Dependence receptors: when apoptosis controls tumor progression.

A novel way of seeing cellular receptors has recently emerged. While a receptor used to be considered as inactive until bound by its ligand, it has been proposed that some receptors may also be active in the absence of their ligand. These so-called dependence receptors induce a specific death signal when the ligand is absent from the cell: Therefore, the expression of one of these receptors leads to the cell becoming dependent on the presence of the ligand for its survival. We have hypothesized that such a trait is a mechanism that allows inhibition of tumor growth, by inducing apoptosis "abnormal" cells that would usually grow in settings of ligand unavailability, i.e. local growth of tumor cells or growth beyond primary tumor site. Along this line, back in the early 90s, Vogelstein and colleagues suggested that a gene called DCC (for deleted in colorectal cancer) could be a tumor 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 fifteen years, controversial data have failed to firmly establish whether DCC is indeed a tumor suppressor gene. However, our observation that DCC behaves as a dependence receptor that induces cell death unless its ligand netrin-1 is present, together with the fact that mice engineered to block DCC-induced cell death by overexpressing netrin-1 are predisposed to develop colorectal tumors, strengthen the role of dependence receptors as tumor suppressors. In this review, we will describe the implication of the netrin-1/receptor pairs as novel negative regulators of tumor development.