Netrin-1, a missing link between chronic inflammation and tumor progression.

Netrin-1 discovered as a neuronal navigation cue, has been recently proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. This survival activity is mediated via the inhibition of the so-called netrin-1 dependence receptors. The netrin-1 receptors, DCC (for Deleted in Colorectal Cancer) and UNC5H (UNC5 homologues), indeed belong to the functional family of dependence receptors that share the ability to induce apoptosis in the absence of their ligands and such a trait has been hypothesized to confer these receptors a tumor suppressor activity as their presence render cell survival dependent on ligand availability. As a consequence, human tumors show either a loss of dependence receptors or a gain of netrin-1, allowing tumors to escape this safeguard mechanism. We recently found that netrin-1 is a direct transcriptional target of the transcription factor NFκB, and that a fraction of colorectal tumors show a netrin-1 gain parallel to NFκB activation. Moreover, colorectal cancers from patients affected by inflammatory bowel diseases (IBD) show upregulation of netrin-1. Several evidences suggest a tight link between chronic inflammation and tumorigenesis, mainly through NFκB activation. We propose that induction of netrin-1 expression via NFκB in IBD patients could affect colorectal tumor promotion and progression and that inhibition of netrin-1 could be an innovative target for drug therapy in inflammation-driven colorectal cancers.