The dependence receptors, which include DCC (deleted in colorectal carcinoma), induce apoptosis when not bound by their ligands, such as netrin-1. DCC has been considered a tumour suppressor, but mice lacking one copy of Dcc are not predisposed to cancer, so its role is unclear. Now, Patrick Mehlen and colleagues show that overexpressing netrin-1 contributes to colorectal tumorigenesis probably by inhibiting DCC-induced apoptosis, indicating that the tumour-suppressive capacity of DCC is conditional on the extracellular concentration of netrin-1.

As decreased DCC expression is associated particularly with colorectal carcinoma, Mehlen and colleagues looked at the expression patterns of netrin-1 and DCC in intestinal epithelium. Netrin-1 was found mainly at the base of the crypts of the intestinal villi and decreased in a gradient towards the distal end, whereas DCC was expressed throughout the intestinal epithelium. These observations fit with the proposal that the physiological role of DCC is to regulate cell survival. That is, apoptosis is not triggered by DCC bound by netrin-1 in the proximal part of the villi, which is a site of intense proliferation, but is triggered by DCC when not bound by netrin-1 in the distal part of the villi, which is a site of cell death. To test this, the authors used transgenic mice that overexpressed netrin-1 throughout the intestinal epithelium, and showed that apoptosis was inhibited by 50% compared with normal mice.

So, does netrin-1 regulate DCC-induced tumour suppression in intestinal epithelium? Seventeen percent of the mice overexpressing netrin-1 developed adenomas (early colorectal tumorigenic lesions), compared with none of the control mice, and 43% had focal or diffuse hyperplasia in the colon, compared with only 13% of control animals. The suppression of apoptosis by netrin-1 therefore increases tumorigenesis.

DCC loss is usually a late-stage event in colorectal cancer progression; so, to test whether netrin-1 influences tumour progression, Mehlen and colleagues crossed the mice overexpressing netrin-1 with mice expressing mutant adenomatous polyposis coli (APC). APC mutations are an early event in human colorectal tumorigenesis. The APC-mutant mice developed mainly low-grade adenomas, but the APC-mutant mice overexpressing netrin-1 had a much higher incidence of high-grade adenomas (40% versus 17%). Furthermore, half of these high-grade adenomas were further classified as adenocarcinomas because of the presence of foci of mucosal invasion.

The authors propose that induction of cell death by DCC due to absence of netrin-1 in a region of the gut exposed to repeated mechanical and chemical insults might limit the risk of transformation. Loss of DCC expression in tumours would then reduce cellular dependence on netrin-1 for survival. Further research will investigate the role of other netrin-1 dependence receptors, the UNC5H proteins, which are also expressed in the gut and are putative tumour suppressors.