Netrin-1 and its receptors in tumorigenesis

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Abstract
Axon guidance molecules are frequently inactivated in various human cancers. In particular, the netrin-1 receptors DCC and the UNC5H family are downregulated in more than half of all colorectal cancers. DCC and the UNC5H proteins regulate apoptosis; positively in the absence of netrin-1, or negatively in the presence of netrin-1. This is designated as the 'dependence receptor' concept. DCC-induced apoptosis defines a novel apoptotic pathway that is dependent on caspase activation, but independent of both the mitochondrial- and death-receptor-mediated apoptotic pathways. The netrin-1-mediated anti-apoptotic signal that inhibits p53-induced apoptosis implies that NTN1 (which encodes netrin-1) could function as an oncogene. A netrin-1 gradient is evident in normal colonic epithelium, with highest expression in the crypts and lowest expression in the upper portion of the villi, correlating with the pattern of cell survival and death in this tissue. NTN1-transgenic mice have reduced apoptosis of intestinal epithelial cells, leading to an increase in the spontaneous formation of hyperplasia and adenoma. The tumour suppressor p53 regulates the expression of netrin-1 and some of its receptors. Therefore, p53 might determine cell fate through regulation of the netrin-1 pathway.