A few years ago, an original concept of cell biology was proposed: whereas the classic dogma postulates that transmembrane receptors are inactive unless bound by their specific ligand, it was suggested that some receptors may be active not only in the presence of their ligand, but also in their absence. In this latter case, the signaling downstream of these unbound receptors leads to apoptosis. These receptors were consequently named “dependence receptors”, as their expression renders the cell’s survival dependent on the presence in the cell environment of its respective ligand. This dual function is hypothesized to lead these receptors to have key roles both during embryonic development and in the regulation of tumorigenesis.
In the context of cancer, the hypothesis is that these receptors are tumor suppressors that would limit tumor progression by inducing apoptosis of tumor cells outside of settings of ligand accessibility/availability. This was recently formally demonstrated for the prototypical dependence receptors that bind netrin-1 –i.e., DCC and UNC5H-. Because expression of DCC and UNC5H is a constraint for tumor progression, their expression is often lost in many aggressive cancers. However, in a large fraction of cancer, tumor cells preferably acquire autocrine expression of netrin-1 to block cell death. It was thus shown that titration of netrin-1 by drug candidates allows tumor cell death in vitro and triggers tumors growth inhibition and metastases in mice. Of interest, this gain of ligand is probably not limited to netrin-1 but may possibly be extended to the other ligands of other dependence receptors. The first human trial (Phase I) using an agent interfering between netrin-1 and its receptors should begin by mid 2016. Thus, from a basic cell biology concept, we hope to provide soon new tools to fight against cancer.