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The TRAIL apoptotic pathway in cancer onset, progression and therapy

Key Points

  • Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent stimulator of apoptosis, and tumour cells are significantly more sensitive to TRAIL-induced apoptosis than normal cells. Although the molecular basis for the tumour-selective activity of TRAIL remains to be fully defined, the TRAIL pathway is an attractive therapeutic target for the treatment of cancer.

  • In addition to triggering a pro-apoptotic signal through activation of caspases, TRAIL can activate diverse intracellular signalling pathways involving NFκB, phosphoinositoide 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) family proteins that can stimulate cell survival and proliferation.

  • TRAIL is an important immune effector molecule in the surveillance and elimination of developing tumours. Moreover, genetic lesions in various components of the TRAIL pathway have been found in human tumour samples, suggesting that inactivation of the TRAIL pathway and/or escape from TRAIL-mediated immunosurveillance might have an important role in tumour onset and progression.

  • In preclinical trials, recombinant forms of TRAIL and agonistic anti-TRAIL receptor antibodies can have single-agent activity against TRAIL-sensitive tumour cells in vitro and in vivo. These agents can synergize with chemotherapeutic drugs and novel molecular therapeutic agents to more effectively kill TRAIL-sensitive tumour cells and TRAIL-resistant tumours.

  • Early-phase clinical trials using recombinant TRAIL and agonistic anti-TRAIL receptor antibodies indicate that these agents can be delivered safely and are generally well-tolerated. Although some objective anti-tumour responses have been reported with these agents as monotherapies, they probably hold greater promise for further clinical development when used in combination with other cancer treatments.

Abstract

Triggering of tumour cell apoptosis is the foundation of many cancer therapies. Death receptors of the tumour necrosis factor (TNF) superfamily have been largely characterized, as have the signals that are generated when these receptors are activated. TNF-related apoptosis-inducing ligand (TRAIL) receptors (TRAILR1 and TRAILR2) are promising targets for cancer therapy. Herein we review what is known about the molecular control of TRAIL-mediated apoptosis, the role of TRAIL in carcinogenesis and the potential therapeutic utility of recombinant TRAIL and agonistic antibodies against TRAILR1 and TRAILR2.

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Figure 1: Apoptotic signalling through the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) pathway.
Figure 2: Additional signal transduction pathways activated by tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL).

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Acknowledgements

R.W.J. and M.J.S. are supported by a National Health and Medical Research Council of Australia (NH&MRC) Program Grant. M.J.S. is supported by a NH&MRC Senior Principal Research Fellowship and R.W.J. by a Pfizer Fellowship and grants from the Leukaemia Foundation of Australia, the Bennelong Foundation and the Cancer Council Victoria. A.J.F. is supported by The Cancer Research Institute Predoctoral Emphasis Pathway in Tumour Immunology. We thank A. Ashkenazi, G. Begley and R. Humphries for helpful discussions.

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Correspondence to Ricky W. Johnstone or Mark J. Smyth.

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Competing interests

R.W.J is the recipient of a collaborative research grant from Merck & Co. R.W.J. and M.J.S. are recipients of a collaborative research grant from Novartis.

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DATABASES

National Cancer Institute

bladder cancer

breast cancer

chronic lymphocytic leukaemia

chronic myeloid leukaemia

colorectal cancer

fibrosarcoma

head and neck cancer

lung cancer

lymphoma

neuroblastoma

non-Hodgkin lymphoma

prostate cancer

National Cancer Institute Drug Dictionary

AMG 655

apomab

bortezomib

cisplatin

doxorubicin

folinic acid

fluorouracil

gefitinib

gemcitabine

irinotecan

lexatumumab

mapatumumab

rapamycin

rituximab

vorinostat

FURTHER INFORMATION

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Glossary

Innate immunity

The innate immune system provides immediate non-specific defence against pathogens. The innate leukocytes include NK cells, mast cells, eosinophils, basophils and the phagocytic cells, including macrophages, neutrophils and dendritic cells. These cells identify and eliminate pathogens, and virus-infected and neoplastic cells.

Adaptive immunity

The adaptive immune system comprises specialized, systemic cells that can recognize and remember specific 'non-self' antigens, responding more vigorously each time this antigen is encountered. The cellular components involved include B lymphocytes, T lymphocytes and antigen-presenting cells (dendritic cells, B cells and macrophages).

Graft versus tumour

(GVT). A beneficial T-cell-mediated immune response to host tumour cells by immune cells present in a donor's transplanted tissue.

Graft-versus-host disease

(GVHD). The pathological consequence of a response initiated by transplanted immunocompetent T lymphocytes into an allogeneic, immunocompromised host. The host is unable to reject the grafted T cells and becomes their target.

Immunoediting

Describes the complex relationship between a developing tumour under constant pressure from the host immune system. Cancer immunoediting consists of three phases: elimination (that is, cancer immunosurveillance), equilibrium and escape. The immune system not only protects the host against development of primary cancers but also sculpts tumour immunogenicity.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). Cell death that occurs when the Fc fragment of a mAb, bound to a target cell, interacts with the Fc receptor on monocytes, macrophages or NK cells. These cells in turn kill the target cell or secrete cytokines. ADCC is part of the adaptive immune response owing to its dependence on a prior antibody response.

Complement-dependent cytotoxicity

(CDC). The effect of a mAb bound to a target cell initiating the complement cascade, leading to the assembly of the membrane attack complex. This disrupts the target cell membrane, resulting in cell lysis.

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Johnstone, R., Frew, A. & Smyth, M. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer 8, 782–798 (2008). https://doi.org/10.1038/nrc2465

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