Increased Susceptibility to Tumor Initiation and Metastasis in TNF-Related Apoptosis-Inducing Ligand-Deficient Mice

Abstract

We have previously implicated TNF-related apoptosis-inducing ligand (TRAIL) in innate immune surveillance against tumor development. In this study, we describe the use of TRAIL gene-targeted mice to demonstrate the key role of TRAIL in suppressing tumor initiation and metastasis. Liver and spleen mononuclear cells from TRAIL gene-targeted mice were devoid of TRAIL expression and TRAIL-mediated cytotoxicity. TRAIL gene-targeted mice were more susceptible to experimental and spontaneous tumor metastasis, and the immunotherapeutic value of α-galactosylceramide was diminished in TRAIL gene-targeted mice. TRAIL gene-targeted mice were also more sensitive to the chemical carcinogen methylcholanthrene. These results substantiated TRAIL as an important natural effector molecule used in the host defense against transformed cells.

New insights into apoptosis signaling by Apo2L/TRAIL

“…mDR5-knockout mice are viable and develop normally (Diehl et al, 2004). Similarly, Apo2L/TRAIL-knockout mice do not display any overt developmental defects, indicating that, as in zebrafish, Apo2L/TRAIL signaling is not essential for normal mouse embryonic development (Cretney et al, 2002). Apo2L/TRAIL is expressed specifically on the surface of natural killer cells, cytotoxic T cells, macrophages and dendritic cells, and transcription of its mRNA can be induced by type I Apoptosis signaling by Apo2L/TRAIL F Gonzalvez and A Ashkenazi interferons (Almasan and Ashkenazi, 2003).…”

“…In mice, either antibody blockade or genetic ablation of Apo2L/TRAIL supports a role for this ligand in the suppression of experimental and spontaneous tumor metastasis in vivo (Takeda et al, 2001;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).…”

“…Apo2L/ TRAIL binds to OPG, although with a lower affinity, and this has been proposed to regulate differentiation and survival of mature osteoclasts (Zauli et al, 2004(Zauli et al, , 2008Vitovski et al, 2007). However, considering that Apo2L/TRAIL-knockout mice are viable and develop normal bone density (Cretney et al, 2002;NewsomDavis et al, 2009), it remains unclear whether this ligand has a significant physiological role in regulating osteoclastogenesis (Labrinidis et al, 2008).…”

“…Its selective expression in immune effector cells suggests that Apo2L/TRAIL may contribute to shaping the immune repertoire and/or regulating the immune response. Genetic ablation of either Apo2L/TRAIL or mDR5 in mice does not affect the resting immune cell populations (T, B, macrophage, dendritic and natural killer cells) (Cretney et al, 2002;Diehl et al, 2004). Patients with multiple sclerosis or systemic lupus erythematosus have elevated serum levels of Apo2L/TRAIL, suggesting upregulation of this ligand in certain autoimmune disorders (Wandinger et al, 2003;Lub-de Hooge et al, 2005).…”

TRAIL and immunity: more than a license to kill tumor cells

“…26 Interestingly, however, while Fas (lpr) and FasL (gld) mutant mice show clear symptoms of uncontrolled immune cell activation, defects in cellular homeostasis, reduced apoptosis and development of autoimmune disease, 27 none of these signs is obvious in the TRAIL-deficient mouse, at least not at the first glance. 28,29 Yet, a more detailed analysis revealed that lack of TRAIL predisposes to increased susceptibility to the development of autoimmune diseases. For example, C57BL/6 mice are usually resistant to collagen-induced arthritis but develop severe disease in the absence of TRAIL expression.…”