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 20 years argue for a complementary 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). Thus, the presence of various dependence receptors at the surface of the cells creates a state of dependence (or addiction) to their respective ligands.


To date, more than twenty of such receptors have been identified:

The concept of Dependence Receptors and its implication in cancer were pioneered by P. Mehlen’s laboratory:


As dependence receptors (DRs) and their respective ligands are controlling cell death, they play a key role in the control of cancer development and DRs are recognized as tumor suppressors.

In order to escape from cell death, aggressive cancer cells are selecting mechanisms to silence the death pathway normally induced by DRs. Accordingly, it has been shown that in a large fraction of cancers, the cancer cells are selecting a self production (i.e., autocrine or paracrine production) of the dependence receptor ligand