Dependence receptors: life or death choices

Whereas the classic dogma postulates that transmembrane receptors remain inactive at the plasma membrane unless bound by their specific ligand, it was suggested that some receptors may actually 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 cell expression renders the survival of the cell dependent on the presence in the cell environment of its respective ligand. This dual function - positive in the presence of ligand, negative in the absence of ligand - 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, a loss of dependence receptors is not always the selective advantage used by tumor cells to escape this survival dependence on the presence of the ligand. Indeed, it was shown that in many cancers, tumor cells acquire the preferred autocrine expression of ligands of dependence receptor. This selective advantage for the tumor is much more appealing in terms of therapeutic opportunities. Drugs based on the interference on the interaction between dependence receptors and their ligands allow tumor cell death in vitro and trigger tumor growth and metastases inhibition in mice. This review describes how a basic cell biology concept has provided in a near future new tools to fight cancer. triangle