It has been known for over half a century that cells depend on external signals for their survival which is then mediated by various transmembrane receptors and sensors. For example, cells may require specific soluble trophic factors, cytokines, hormones, extracellular matrix interactions, cell-cell interactions, or electrical activity for survival. For any given required stimulus, withdrawal leads to programmed cell death (or apoptosis). It has generally been assumed that apoptosis induced by withdrawal of supporting factors is due to the loss of the associated positive survival signals. While such survival signals are clearly very important, data obtained over the past 15 years argue for a complementary and novel form of signal transduction that actively induces cell death following stimulus withdrawal.
This “negative signal transduction” is mediated by specific “dependence receptors (DRs)” that induce apoptosis in the absence of the required stimulus (e.g., when unbound by a trophic ligand), but block apoptosis in the presence of the required stimulus (e.g., when bound by a trophic ligand). Thus, the expression of various dependence receptors creates a state of dependence (or addiction) to their respective ligands. To date, more than twenty of such receptors have been identified.
LINK TO CANCER
Dependence Receptors play a key role in the control of tumor development and can be considered as tumor suppressors.
In the context of cancer, the hypothesis is that dependence 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 DCC and UNC5H with their ligand Netrin-1. Because dependence receptor expression offers a constraint for tumor progression, their expression is often lost in many aggressive cancers.
At least two types of mechanism can be used by a tumor cell to escape cell death by apoptosis, both of which will lead to the inactivation of Dependence Receptors :
- Deletion or mutation of the receptor (ex: DCC (deleted in colorectal cancer));
- Autocrine over-expression of the ligand.
The latter situation is the most frequently observed in screened tumors. It has been shown that 60% of breast tumors over-express the Netrin-1 ligand. In addition, the level of Netrin-1 produced by tumor cells appears to be highly correlated to the aggressiveness of the cancer and its metastatic potentiality.
Over-expression of the Dependence Receptor ligand has also been observed in lung cancer and in neuroblastoma (a pediatric cancer). Several other types of cancer are currently being investigated.