Key Points
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Semaphorins are members of a large gene family of secreted and membrane-anchored proteins containing more than 20 vertebrate genes. They were initially characterized as axon guidance factors and are divided into eight subfamilies. The nine receptors belonging to the plexin family function as semaphorin receptors.
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The secreted semaphorins belonging to the class 3 semaphorin subfamily are unique as they do not bind to plexins but instead bind to the neuropilin 1 or neuropilin 2 receptors. The neuropilins form complexes with members of the plexin family and function as the semaphorin binding elements and the plexins function as the signal transducing elements. The neuropilins also function as receptors for several pro-angiogenic factors, including several heparin-binding forms of vascular endothelial growth factor and hepatocyte growth factor.
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Because of their role as transducers of pro-angiogenic signals, the neuropilins are viewed as targets for the development of anti-angiogenic drugs that function by inhibiting the binding of vascular endothelial growth factor to neuropilins.
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The activation of plexins by semaphorins modulates cell adhesion and induces changes in the organization of the cytoskeleton of target cells. Prolonged exposure inhibits cell proliferation and induces apoptosis.
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Several class 3 semaphorins such as semaphorin 3B and semaphorin 3F have been characterized as tumour suppressors.
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The presence of neuropilins and plexins on endothelial cells also resulted in the realization that semaphorins such as semaphorin 3F and semaphorin 3A can function as anti-angiogenic factors and semaphorin 3F can inhibit the development of tumours by inhibition of tumour angiogenesis.
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By contrast, semaphorins such as semaphorin 4D have been found to function as pro-angiogenic factors and to promote tumour progression.
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Many types of tumour cells express semaphorin receptors. Several types of semaphorins have been found to induce pro-tumorigenic or anti-tumorigenic effects as a result of their interaction with semaphorin receptors expressed by tumour cells.
Abstract
The semaphorins and their receptors, the neuropilins and the plexins, were originally characterized as constituents of the complex regulatory system responsible for the guidance of axons during the development of the central nervous system. However, a growing body of evidence indicates that various semaphorins can either promote or inhibit tumour progression through the promotion or inhibition of processes such as tumour angiogenesis, tumour metastasis and tumour cell survival. This Review focuses on the emerging role of the semaphorins in cancer.
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Acknowledgements
This work was supported by grants from the Israel Science Foundation (ISF), by the Komen breast cancer foundation, by the International Union against Cancer (AICR), by the McDonnel foundation and by the Rappaport Family Institute for Research in the Medical Sciences of the Faculty of Medicine at the Technion, Israel Institute of Technology (to G.N.).
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Glossary
- Complement binding (CUB) domain
-
A conserved domain, spanning approximately 110 residues, originally identified in complement sub-components Cls/Clr. Complement refers to a group of about 20 interacting proteins that complement the action of antibodies.
- Coagulation factor V/VIII homology domain
-
A domain that displays homology to the C1 and C2 domains of coagulation factors V and VIII.
- VEGF165
-
A 165 amino acid-long splice form of VEGF. Contains exon 7 of the VEGF gene, which encodes a heparin binding domain.
- VEGF121
-
A 121 amino acid-long splice form of VEGF that lacks exon 7.
- Chick chorioallantoic membrane angiogenesis assay
-
The chick embryo chorioallantoic membrane is located just underneath the shell of the egg. Angiogenic substances placed on top of this membrane induce the growth of new blood vessels.
- Flavoprotein monooxygenases
-
A family of enzymes that specifically catalyse the oxidation of a number of substrates, and in some contexts can generate reactive oxygen species.
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Neufeld, G., Kessler, O. The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nat Rev Cancer 8, 632–645 (2008). https://doi.org/10.1038/nrc2404
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DOI: https://doi.org/10.1038/nrc2404
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