There is strong experimental evidence that the TRAIL pathway has an important role in the regulation of cancer initiation and development. As detailed below, TRAIL may contribute to host immune surveillance against cancers. Moreover, dysfunction of TRAIL-Rs through mutation or decreased expression may promote cancer progression and confer intrinsic resistance to TRAIL-induced apoptosis. TRAIL is expressed by effector lymphocytes, which are well known to contribute to host immune surveillance against primary tumor development and metastasis. TRAIL, along with perforin 1 and CD95L, is constitutively expressed on murine natural killer (NK) cells in the liver, but not NK T cells or ordinary T cells, and is responsible for spontaneous cytotoxicity against TRAIL-sensitive tumor cells in vitro and in vivo. Both the mouse and human Apo2L/TRAIL promoters are regulated by interferon-gamma (IFN-γ), and Apo2L/TRAIL expression and its contribution to preventing liver metastases depend on IFN-γ signaling. Furthermore, the IFN-γ-induced expression of TRAIL might change the tumor microenvironment to enable enhanced antigen presentation and tissue infiltration. The TRAIL-sensitive cancer cells interaction with TRAIL-expressing tumor infiltrating immune cells might be involved in tumor resistance and metastasis. In addition to Apo2L/TRAIL's contribution to immune surveillance, Apo2L/TRAIL appears to play an important role in suppressing tumor progression and determining chemosensitivity. Both neutralization of TRAIL by monoclonal antibody and TRAIL knockout mice promoted tumor development in mice and supported a direct role for NK cells expressing TRAIL in the suppression of tumor metastasis, while no metastasis occurred with the TRAIL-resistant cells. A more recent study shows that syngeneic renal cell carcinomas grow faster and shows increased metastasis to the liver in Apo2L/TRAIL knockout mice as compared with wild-type controls. Furthermore, metastasis to lymph nodes was significantly enhanced in TRAIL-R-deficient mice, which indicates that TRAIL-R2 is a metastasis suppressor in the mouse multistage model of squamous cell carcinoma. Wang and El-Deiry65 showed that silencing of TRAIL-R2/DR5 in vivo promotes tumor growth and renders tumor cells resistant to the chemotherapeutic agent 5-fluorouracil. These findings provide the evidence for the physiological function of TRAIL as a tumor suppressor.
Dai X, Zhang J, Arfuso F, et al. Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy. Experimental Biology and Medicine. 2015;240(6):760-773.