 2008) However, even when the apoptosis-inducing TRAIL receptors can be detected, the majority of human primary tumor cells are only partially sensitive or completely desensitized to TRAIL-induced apoptosis. This presents a handicap in the use of TRAIL as a therapeutic molecule in many diseases.…”