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Novel roles for Slits and netrins: axon guidance cues as anticancer targets?

Key Points

  • The axon guidance cues netrin 1 and Slits are causally implicated in human cancer. They are deregulated in a large proportion of human cancer, and the analysis of various mouse models has revealed that this deregulation is associated with tumour progression.

  • Netrin 1, Slits and their respective receptors are implicated in tumorigenesis via the regulation of tumour cell migration, tumour cell survival and tumour angiogenesis.

  • The netrin 1 receptors deleted in colorectal cancer (DCC) and UNC5 (UNC5A, UNC5B, UNC5C and UNC5D) are dependence receptors. They actively trigger apoptosis in the absence of netrin 1. This activity can function as a safeguard mechanism against tumour development.

  • Slits–roundabout receptors (Robos) have a dual role in regulating angiogenesis. SLIT2–ROBO1 inhibits angiogenesis while SLIT2–ROBO4 promotes the stability of established vessels.

  • Netrin 1 is upregulated in a large proportion of cancers, and an appealing therapeutic strategy could be to inhibit the interaction of netrin 1 with its receptors.

Abstract

Over the past few years, several genes, proteins and signalling pathways that are required for embryogenesis have been shown to regulate tumour development and progression by playing a major part in overriding antitumour safeguard mechanisms. These include axon guidance cues, such as Netrins and Slits. Netrin 1 and members of the Slit family are secreted extracellular matrix proteins that bind to deleted in colorectal cancer (DCC) and UNC5 receptors, and roundabout receptors (Robos), respectively. Their expression is deregulated in a large proportion of human cancers, suggesting that they could be tumour suppressor genes or oncogenes. Moreover, recent data suggest that these ligand–receptor pairs could be promising targets for personalized anticancer therapies.

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Figure 1: Slits and netrin 1 and their receptors.
Figure 2: Implication of SLIT2–ROBO1 in the regulation of tumour cell migration.
Figure 3: The dual signalling of dependence receptors.

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Acknowledgements

The authors wish to thank H. Bilak for text correction. The work carried out in the laboratories of P.M. and A.C. is supported by the Agence Nationale pour la Recherche (ANR) (to P.M.), Ligue contre le Cancer (to P.M.), The Institut National du Cancer (INCA) (to P.M.) and the Fondation pour la Recherche Médicale (Equipes labellisées FRM) (to A.C.).

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P.M. is a shareholder and co-founder of Netris Pharma.

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Glossary

Floor plate

A group of cells that occupy the ventral midline of the developing vertebrate nervous system, extending from the spinal cord to the diencephalon. They secrete morphogens and axon guidance molecules.

Commissural axons

Neurons that extend or project axons across the dorsal or ventral midline of the nervous system and have an important role in the coordination of sensory information received on both sides of the body.

Structural supramodule

In UNC5B, several domains form a larger, structural module that inhibits the pro-apoptotic activity of the death domain and might also confer other activities.

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Mehlen, P., Delloye-Bourgeois, C. & Chédotal, A. Novel roles for Slits and netrins: axon guidance cues as anticancer targets?. Nat Rev Cancer 11, 188–197 (2011). https://doi.org/10.1038/nrc3005

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