ReviewExploring death receptor pathways as selective targets in cancer therapy
Graphical abstract
Introduction
Since its first appearance in the Literature [1], the term “apoptosis” has been used to describe a mode of cell death, morphologically distinct from “necrosis”. In recent years, apoptosis became more commonly known as “programmed cell death”, to indicate a genetically programmed cell suicide which play a central homeostatic role during development [2], [3]. Apoptosis of pre-malignant or malignant cells represents a protective mechanism against tumour formation and development, since it removes from the body genetically damaged cells induced to proliferate under uncontrolled mitogenic stimuli. Apoptosis can be triggered by two major mechanisms: the intrinsic pathway involving mitochondrial dysfunction, and an extrinsic pathway associated with stimulation of death receptors (DRs) located on the cell membrane (Fig. 1). These DRs belong to the tumour necrosis factor (TNF) receptor (TNF-R) superfamily and include well-known members listed in Table 1. DR-induced apoptosis is an innovative way to selectively kill cancer cells compared to modern anticancer drugs (protein kinase inhibitors or monoclonal antibody agonists for growth receptors), since DR-based cancer therapy could be selective and effective against a broad range of cancers. In addition, DR engagement, using recombinant death ligands, or agonistic antibodies, activates the extrinsic apoptosis pathway, while, generally, chemotherapy or radiotherapy trigger the mitochondrial/intrinsic pathway (Fig. 1). Therefore, the conventional therapeutic approach could be complemented and implemented by DR-induced apoptosis, when DRs are expressed and functional on tumour cells. This double strategy may reduce excessive systemic toxicity toward normal cells and tumour resistance after recurrent treatments.
Excellent reviews have been recently published on different therapeutic approaches to specifically target tumours by activating DR pathways [4], [5]. Here, we will discuss new insights in the signalling and clinical application of TNF, CD95 and TRAIL receptors.
Section snippets
Death receptor signalling
The TNF-R superfamily includes several members, which can be divided into three major groups based on the structure of their cytoplasmic region and the signalling generated by interaction with downstream ligands. The first group includes the six receptors listed in Table 1 possessing a death domain (DD) which, upon interaction and trimerization with their specific ligands, recruits intracellular DD containing adaptors, such as FADD (FAS-associated death domain) and TRADD (tumour necrosis factor
Cancer resistance targeting DRs
The balance between cell death and cell survive is tightly controlled at several levels. In cancer cells, an enhanced anti-apoptotic response might generate resistance to DR-mediated apoptosis. This is particularly true for TRAIL-R1/R2, considering their potential clinical applications (see below). An interesting characteristic in the family of DR is that normal cells are TRAIL resistant, but the molecular basis for TRAIL tumour selectivity is still unclear. Defects in either of different
TNF-alpha
The limited use of TNF-alpha in clinical oncology has been due to the powerful and toxic systemic side effects of this cytokine, which many research groups are trying to bypass targeting TNF-alpha specifically to tumours. In fact, TNF-alpha is not only able to initiate cellular apoptosis at higher doses, as discussed above, but a further advantage of TNF-alpha treatment in cancer therapy is related to its anti-vascular activity which can be used clinically to destroy tumour vasculature also
Conclusion and perspectives
More than one century ago, Paul Ehrlich introduced the concept of “magic bullet”, a compound which selectively targets disease-causing microorganisms, seeking out and destroying them, avoiding other organisms and having no harmful effects on the bodies of patients [74]. Hence, the “magic bullet” represents, still now, the goal in molecular oncology: it should eradicate malignant cells without killing normal cells. However, cancer is a complex and heterogeneous disease, and until recent years,
Acknowledgements
C.S. is partially supported by a grant from National Research Council, Italy (Basic Science Research Grant).
References (75)
- et al.
Apoptosis control by death and decoy receptors
Curr Opin Cell Biol
(1999) - et al.
Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family
Cell
(1993) - et al.
FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis
Cell
(1995) - et al.
Differential modulation of apoptosis sensitivity in CD95 type I and type II cells
J Biol Chem
(1999) - et al.
DNA damage-induced cell death by apoptosis
Trends Mol Med
(2006) - et al.
