Expression of neuregulin and activation of erbB receptors in vestibular schwannomas: possible autocrine loop stimulation
We sought to determine whether vestibular schwannomas are capable of producing and responding to the glial growth factor neuregulin. Neuregulin is a neuronally derived trophic factor that interacts with erbB2 and erbB3 receptors on Schwann cells and is required for normal Schwann cell proliferation, survival, and development. Vestibular schwannomas grow several millimeters or even centimeters away from adjacent axons, suggesting that vestibular schwannomas do not depend critically on axons for their proliferation or survival. This raises the possibility that vestibular schwannomas themselves produce and respond to trophic factors in an autocrine fashion. Pathologic specimens from eight patients undergoing microsurgical removal of vestibular schwannomas and one patient undergoing vestibular nerve section were immunostained with anti-neuregulin, anti-erbB2, anti-erbB3, and anti-phosphorylated-erbB2 antibodies. Three patients had received previous gamma knife radiation therapy and two patients had neurofibromatosis Type 2. The Scarpa ganglion neurons express neuregulin, and normal vestibular Schwann cells express erbB2 and erbB3. Vestibular schwannomas from all eight patients demonstrated neuregulin, erbB2, and erbB3 immunoreactivity. In addition, all vestibular schwannomas demonstrated immunoreactivity to anti-phosphorylated-erbB2 antibody that only recognizes erbB2 when it is phosphorylated, or activated. These results demonstrate that vestibular schwannomas express neuregulin and its receptors, erbB2 and erbB3. Because erbB2 exists in an activated state, as evidenced by phosphorylated-erbB2 immunoreactivity, it likely responds to the locally produced neuregulin. This suggests the possibility that vestibular schwannomas produce and respond to neuregulin in an autocrine fashion.