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

Abstract

N etrin-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.

Netrin-1 in the developing enteric nervous system and colorectal cancer

“…9 Therapeutic use of netrin-1 The effect of netrin-1 on cell survival depends upon its receptors, DCC and UNC-5H. This phenomenon has primarily been investigated in the context of cancer [4,17,70,71], and these studies have brought attention to netrin-1 as a possible therapeutic target for cancer therapy [27,72,73]. This ability of netrin-1 to induce cell survival is also observed in commissural neurons prepared in primary culture from DCC-mutant mice embryos [74].…”

A Signaling Mechanism Coupling Netrin-1/Deleted in Colorectal Cancer Chemoattraction to SNARE-Mediated Exocytosis in Axonal Growth Cones

“…Tetanus neurotoxin (TeNT) was purchased from Calbiochem. Rat pRc/CMVSytx1A was cloned as described previously (Paradisi and Mehlen, 2010). Fulllength Sytx1A or truncated DNAs (Sytx1ACYT, Sytx1AHabc, Sytx1AH3TM, Sytx1AH3, and Sytx1ATM) were cloned into EcoRI sites in pEGFPC1 fusion mammalian protein expression vector (Clontech).…”

The Tumor-Suppressive Function ofUNC5Dand Its Repressed Expression in Renal Cell Carcinoma

“…Netrin-1 and its receptors are expressed extensively in multiple tissues and participate in an array of cell processes (16)(17)(18). An important feature of Netrin-1 receptors is that they function as "dependence receptors."…”