| Abstract: | ![]()
Neuroblastoma (NB), the most frequent solid tumor of early childhood, is diagnosed as a disseminated disease in >60% of cases, and several lines of evidence support the resistance to apoptosis as a prerequisite for NB progression. We show that autocrine production of netrin-1, a multifunctional laminin-related molecule, conveys a selective advantage in tumor growth and dissemination in aggressive NB, as it blocks the proapoptotic activity of the UNC5H netrin-1 dependence receptors. We show that such netrin-1 up-regulation is a potential marker for poor prognosis in stage 4S and, more generally, in NB stage 4 diagnosed infants. Moreover, we propose that interference with the netrin-1 autocrine loop in malignant neuroblasts could represent an alternative therapeutic strategy, as disruption of this loop triggers in vitro NB cell death and inhibits NB metastasis in avian and mouse models.Dependence receptors now number more than a dozen, including deleted in colorectal cancer (DCC) (1), UNC5H (2), Patched (3), some integrins (4), neogenin (5), p75NTR (6), RET (7), ALK (8), and TrkC (9). Although they have no structural homology (other than possibly in a domain referred to as the DART [dependence-associated receptor transmembrane] domain) (10), they all share the functional property of inducing cell death when disengaged from their trophic ligands, whereas the presence of their trophic ligands blocks this proapoptotic activity. Such receptors thus create cellular states of dependence on their respective ligands (11, 12).The prototype dependence receptors are the netrin-1 receptors. Netrin-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 (13, 14, 15) and UNC5H (16, 17). However, DCC and UNC5H (i.e., UNC5H1, UNC5H2, UNC5H3, and UNC5H4) have been shown to belong to the dependence receptor family (1, 2). This dependence effect upon netrin-1 has been suggested to act as a mechanism for eliminating tumor cells that would develop in settings of ligand unavailability (for reviews see references 18, 19). Along this line, disruption of the proapoptotic signaling of these netrin-1 receptors in the gastrointestinal tracts of mice, by netrin-1 overexpression or by inactivation of UNC5H3, is associated with intestinal tumor progression (20, 21).Thus, loss of the dependence receptors'' proapoptotic activity represents a selective advantage for tumor cells. In this respect, DCC was proposed in the early 1990s to function as a tumor suppressor gene, whose expression is lost in the vast majority of human cancers (22, 23). This hypothesis also fits with the observation that UNC5H genes are down-regulated in most colorectal tumors, hence suggesting that loss of UNC5H genes represents a selective advantage for tumor development (21, 24, 25). We have analyzed expression of netrin-1 and its receptors in neuroblastoma (NB), the most frequent extracranial solid tumor of early childhood. The aggressive and metastatic stage 4 NB displays three distinct clinical patterns at presentation and dissemination sites based on patients'' ages. Indeed, neonates and infants (<1 yr of age) with stage 4S and stage 4 without 4S features have an overall good prognosis, whereas stage 4 in children (>1 yr of age) shows a poor prognosis. We describe in this paper that, rather than the loss of netrin-1 receptor expression, a large fraction of aggressive NBs has evolved to select a gain of ligand expression that apparently represents a similar selective growth advantage. We therefore propose to use disruption of this selective advantage as an anticancer strategy in NB. |
