Prognostic significance of erythropoietin expression in human endometrial carcinoma.
BACKGROUND
Erythropoietin (Epo), which is induced by hypoxia, controls erythropoiesis and protects neurons from hypoxic damage. Hypoxia in malignant disease is associated with invasion, metastasis, and resistance to therapy. The authors recently demonstrated hypoxia-stimulated expression of Epo and Epo receptor (EpoR) in human breast and cervical carcinomas, suggesting a role for autocrine Epo signaling in the hypoxic adaptations of carcinomas.


METHODS
The authors characterized the expression of Epo, EpoR, hypoxia-inducible factor (HIF)-1alpha, estrogen receptor (ER), and progesterone receptor (PR) by immunohistochemical methods using endometrial carcinoma samples from 107 women and benign endometrial samples from 59 women in various phases of the menstrual cycle. They then analyzed potential correlations of Epo and EpoR immunostaining and clinicopathologic tumor features with outcome.


RESULTS
In benign endometrial tissue samples, Epo and EpoR expression increased over the course of the cycle, with the highest levels observed in the late secretory phase. Epo expression in benign endometrial samples showed a negative correlation with ER and PR expression. The authors found Epo and EpoR expression in 95.3 % and 100% of endometrial carcinoma samples, respectively. Increased EpoR, but not Epo, expression in tumors was associated with advanced-stage disease, lymphovascular invasion, lymph node metastasis, and loss of ER expression. Increased Epo expression was observed in perinecrotic tumor regions in a pattern similar to the HIF-1alpha expression pattern. Increased Epo expression was significantly associated with adverse clinical outcome on both univariate and multivariate analysis.


CONCLUSIONS
Hypoxia-inducible autocrine Epo signaling in endometrial carcinoma may contribute to tumor progression and increased aggressiveness. Increased Epo expression in endometrial carcinomas may be an independent prognostic and/or predictive factor.
Acs
Geza
G
Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA. geza@mail.med.upenn.edu
Xu
Xiaowei
X
Chu
Christina
C
Acs
Peter
P
Verma
Ajay
A
D018262:Adenocarcinoma, Clear Cell / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015687:Cell Hypoxia; D018284:Cystadenocarcinoma, Serous / Q000378:metabolism / Q000473:pathology; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D004921:Erythropoietin / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008597:Menstrual Cycle; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D017467:Receptors, Erythropoietin / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015996:Survival Rate; D014157:Transcription Factors / Q000378:metabolism
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017467:Receptors, Erythropoietin; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014157:Transcription Factors; D004921:Erythropoietin