Apoptosis and the expression of apoptosis regulating factors in human endometrial hyperplasia and carcinoma

TE Vaskivuo MD a,b, F Stenbäck MD PhD b, JS Tapanainen MD PhD a,b

a Department of Obstetrics and Gynecology, University Hospital of Oulu, Oulu, Finland, b Department of Pathology, University of Oulu, Oulu, Finland

AIM: Apoptosis controls cell homeostasis in the endometrium during menstrual cycle. Several genes, including those of the Bcl-2 family and TNF-α regulate apoptosis in normal endometrium but their significance in endometrial pathologies is poorly understood. We studied the role of apoptosis and its regulation in endometrial hyperplasia and carcinoma. METHODS: Apoptosis and the expression of apoptosis-related factors Bcl-2, Bax, TNF-α and NF-κB were investigated using in situ 3-end labeling of apoptotic cells, in situ hybridization and immunohistochemistry in human endometrial specimens. RESULTS: Apoptosis was scarce in normal proliferating endometrium as well as in endometrial hyperplasia and grade I adenocarcinoma. In grade II adenocarcinoma a marked increase in the rate of apoptosis was observed. Apoptosis decreased in grade III adenocarcinoma but was still higher than in normal or hyperplastic endometrium. Bcl-2 and Bax were expressed in normal and hyperplastic endometrium, and the Bcl-2/Bax ratio was decreased in endometrial carcinoma. TNF-α was expressed in normal endometrium, and in simplex and complex hyperplasia, but it was down-regulated in atypical hyperplasia and endometrial carcinoma. The transcription factor NF-κB was present in proliferating endometrium and in endometrial hyperplasia, but its expression was clearly decreased in carcinoma. CONCLUSIONS: In proliferating endometrium and in endometrial hyperplasia the rate of apoptosis is low, while in endometrial carcinoma a marked increase in apoptosis takes place. This coincides with a decrease in the Bcl-2/Bax ratio and down-regulation of NF-κB. The decreased number of apoptotic in grade III adenocarcinoma may reflect lost control of cell homeostasis, decreased differentiation and increased malignancy.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Apoptosis - Molecular Mechanisms.