Erythropoietin and Erythropoietin Receptor Expression in Vestibular Schwannoma: Potential Role in Tumor Growth

The vestibular schwannoma (VS) is a benign, slow-growing neoplasm that originates from the eighth cranial nerve sheath with an annual incidence of 13 per million. The pathogenesis of both sporadic VS and those associated with neurofibromatosis type II appears to be associated with an aberration of a tumor suppressor gene on chromosome 22q12. The biological background for the diverse growth patterns of VS is, however, largely unknown. This differing clinical and biological behavior of VS may be explained by the presence of growth factors. Tumor expression of different growth factors indicating Schwann cell proliferation and tumor growth have recently been addressed in studies of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), nerve growth factor (NGF), neuregulin-1 (NRG), and epidermal growth factor (EGF). The present study was conducted to investigate the expression of erythropoietin (Epo) and its receptor EpoR in VS tissue.

Epo expression is regulated by the transcription factor hypoxia-inducible factor-1α. Epo signaling via EpoR results in stimulation of cell proliferation and elevated expression of the antiapoptotic protein bcl-2 followed by inhibition of apoptosis. Epo has been shown to be associated with Schwann cell proliferation and a recent report suggested a role in VS growth.

Immunohistochemical analysis of hypoxia-inducible factor-1α (HIF-1), Epo, EpoR, and bcl-2 was performed on formalin-fixed, paraffin-embedded archival surgical specimens. Microvessel density and Ki-67-labeling index of vestibular schwannoma were determined and correlated with the immunoreactivity pattern of the examined factors.

Immunoreactivity data demonstrate expression for HIF-1α, Epo, EpoR, and bcl-2 in VS. Sixty-six percent of the cases showed Epo expression and EpoR was found in 86% of tumor samples. A significantly positive correlation of the immunoreactivity scores of Epo/EpoR and bcl-2 expression could be noted. In cases of tumor specimens with high levels of HIF-1α expression, a significantly higher Ki-67-labeling index was observed.

Expression of Epo and EpoR might suggest a role in vestibular schwannoma biology. The observed correlation of Epo/EpoR and bcl-2 expression levels may suggest a proliferative and antiapoptotic role of the Epo/EpoR system in VS.