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Targeting death and decoy receptors of the tumour-necrosis factor superfamily

Key Points

  • Tumour-necrosis factor (TNF) was discovered many years ago as a serum factor that was able to kill cancer cells in mice. The TNF receptor (TNFR) was shown to be expressed by mammalian cells years later, and led to the discovery of a superfamily of transmembrane proteins. These discoveries led to the identification of two gene families that include 18 ligands and 28 receptors, many of which are being targeted as anticancer therapies.

  • TNFR signalling was discovered to be an important aspect of the immune response, and family members such as FASL and APO2L/TRAIL induce apoptosis through a p53-independent mechanism. The signalling members of the TNFR superfamily can be divided into two main subgroups on the basis of their cytoplasmic region. One class of receptors, called death receptors (DR), contains a cytoplasmic death domain, whereas the other class does not.

  • APO2L/TRAIL has been shown to induce apoptosis in a wide variety of cancer cells, whereas most normal human cell types are resistant to APO2L/TRAIL-induced cell death.

  • Some TNFR family members do not signal, but act as 'decoys' that compete with receptors for ligands. A number of tumour types overexpress decoy receptors.

  • Treatment with factors that activate death-receptor signalling on cancer cells, and antibodies or small molecules that antagonize decoy receptors, might be an effective anticancer strategy.

Abstract

Cancer cells often develop resistance to chemotherapy or irradiation through mutations in the p53 tumour-suppressor gene, which prevent apoptosis induction in response to cellular damage. Death receptors — members of the tumour-necrosis factor receptor (TNFR) superfamily — signal apoptosis independently of p53. Decoy receptors, by contrast, are a non-signalling subset of the TNFR superfamily that attenuate death-receptor function. Agents that are designed to activate death receptors (or block decoy receptors) might therefore be used to kill tumour cells that are resistant to conventional cancer therapies.

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Figure 1: The TNF and TNFR superfamilies.
Figure 2: Signal transduction by death receptors.
Figure 3: Molecular approaches to death-receptor activation.
Figure 4: Hypothetical model of tumour-DcR3 action.

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DATABASES

Cancer.gov

breast cancer

central nervous system cancer

colon cancer

endometrial cancer

gastric cancer

liver tumour

lung cancer

melanoma

multiple myeloma

oesophageal cancer

pancreatic cancer

prostate cancer

rectal cancer

renal-cell carcinoma

thyroid cancer

LocusLink

4-1BB

APO2L

APRIL

Bak

BAK

Bax

BAX

BCL2

BCMA

BID

BLYS

BR3

caspase-3

caspase-6

caspase-7

caspase-8

caspase-9

caspase-10

CD4

CD8

CD27

CD27L

CD30

CD30L

CD40

CD40L

DcR1

DcR2

DcR3

DR4

DR5

DR6

EGFR

ERBB2

ERK

FADD

FAS

FASL

FLICE

FLIP

FN14

HVEM

IKK

interferon-γ

interleukin-1

interleukin-6

interleukin-8

LIGHT

LT-α

LT-β

LT-βR

MAPK

matrix metalloproteinases

MDM2

NF-κB

NGFR

OPG

OPGL

OX40

OX40L

perforin

RANKL

RIP

SMAC

TACI

TL1A

TNF-α

TNF-β

Tnfr1

TNFR2

TP53

TRADD

TRAF family

TRAF2

type 1 TNFR

type 2 TNFR

Medscape DrugInfo

melphalan

OMIM

Crohn's disease

rheumatoid arthritis

<i>Saccharomyces</i> Genome Database

Gal4

FURTHER INFORMATION

American College of Physicians

Avi Ashkenazi's lab at Genentech

The European Agency for Evaluation of Medicinal Products

HGNC gene family nomenclature

Glossary

FC DOMAIN

The antibody molecule can be proteolytically cleaved into two pieces — the F(ab′)2 fragment, which contains the antigen-binding activity, and the Fc domain, which carries out the effector function of the immunoglobin molecule.

POLYHISTIDINE TAG

A type of epitope tag that is made up of six histidine residues (6X-His).

EPITOPE TAG

A short amino-acid sequence that is added, in frame, to either end of a gene. This allows the recombinant protein to be easily detected and purified using antibodies against the tag. Commonly used tags include MYC, glutathione-S-transferase, and FLAG.

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Ashkenazi, A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2, 420–430 (2002). https://doi.org/10.1038/nrc821

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