Role of netrin-1 and netrin-1 dependence receptors in colorectal cancers

Abstract

Although cancer is a multifaceted disease, all cancer types share identical molecular and cellular mechanisms. These mechanisms involve a collection of alterations critical to the normal physiological functioning of cells, such as alterations of growth factor signalling pathways, angiogenesis, cell adhesion signals, DNA replication and apoptotic cell death. Many genes involved in the processes enumerated above are functionally inactive in tumour cells, designating them as putative 'tumour suppressor genes'. Back in the early 1990s, Vogelstein and colleagues suggested that a gene called DCC (for Deleted in Colorectal Cancer) could be a tumour suppressor gene because it was found to be deleted in more than 70% of colorectal cancers, as well as in many other cancers. During the last 15 years, controversial data have failed to firmly establish whether DCC is indeed a tumour suppressor gene. However, the recent observations that DCC triggers cell death and is a receptor for netrin-1, a molecule recently implicated in colorectal tumorigenesis, have prompted a renewal of interest in the role of DCC in tumorigenesis and suggest that the netrin-1/receptor pairs act as novel negative regulators of tumour development.

Figure 1

Structure of netrin-1 and netrin-1 dependence receptors. DCC is a type I transmembrane protein with an extracellular domain composed of four immunoglobulin domains, six fibronectin type III domains, a single transmembrane spanning region and a cytoplasmic domain including ADD. The four UNC5H receptors all have two immunoglobulin domains and two thrombospondin domains in the extracellular region and a ZU-5 domain (a domain of homology found in Zona Occludens-1 and UNC-5 protein). Their ligand, netrin-1, is a laminin-related secreted protein with V and VI domains (three epidermal growth factor domains) related to laminin and a positively charged carboxy (C)-terminal domain.

Figure 2

(A) View of normal intestinal villi. Cells are produced in the intestinal crypts at the base of the villi. As they differentiate, they migrate to the surface of the epithelium (intestinal lumen) where they are eventually eliminated. Netrin-1 is preferentially expressed at the base of intestinal crypts, whereas its receptor DCC is evenly distributed throughout the villi. Netrin-1 binding to DCC in crypt cells contributes to cell survival. On the contrary, the absence of netrin-1 at the villus surface induces apoptotic cell death. (B) View of intestinal villi overexpressing netrin-1. The even distribution of netrin-1 on the villus surface prevents apoptotic cell death, thus promoting tumour growth.