Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma.

Abstract

Medulloblastoma, the most common malignant brain tumor of childhood, has a variable prognosis. Although half of the children and young adults with the disease survive longer than 10 years after diagnosis, the others relapse and die despite identical therapy. We have examined the expression of neurotrophins and their receptors in medulloblastoma samples snap frozen in the operating room to preserve RNA integrity. All tumors (n = 12) were found to express mRNA encoding neurotrophin 3 and its receptor TrkC. The level of trkC expression was highly variable, with a more than 50-fold difference between the highest and lowest values. By Kaplan-Meier analysis, patients with tumors expressing high levels of trkC mRNA had significantly longer intervals without disease progression than those with low levels (log-rank, P = 0.03) and a more favorable overall survival (log-rank, P = 0.05). Thus, trkC expression is a prognostic indicator for patients with medulloblastoma.

The Scatter Factor/Hepatocyte Growth Factor: c-Met Pathway in Human Embryonal Central Nervous System Tumor Malignancy

“…Trks are the most studied receptor tyrosine kinases in medulloblastoma. A few studies have shown that TrkC receptor expression is associated with better prognosis of medulloblastoma patients and that activation of TrkC induces apoptosis of tumor cells (40,42). Two reports also linked FGFR expression with antitumor activity in classic medulloblastoma subtype (39,43).…”

A Novel Apoptotic Pathway Induced by Nerve Growth Factor-mediated TrkA Activation in Medulloblastoma

“…Morphologically, MBs resemble neuroectodermal stem cells, and they often show a neuron-like phenotype, as evidenced by the expression of neuron-specific lineage markers (20). MBs are thought to arise from granule cell progenitors in the external granule layer of the developing cerebellum (21), and it has been reported that the abundance of trkC mRNA expression correlates with a better response to therapy in pediatric patients with MB (22). Although our earlier studies failed to implicate NGF and low affinity NGF receptor in modulating the behavior of MB cells (23), a subsequent study of the same MB cells engineered to express TrkA on their cell surface yielded the unexpected finding that activation of these receptors led to extensive apoptosis (24).…”

Targeting the Inhibitor of Apoptosis Proteins as a Novel Therapeutic Strategy in Medulloblastoma

“…The overexpression of antiapoptotic proteins has recently been shown to be critical to the development of medulloblastomas in a mouse model (14) and the efficacy of radiotherapy has been shown to depend on activation of the apoptotic pathway (15). In medulloblastoma samples, high levels of antiapoptotic proteins have been shown to correlate with tumor grade and poor outcomes (16,17). Together, these data provide a compelling rationale for targeting the apoptotic pathway in medulloblastoma; however, this novel approach has not yet been tested as a therapeutic strategy.…”