Erythropoietin and erythropoietin receptor expression in vestibular schwannoma: potential role in tumor progression.
OBJECTIVE
Hypoxia-inducible factor (HIF)-1alpha, 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-1alpha. 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-1alpha, 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-1alpha, 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-1alpha expression, a significantly higher Ki-67-labeling index was observed. There was no correlation between the expression of HIF-1alpha, Epo, EpoR, and bcl-2 and microvessel density, tumor size, sex, and age.


CONCLUSIONS
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.
Diensthuber
Marc
M
Department of Otorhinolaryngology, Medical University of Hannover, Germany. Diensthuber.Marc@MH-Hannover.de
Ilner
Torben
T
Rodt
Thomas
T
Samii
Madjid
M
Brandis
Almuth
A
Lenarz
Thomas
T
Stöver
Timo
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D002196:Capillaries / Q000473:pathology; D049109:Cell Proliferation; D018450:Disease Progression; D004428:Ear Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004921:Erythropoietin / Q000096:biosynthesis* / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D019254:Genes, bcl-2 / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008866:Microsurgery; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000473:pathology; D009464:Neuroma, Acoustic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017467:Receptors, Erythropoietin / Q000096:biosynthesis* / Q000235:genetics*; D015837:Vestibular Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; D017467:Receptors, Erythropoietin; D004921:Erythropoietin