Expression of erythropoietin and erythropoietin receptor in cervical cancer and relationship to survival, hypoxia, and apoptosis.
OBJECTIVE
Physiologically, hypoxia induces the expression of erythropoietin (Epo) in adult kidney cells. Epo, in turn, acts on the Epo receptor (EpoR) in RBC precursors to stimulate growth and prevent apoptosis. Because hypoxia plays a major role in the malignant progression of tumors and Epo and its receptors have also been detected in malignant tumors, we investigated the expression of Epo and EpoR and their relationship with hypoxia, proliferation, apoptosis, and clinicopathologic variables in cervical cancer.


METHODS
Intratumoral oxygen measurement and needle biopsies of the tumors were done in 48 patients with cervical cancer. The obtained tissue was analyzed by immunohistochemistry with antibodies against Epo, EpoR, and Ki-67 as well as by terminal deoxynucleotidyl transferase-mediated deoxyuracil triphosphate nick-end labeling assays.


RESULTS
Epo and EpoR were expressed in 88% and 92% of samples, respectively. Cervical cancers with higher Epo expression showed a significantly reduced overall survival (3 years, 50.0% versus 80.6%; P = 0.0084). Epo and EpoR expression correlated significantly with apoptosis (r = 0.49, P = 0.001 and r = 0.36, P = 0.021). Furthermore, EpoR expression correlated significantly with tumor size (r = 0.32, P = 0.032) and was significantly associated with the presence of lymphovascular space involvement (P = 0.037). However, we observed no correlation between Epo or EpoR expression and intratumoral hypoxia, although in well-oxygenated tumors, EpoR localized significantly more often to the invasion front (P = 0.047).


CONCLUSIONS
This study analyzes Epo/EpoR expression and their relationship with intratumoral pO(2) levels as well as with survival in patients with cervical cancer. The data suggest a critical role of the endogenous Epo/EpoR system in cervical cancer.
Leo
Cornelia
C
Department of Gynecology, Leipzig University, Leipzig, Germany. leo@medizin.uni-leipzig.de
Horn
Lars-Christian
LC
Rauscher
Cora
C
Hentschel
Bettina
B
Liebmann
Andre
A
Hildebrandt
Guido
G
Höckel
Michael
M
D000328:Adult; D000368:Aged; D017209:Apoptosis; D049109:Cell Proliferation; D018450:Disease Progression; D018572:Disease-Free Survival; D004921:Erythropoietin / Q000096:biosynthesis*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D017467:Receptors, Erythropoietin / Q000096:biosynthesis*; D012008:Recurrence; D015996:Survival Rate; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy
D017467:Receptors, Erythropoietin; D004921:Erythropoietin