Erythropoietin and erythropoietin receptor expression in vestibular schwannoma:: Potential role in tumor progression

Hypothesis: Hypoxia-inducible factor (HIF)-1 alpha-, erythropoietin (Epo), Epo receptor (EpoR), and bcl-2 are expressed in both sporadic unilateral vestibular schwannomas (VSs) and those associated with neurofibromatosis Type 2, and the expression data correlate with clinicopathological tumor features including microvessel density and Ki-67-labeling index. Background: Erythropoietin expression is regulated by the transcription factor, HIF-1a. Erythropoietin signaling via EpoR results in stimulation of cell proliferation and elevated expression of the antiapoptotic protein, bcl-2, and then inhibition of apoptosis. Erythropoietin has been shown to be associated with Schwann cell proliferation, and a recent report suggested a role in VS growth. Methods: Immunohistochemical analysis of HIF-1 alpha, Epo, EpoR, and bcl-2 was performed on formalin-fixed paraffin-embedded archival surgical specimens. Microvessel density and Ki-67-labeling index of VS were analyzed and correlated with the immunoreactivity pattern of the examined factors. Results: Immunoreactivity data demonstrate robust protein expression for HIF-1 alpha, Epo, EpoR, and bcl-2 in VS. Sixty-six percent of the cases showed Epo expression, and EpoR was found in 85% of tumor samples. A significantly positive correlation of the immunoreactivity scores of Epo/EpoR and bcl-2 expression could be noted. In case of tumor specimens with high levels of HIF-1 alpha expression, a significantly higher Ki-67-labeling index was observed. There was no correlation between the expression of HIF-1 alpha, Epo, EpoR, and bcl-2 and microvessel density, tumor size, sex, and age. Conclusion: Expression of Epo and EpoR might suggest a functional role in VS 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.