October 7, 2009, Updated September 13, 2012

Israeli scientists have discovered a new protein partnership that leads to regression in certain pediatric tumors, holding out hope for a new breed of anti-cancer drugs.

Israeli researchers have discovered what they believe could be a key reason why one common childhood cancer can spontaneously regress – a breakthrough that could in future lead to a new breed of drugs against tumors.

Prof. Michael Fainzilber and his team at the Weizmann Institute in Rehovot made their discovery after studying two types of common pediatric tumors in children – medulloblastoma, the most common malignant brain tumor and the second most common malignancy among children under 20 years old; and neuroblastoma – the most common extracranial solid cancer in childhood.

Neuroblastoma displays unusual behavior, and is one of the few human malignancies that can spontaneously regress in some cases.

In previous studies, it was found that the tumors that regress usually express TrkA, a cell receptor well known for its “pro-life” advocacies, while aggressive forms of the tumor do not. Until now, however, no one knew or understood how TrkA did this, or the mechanism involved.

Partners in crime

Fainzilber, working with Ph.D. student Liraz Harel, postdoctoral student Dr. Barbara Costa, technician Zehava Levy and former Ph.D. student Dr. Marianna Tcherpakov, carried out screening tests to identify other molecules involved in this signaling cascade.

During the process they discovered a new molecule called CCM2, and found that if it teams up with TrkA they become “partners in crime,” with TrkA turning into a cell killer – atypical behavior that could be responsible for destroying tumor cells.

Together with a group of scientists in Germany who were conducting a large-scale gene expression study in tumors from neuroblastoma patients, Fainzilber checked the expression levels of CCM2 and TrkA from the patient samples collected.

The results were clear-cut: TrkA and CCM2 were always expressed together in tumors that showed the highest incidences of regression and patient survival.

A crucial mechanism in tumor regression

The scientists confirmed their results by blocking the expression of either TrkA or CCM2 in some cells, which resulted in cell survival. On the other hand, by introducing CCM2 to cells lacking it, cell death was induced if TrkA was also present, suggesting that this mechanism could lead to tumor regression.

This research, which was recently published in the neuroscience academic journal Neuron, is one of the first to identify and describe this paradoxical “pro-cell death” behavior of TrkA and the first to identify CCM2 as a crucial accessory in this particular pathway, as well as describing in detail just how these two molecules interact.

When nerve growth factor proteins bind to TrkA receptors, it activates the receptors into promoting the growth and survival of neurons.

Further research toward a better understanding of the mechanism of the action could hopefully lead to the development of drugs that will be able to induce regression of certain tumors.

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Jason Harris

Jason Harris

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