Apoptosis and apoptosis‐related factors Bcl‐2, Bax, tumor necrosis factor‐α, and NF‐κB in human endometrial hyperplasia and carcinoma

Abstract

BACKGROUNDApoptosis controls cell homeostasis in the endometrium during normal menstrual cycles, and morphologic studies have suggested its association with the development of endometrial carcinoma. Apoptosis is regulated by several genes, especially those of the Bcl‐2 gene family, but their significance in endometrial pathologies is not well understood.METHODSTo study the role and regulation of apoptosis in endometrial hyperplasia and carcinoma, human endometrial specimens were analyzed using in situ 3′‐end labeling of apoptotic cells and in situ hybridization and immunohistochemistry of apoptosis‐related factors.RESULTSApoptosis was scarce in normal proliferating endometrium as well as in simplex, complex, and atypical hyperplasia and was low in Grade I adenocarcinoma. In Grade II adenocarcinoma a significant increase in the rate of apoptosis was observed. Apoptosis decreased in Grade III adenocarcinoma, but it 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 lower in endometrial carcinoma. Tumor necrosis factor‐α was expressed in normal endometrium and 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 lower in carcinoma.CONCLUSIONSIn endometrial proliferation and hyperplasia a low rate of apoptosis is present. In Grade I carcinoma the rate of apoptosis is decreased, but the rate is subsequently increased in advanced carcinoma. The decrease in the rate of apoptosis in Grade III adenocarcinoma may reflect loss of control of cell homeostasis, decreased differentiation, and increased malignancy. Cancer 2002;95:1463–71. © 2002 American Cancer Society.DOI 10.1002/cncr.10876

The Combination of the Proteasome Inhibitor Bortezomib and the Bcl-2 Antisense Molecule Oblimersen Sensitizes Human B-Cell Lymphomas to Cyclophosphamide

“…The relationship between the induction of apoptosis and proteasome inhibition is likely to involve both direct and indirect influences (8). Nuclear factor nB (NF-nB) itself is known to elicit an antiapoptotic effect by suppressing tumor necrosis factor-a.…”

The role of chorionic gonadotropin and Notch1 in implantation

“…Studies in human endometrial fibroblasts with an apoptosis-inducing agent which disrupts the actin microfilaments, cytochalasin D indicate that (h) CG can significantly inhibit cytochalasin D-induced apoptosis of stromal cells, and this effect is enhanced in the presence of estrogen and progesterone [70]. Studies in human endometrial tissue suggest that ovarian steroids regulate three apoptotic related proteins (Bcl-2, Bcl-X and Bax) [59,71,72]. Thus, (h)CG and progesterone significantly reduce apoptosis in the endometrium.…”

Nuclear factor κB pathway and interleukin-6 are affected in eutopic endometrium of women with endometriosis

“…All the components of the NFKB system have been described in normal endometrium (Laird et al 2000, King et al 2001, and there are some reports of the role of the NFKB system in benign endometrial hyperplasia and endometrial cancer (Vaskivuo et al 2002), both pathologies that present deregulated tissue homeostasis. However, the expression of these proteins in the eutopic endometrium in endometriosis, a disease that also presents abnormal endometrial homeostasis with reduced apoptosis (Meresman et al 2000, Braun et al 2002, Johnson et al 2005, is not clear.…”