Dependence Receptors : A New Weapon To Inhibit Tumors?

The interaction of a ligand (Neurotrophine-3) and its dependence receptor (TrkC) constitutes a novel mechanism for tumor control in pediatric cancers such as neuroblastoma, and may also be important to the inhibition of other cancers such as breast cancer. These findings by a team in the Laboratoire Apoptose, Cancer et DГ©veloppement (CNRS/UniversitГ© Lyon 1/Centre de Lutte contre le Cancer LГ©on BГ©rard), support the concept put forward several years ago by the same laboratory concerning the design of anti-tumor therapeutic strategies targeting a new type of receptor, the dependence receptor. These receptors are indeed able to induce cell death when they are deprived of their ligand. This study is published in the March 2010 issue of the Journal of Clinical Investigation.


Situated on the cell surface, a receptor captures signals from the extracellular medium (ligands) in order to induce a signal within the cell via different molecular cascades. A receptor is thus considered as a switch that is in "off" position if its ligand is absent. During the past ten years, a team in the Laboratoire Apoptose, Cancer et DГ©veloppement (CNRS/UniversitГ© Lyon 1/Centre de Lutte contre le Cancer LГ©on BГ©rard), led by Patrick Mehlen, has been working on specific receptors called dependence receptors which, in the absence of their ligand, induce a signal that triggers cell death. It has been shown that these receptors can control tumor progression: indeed, supernumerary cancer cells compete to bind the available ligand and then die because of their dependence receptor. The latter may thus constitute a new mechanism for tumor control.


During this study, the researchers focused in particular on the TrkC dependence receptor and its ligand, NT-3. In pediatric cancers such as neuroblastoma, it has been shown that the presence of TrkC is a factor for a good prognosis. The scientists thus sought to determine whether TrkC, as a dependence receptor, could control tumor progression. They studied specimens from particularly aggressive tumors obtained from the Biological Resources Centers (Centres de Ressources biologiques) at the Centre de Lutte contre le Cancer LГ©on BГ©rard in Lyon and the Institut Gustave Roussy in Villejuif, which collect such specimens for the purposes of diagnosis and research.


The results obtained showed that nearly 40% of the most aggressive neuroblastoma tumors themselves produced the NT-3 ligand so that they could grow without triggering death induced by the TrkC dependence receptor. By preventing tumor cells from producing NT-3, the researchers were thus able to restore the cell death process.


This team in Lyon has also developed a model for the tumor progression characteristic of neuroblastoma using chicken eggs (a model that is close to embryonic development). Human tumor cells were applied to the vascularized membrane that allows gas exchanges with the shell (the chorioallantoic membrane). Within a week, the human tumor cells formed a tumor, entered into blood vessels, reached the lungs of the chick and there developed metastases. However, when they applied a treatment that blocked the binding of NT-3 to its TrkC receptor, the scientists observed a reduction in the number of metastases and in the size of the primary tumors that developed. They also obtained similar results in a mouse model for tumorigenesis.


The NT-3/TrkC ligand/dependence receptor interaction thus exerts partial control on tumorigenesis in the context of neuroblastoma. These findings therefore prove that interference with the TrkC/NT-3 interaction may constitute a targeted therapeutic strategy, a discovery which has been protected by a patent. The team will now try to determine whether it can be applied to other types of cancer. Preliminary findings have already suggested that the NT-3/TrkC interaction may also play an important role in breast cancer.


Netris Pharma, a start-up initiated by the Laboratoire Apoptose, Cancer et DГ©veloppement, is now developing therapeutic agents that target NT-3. Preclinical development phases should be starting in the near future.


Source: CNRS (DГ©lГ©gation Paris Michel-Ange)