Netrin-1, an axon navigation cue was proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. The netrin-1 receptors DCC and UNC5H were shown to belong to the family of dependence receptors that share the ability to induce apoptosis in the absence of their ligands. Such a trait confers on these receptors a tumor suppressor activity. Expression of one of these dependence receptors at the surface of a tumor cell is indeed speculated to render this cell dependent on ligand availability for its survival, hence inhibiting uncontrolled cell proliferation or metastasis. Consequently, it is a selective advantage for a tumor cell to lose this dependence receptor activity, as previously described with losses of DCC and UNC5H expression in human cancers. However, the model predicts that a similar advantage may be obtained by gaining autocrine expression of the ligand. We describe here that, unlike human nonmetastatic breast tumors, a large fraction of metastatic breast cancers overexpress netrin-1. Moreover, we show that netrin-1-expressing mammary metastatic tumor cell lines undergo apoptosis when netrin-1 expression is experimentally decreased or when decoy soluble receptor ectodomains are added. Such treatments prevent metastasis formation both in a syngenic mouse model of lung colonization of a mammary cancer cell line and in a model of spontaneous lung metastasis of xenografted human breast tumor. Thus, netrin-1 expression observed in a large fraction of human metastatic breast tumors confers a selective advantage for tumor cell survival and potentially represents a promising target for alternative anticancer therapeutic strategies.apoptosis ͉ DCC ͉ dependence receptor N etrin-1, a diffusible laminin-related protein, has been shown to play a major role in the control of neuronal navigation during the development of the nervous system by interacting with its main receptors, DCC (Deleted in Colorectal Cancer) (1-3) and UNC5H (4, 5). However, more recently, netrin-1 has emerged as a completely different molecule that regulates cell survival. Indeed, the netrin-1 receptors DCC and UNC5H, i.e., UNC5H1, UNC5H2, and UNC5H3, belong to the so-called dependence receptor family (6, 7). Such receptors share the functional property of inducing cell death when disengaged from their ligands, whereas the presence of their ligands blocks this proapoptotic activity. Such receptors thus create cellular states of dependence on their respective ligands (8,9).This dependence effect has been suggested to act as a mechanism for eliminating tumor cells that would develop in settings of ligand unavailability: proliferation of tumor cells in a cell environment with constant and limited ligand presence or migration of metastatic tumor cells toward tissues where the ligand is not expressed. A selective advantage for a tumor cell would then be to lose the proapoptotic activity of its dependence receptors. Along this line, DCC was proposed in the early 1990s to be a tumor-suppressor gene, whose expression is lost in ...
