Aberrant expression of erythropoietin in uterine leiomyoma: implications in tumor growth.
OBJECTIVE
Myomatous erythrocytosis syndrome is a rare complication of uterine leiomyoma caused by erythropoietin (EPO) that is produced by tumor cells. We assessed the EPO expression in leiomyomas and investigated the effects of EPO on the tumor growth.


METHODS
Tissue samples were collected from 114 patients with uterine leiomyomas who underwent myomectomy or hysterectomy in Yokohama City University Hospital. From 17 patients, the corresponding normal myometrium was also collected. All samples were analyzed for EPO messenger RNA (mRNA) expression by real-time reverse transcription-polymerase chain reaction. EPO protein expression was determined by an enzyme-linked immunosorbent assay. The relationships between EPO expression and clinicopathological features were retrospectively analyzed using the patients' charts. Blood vessel density and maturity were assessed using hematoxylin-eosin staining and CD34 immunohistochemistry.


RESULTS
EPO mRNA expression was detected in 108 of 114, or 95%, of the leiomyomas. The mean EPO mRNA expression in the leiomyoma was higher than the corresponding normal myometrium (3836 ± 4122 vs 1455 ± 2141; P = .025 by Wilcoxon rank test). The EPO mRNA expression in the leiomyomas varied extensively among samples, ranging from undetectable levels to 18-fold above the mean EPO mRNA of normal myometrium. EPO protein production was observed concomitant with mRNA expression. A positive correlation of leiomyoma size and EPO mRNA expression was shown by Spearman rank correlation coefficient (ρ = 0.294; P = .001), suggesting the involvement of EPO in leiomyoma growth. The blood vessel maturity was also significantly increased in EPO-producing leiomyomas (high vessel maturity in high vs low EPO group: 67% vs 20%; P = .013 by Fisher exact test).


CONCLUSIONS
This report demonstrates that EPO is produced in most of conventional leiomyomas and supports a model in which EPO accelerates tumor growth, possibly by inducing vessel maturity. Our study suggests one possible mechanism by which some uterine leiomyomas reach a large size, and the understanding of EPO expression patterns in these tumors may be useful for management of the patients with leiomyomas.
Department of Obstetrics, Gynecology, and Molecular Reproductive Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Ryoko
R
Asano
Department of Obstetrics, Gynecology, and Molecular Reproductive Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan. Electronic address: mikikos@yokohama-cu.ac.jp.
Mikiko
M
Asai-Sato
Division of Molecular Pathology and Genetics, Kanagawa Cancer Center Research Institute, Yokohama, Japan.
Yohei
Y
Miyagi
Department of Obstetrics, Gynecology, and Molecular Reproductive Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Taichi
T
Mizushima
Department of Obstetrics, Gynecology, and Molecular Reproductive Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Makiko
M
Koyama-Sato
Department of Surgical Pathology, Tokyo Women's Medical University Hospital, Tokyo, Japan.
Yoji
Y
Nagashima
Department of Biostatistics and Epidemiology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Masataka
M
Taguri
Department of Obstetrics, Gynecology, and Molecular Reproductive Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Hideya
H
Sakakibara
Department of Obstetrics, Gynecology, and Molecular Reproductive Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Fumiki
F
Hirahara
Department of Obstetrics, Gynecology, and Molecular Reproductive Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Etsuko
E
Miyagi
D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D004921:Erythropoietin / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007889:Leiomyoma / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009215:Myometrium / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014594:Uterine Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism
D018952:Antigens, CD34; D012333:RNA, Messenger; D004921:Erythropoietin
erythropoietin; myomatous erythrocytosis syndrome; uterine leiomyoma; vessel maturity