Dependence receptors are receptors that display two totally different signal transductions depending on ligand availability. If in the presence of ligand, these receptors transduce a positive signal leading to differentiation/proliferation/migration, in the absence of ligand these receptors induce an active process of cell death. Thus, such receptors create cellular states of dependence on their respective ligands by inducing apoptosis when unoccupied by ligand. This growing family of such bi-functional receptors now includes p75ntr, DCC, UNC5H1-3, neogenin, Patched, the androgen receptor, some integrins and two tyrosine kinase receptors RET and TrkC. As example, the DCC (Deleted in Colorectal Cancer), a candidate tumor suppressor, which encodes a receptor for netrin-1, a laminin-related molecule involved in axon guidance and UNC5H, another netrin-1 receptors have been shown to be pro-apoptotic unless netrin-1 is present. In the absence of netrin-1, DCC and UNC5H are cleaved by caspases and release/expose a pro-apoptotic domain that is able to drive apoptosis through interaction with pro-apoptotic proteins. Remarkably both DCC and UNC5H expression appears drastically inhibited in numerous carcinomas including colorectal tumors. We then have proposed that UNC5H and DCC may be considered as tumor suppressors. Indeed, ectopic expression of netrin-1 or inactivation of UNC5H3 in mice gut leads to i) a decreased cell death in the intestinal epithelium and ii) an increased tumorigenesis. Thus dependence receptors may turn as sensors that limit tumor growth out of ligand availability by inducing apoptosis. Here we will provide an overview of the implication of the netrin-1 dependence receptors in primary cancer and metastasis and will describe how this may be used to propose novel therapeutic approaches.
03 - 07 May 2008
European Society of Endocrinology