GDE2 protein could help predict course of neuroblastoma

The research group of Wouter Moolenaar of the Netherlands Cancer Institute (NKI) has, in collaboration with the group of Rogier Versteeg of the AMC Amsterdam, discovered a protein that can predict the course of neuroblastoma. An important discovery, because little is still known about this type of childhood cancer. The results of the study were published on September 29 in the journal Cancer Cell.

Neuroblastoma is one of the most common types of cancer in infants and young children. It is a tumor of the sympathetic nervous system, and usually grows within the abdomen. The tumor arises when primitive nerve cells don’t ripen (‘’differentiate’’) in the right way. A remarkable characteristic of neuroblastoma is that the tumor sometimes disappears by itself, especially in the youngest patients (children below the age of two), a remarkable phenomenon that is not understood. But in slightly older children the tumor often continues to grow, and is very hard to treat. Especially when it metastasizes.  

There is still  little known about the exact biology of neuroblastoma. Researchers around the world are studying this in the hope of finding clues for new treatments. Moolenaar and Versteeg have now solved a  small part of  the biological puzzle. They discovered that a protein called GDE2 is involved in the disease. But in a positive way: if neuroblastoma cells produce a lot of GDE2, they undergo differentiation in cell culture. Patients whose tumors contain much GDE2 have a more favorable outlook than patients with tumors with little GDE2.  It thus appears that GDE2 is a favorable  prognostic marker in neuroblastoma.  

Moolenaar’s  group also figured out what GDE2 exactly does  in neuroblastoma cells. The protein is  located on the outside of the cell membrane, where  it functions  to cleave another protein, called glypican-6 (GPC6). This results in an alteration in gene expression which causes the tumor cells to differentiate . What’s more ,GDE2  also inhibits neurite retraction and  reduces the motility of the tumor  cells. The latter means that cells are much less likely to migrate throughout the body and form metastases.

Moolenaar:

We now understand a lot about GDE2, but not everything. It appears  that GDE2 activates  a transmembrane effector through  cleavage of GPC6 . Depletion of GPC6  in neuroblastoma cells had the same effect as high GDE2 levels.  We haven’t identified the effector protein yet, although we have our suspicions. Identifying this effector signaling system isn’t just important for our basal knowledge about neuroblastoma, it may also motivate the future development of new drugs. And there is an urgent need for new treatment options for this aggressive type of childhood cancer.