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Netrin-1 and its receptors in tumorigenesis

Key Points

  • Axon guidance molecules are frequently inactivated in various human cancers. In particular, the netrin-1 receptors DCC and the UNC5H family are downregulated in more than half of all colorectal cancers.

  • DCC and the UNC5H proteins regulate apoptosis; positively in the absence of netrin-1, or negatively in the presence of netrin-1. This is designated as the 'dependence receptor' concept.

  • DCC-induced apoptosis defines a novel apoptotic pathway that is dependent on caspase activation, but independent of both the mitochondrial- and death-receptor-mediated apoptotic pathways.

  • The netrin-1-mediated anti-apoptotic signal that inhibits p53-induced apoptosis implies that NTN1 (which encodes netrin-1) could function as an oncogene.

  • A netrin-1 gradient is evident in normal colonic epithelium, with highest expression in the crypts and lowest expression in the upper portion of the villi, correlating with the pattern of cell survival and death in this tissue.

  • NTN1-transgenic mice have reduced apoptosis of intestinal epithelial cells, leading to an increase in the spontaneous formation of hyperplasia and adenoma.

  • The tumour suppressor p53 regulates the expression of netrin-1 and some of its receptors. Therefore, p53 might determine cell fate through regulation of the netrin-1 pathway.

Abstract

Netrin-1 and its receptors DCC (deleted in colorectal cancer) and the UNC5 orthologues (human UNC5A–D and rodent UNC5H1–4) define a new mechanism for both the positive (induction) and negative (suppression) regulation of apoptosis. Accumulating evidence implies that for human cancers, this positive signalling pathway is frequently inactivated. Surprisingly, binding of netrin-1 to its receptors inhibits tumour suppressor p53-dependent apoptosis, and p53 is directly involved in transcriptional regulation of netrin-1 and its receptors. So, the netrin-1 receptor pathways probably play an important part in tumorigenesis.

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Figure 1: Structure of human netrin-1 and its receptors.
Figure 2: Pro-apoptotic signalling from the netrin-receptors.
Figure 3: Anti-apoptotic signalling pathways of netrin-1.
Figure 4: p53 transcriptional regulation of netrin-1 and UNC5B.
Figure 5: Expression of netrin-1 and its receptors in colorectal epithelial cells.

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Acknowledgements

The author thanks P. Mehlen for helpful suggestions and discussions. This work was supported by grants from the Ministry of Health, Labour and Welfare, Japan, and by grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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DATABASES

Entrez Gene

AKT2

ALDH41

APAF1

APPL

BAX

caspase-3

caspase-8

caspse-9

DCC

DDB2

EPHB2

ERK1

ERK2

NOXA

NRAGE

NTN1

p53AIP1

p75-NTR

PUMA

RRM2B

ROBO1

SCARA3

SEMA3B

SEMA3F

SLIT2

SMAD2

SMAD4

TP53

UNC5A

UNC5B

UNC5C

XPC

National Cancer Institute

colorectal cancer

gastric cancer

pancreatic cancer

prostate cancer

testicular cancer

Glossary

COMMISSURAL AXONS

Neurons that cross from one side of the body to the other.

LOSS OF HETEROZYGOSITY

All somatic genes have two alleles, which can be identical or different. The loss of one of these alleles from one homologous chromosome is known as loss of heterozygosity and is a common feature of cancer cells.

SMADs

SMAD2 and SMAD4 belong to a class of proteins that mediate signals of the TGFβ superfamily. Activated TGFβ receptors stimulate the phosphorylation of receptor-regulated Smad proteins, which in turn form complexes with SMAD4 that accumulate in the nucleus and regulate the transcription of target genes.

TYPE I TRANSMEMBRANE PROTEINS

Type I transmembrane proteins span the membrane once, with the N-terminus on the far side and the C-terminus in the cytosol. Type II transmembrane proteins also span the membrane once, but with the C-terminus on far side and the N-terminus in the cytosol.

CASPASE SUBSTRATE

Caspases are cysteine proteases that become activated during the apoptotic process. A number of proteins are cleaved by caspases (caspase substrates) during apoptosis, a process that is required for apoptosis to proceed efficiently.

DEATH DOMAIN

An apoptotic response can be triggered by an 80-amino-acid intracellular domain near the C-terminus of tumour necrosis factor receptor (TNFR) — also know as the death domain. This region is loosely conserved in cell-death-related receptors of the TNFR superfamily members.

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Arakawa, H. Netrin-1 and its receptors in tumorigenesis. Nat Rev Cancer 4, 978–987 (2004). https://doi.org/10.1038/nrc1504

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