Netrin-1 and its dependence receptors as original targets for cancer therapy

The dependence receptor notion has recently seen an interesting development. From a basic cell biology concept, which proposes that some transmembrane receptors can be active in the absence of their ligand and induce in the setting apoptosis, recent observations have provided new hope for the development of alternative targeted therapies. The purpose of this review is to show, with the example of netrin-1 dependence receptors, the path from cell biology to promising anticancer-targeted therapy.

The dependence receptors Deleted in Colorectal Cancer and Unc-5 homolog that bind netrin-1 had been implicated in nervous system development as they participate in neuronal navigation. They were also implicated beyond the developing brain with roles in angiogenesis regulation and homeostasis of various tissues. However, these receptors were shown to trigger apoptosis in the absence of netrin-1 and, as such, act as tumor suppressors. Recent data support the view that Deleted in Colorectal Cancer/Unc-5 homolog proapoptotic signals are indeed a safeguard mechanism regulating tumor growth and metastasis.

In this review, we will develop the different data supporting the view that a selective advantage for a tumor is to inactivate this dependence receptor's proapoptotic signal and will describe a putative therapeutic approach that is to reactivate this death signaling in tumor cells.