The interplay between the Bcl-2 family and death receptor-mediated apoptosis
Biochim Biophys Acta
(2004) - et al.
The C-terminal tails of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas receptors have opposing functions in Fas-associated death domain (FADD) recruitment and can regulate agonist-specific mechanisms of receptor activation
J Biol Chem
(2004) - et al.
The signaling adaptors and pathways activated by TNF superfamily
Cytokine Growth Factor Rev
(2003) - et al.
Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes
Cell
(2003) - et al.
Tumor necrosis factor receptor-associated factor (TRAF) 2 and its role in TNF signaling
Int J Biochem Cell Biol
(2001)
Early lethality, functional NF-kappaB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice
Immunity
TRAIL signalling: decisions between life and death
Int J Biochem Cell Biol
Nonapoptotic functions of FADD-binding death receptors and their signaling molecules
Curr Opin Cell Biol
FADD-deficient T cells exhibit a disaccord in regulation of the cell cycle machinery
J Biol Chem
Phosphorylation of FADD at serine 194 by CKIalpha regulates its nonapoptotic activities
Mol Cell
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt
J Biol Chem
Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death
Cancer Cell
Tumour necrosis factor alpha: a potential target for the therapy of solid tumours
Lancet Oncol
A complex adenovirus vector that delivers FASL-GFP with combined prostate-specific and tetracycline-regulated expression
Mol Ther
Intracellular Fas ligand expression causes Fas-mediated apoptosis in human prostate cancer cells resistant to monoclonal antibody-induced apoptosis
Mol Ther
microRNAs and death receptors
Cytokine Growth Factor Rev
Tumor therapeutics by design: targeting and activation of death receptors
Cytokine Growth Factor Rev
Receptor-selective mutants of apoptosis-inducing ligand 2/tumor necrosis factor-related apoptosis-inducing ligand reveal a greater contribution of death receptor (DR) 5 than DR4 to apoptosis signaling
J Biol Chem
Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer
Lung Cancer
Antibody cocktails: next-generation biopharmaceuticals with improved potency
Trends Biotechol
Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics
Br J Cancer
The genetics of programmed cell death in the nematode Caenorhabditis elegans
Cold Spring Harb Symp Quant Biol
Apoptosis in the pathogenesis and treatment of disease
Science
The TRAIL apoptotic pathway in cancer onset, progression and therapy
Nat Rev Cancer
Death receptors as targets for anti-cancer therapy
J Cell Mol Med
Death receptor signal transducers: nodes of coordination in immune signaling networks
Nat Immunol
The death effector domain protein family: regulators of cellular homeostasis
Nat Immunol
Functional analysis of TRAIL receptors using monoclonal antibodies
J Immunol
The CD95(APO-1/Fas) DISC and beyond
Cell Death Differ
Ligand-independent redistribution of Fas (CD95) into lipid rafts mediates clonotypic T cell death
Nat Immunol
The Fas-FADD death domain complex structure unravels signalling by receptor clustering
Nature
BCL-2 family members and the mitochondria in apoptosis
Genes Dev
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2016, Biochemical and Biophysical Research CommunicationsCitation Excerpt :TRAIL has a potent ability to trigger cell death in a variety of tumor cell lines but has little or no effect on most normal cells [20,21]. Several studies have revealed that DR5 may play a more prominent role than DR4 in TRAIL-induced apoptosis in cancer cells derived from solid tumors [22–24]. Therefore, the combination of TRAIL and agents that increase the expression of DR5 makes sense as a novel anti-cancer therapy.
Studying cancer metastasis: Existing models, challenges and future perspectives
2016, Critical Reviews in Oncology/HematologyCitation Excerpt :An important drawback of these models is that immune compromised animals lack elements of the innate and adaptive immune system that both play an important role in tumor development and the metastatic process (Table 2) (Khanna and Hunter, 2005). For example, during the process of cancer immunosurveillance, the immune system identifies and destroys nascent tumor cells (Green and Kroemer, 2004; Russo et al., 2010). Tumor cells that are not completely eliminated may enter an equilibrium phase where tumor cells become dormant.
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These two authors equally contributed to the preparation of the present work.