Abstract
Background: Clear cell adenocarcinomas (CCAs) of the vagina and cervix are rare tumors that often overexpress wild-type p53. In vitro, expression of protooncogene bcl-2 can block p53-mediated apoptosis. The objective of this study was to determine if bcl-2 is expressed in CCAs and whether this expression is associated with inhibition of apoptosis.
Methods: Twenty-one paraffin-embedded clear cell adenocarcinomas were immunohistochemically stained for bcl-2 (antibody M 887, Dako, Carpinteria, CA) and DNA fragmentation (Apop-Tag, Oncor, Gaithersburg, MD), a marker for apoptosis. Fifteen tumors were associated with in utero exposure to diethylstilbestrol (DES). Prior p53 gene analysis had indicated the presence of wild-type p53 in each tumor. Human lymphoid tissue containing bcl-2-expressing lymphocytes and DNase I-exposed CCA tissue sections were used as positive controls for the bcl-2 and apoptosis assays, respectively. Expression of bcl-2 and DNA fragmentation was classified (0 to 3+) according to percentage of positive cells and intensity of staining.
Results: Expression of bcl-2 was identified in each CCA examined, and was strongly positive (2+ to 3+) in 18 of 21 samples. Despite the presence of wild-type p53, only 4 of 21 tumors showed evidence of apoptosis as assessed through DNA fragmentation.
Conclusions: DNA damage leads to increased intracellular p53 levels. Overexpression of p53 induces apoptosis as a means of protecting organisms from the development of malignancy. CCAs of the vagina and cervix, which contain wild-type p53 genes and often overexpress p53 protein, presumably have evolved mechanisms to avoid p53-induced apoptosis. Our observations are consistent with the hypothesis that overexpression of bcl-2 can inhibit p53-mediated apoptosis and suggest a mechanism by which these rare tumors can arise without mutation of the p53 gene.
Similar content being viewed by others
References
Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women.N Engl J Med 1971;284:878–81.
Noller KL, Decker DG, Lanier AP, Kurland LT. Clear cell adenocarcinoma of the cervix after maternal treatment with synthetic estrogens.Mayo Clinic Proc 1972;47:620–30.
Adenocarcinoma Registry.Am J Obstet Gynecol 1972;113:118.
Yonish-Rouch E, Grunwald S, Wilder S, et al. p53-mediated cell death: relationship to cell cycle control.Mol Cell Biol 1993;13:1415–23.
Thompson C. Apoptosis in the pathogenesis and treatment of disease.Science 1995;267:1456–61.
Vaux D. Toward an understanding of the molecular mechanisms of physiologic cell death.Proc Natl Acad Sci USA 1993;90:786–9.
Stellar H. Mechanisms and genes of cellular suicide.Science 1995;267:1445–9.
Lane DP. p53, guardian of the genome.Nature 1992;358:15–6.
Lane DP. The regulation of p53 function: Steiner Award Lecture.Int J Cancer 1994;57:623–7.
Levine AJ, Momand J, Finlay CA. The p53 tumour suppressor gene.Nature 1991;351:453–6.
Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers.Science 1991;253:49–53.
Waggoner SE, Anderson SM, Van Eyck S, Fuller J, Luce MC, Herbst AL. Human papillomavirus detection and p53 expression in clear-cell adenocarcinoma of the vagina and cervix.Obstet Gynecol 1994;84:404–8.
Waggoner SE, Anderson SM, Luce MC, Takahashi H, Boyd J. p53 protein detection and gene analysis in clear cell adenocarcinoma of the vagina and cervix.Gynecol Oncol 1996;60:339–44.
Hockenberry D, Nunez G, Millman C, Schreiber RD, Korsmeyer SJ. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death.Nature 1990;348:334–6.
Korsmeyer SJ. Bcl-2 initiates a new category of oncogenesis: regulators of cell death.Blood 1992;80:879–86.
Silvestrini R, Vencroni S, Daidone MG, et al. The bcl-2 protein: a prognostic indicator strongly related to p53 protein in lymph node-negative breast cancer patients.J Natl Cancer Inst 1994;86:499–504.
Hockenberry DM, Zutter M, Hickey W, Nahm M, Korsymeyer SJ. Bcl-2 protein is topographically restricted in tissues characterized by apoptotic cell death.Proc Natl Acad Sci USA 1991;88:6961–5.
Shaw P, Bovey R, Tardy S, Schli R, Jordat B. Induction of apoptosis by wild type p53 in a human colon tumor derived cell line.Proc Natl Acad Sci USA 1992;89:4495–9.
Alderson LM, Castleberg RL, Harsh GR, Louis DN, Henson JW. Human gliomas with wild type p53 express bcl-2.Cancer Res 1995;55:999–1001.
Reed JC, Meister L, Tanaka S, Cuddy M, Yun S, Geyer C, Pleasure D. Differential expression of bcl-2 protooncogene in neuroblastoma and other human tumor cell lines of neural origin.Cancer Res 1991;51:6529–38.
Chiou SK, Rao L, White E. Bcl-2 blocks p53-dependent apoptosis.Mol Cell Biol 1994;14:2556–63.
Hoffman B, Lieberman DA. Molecular controls of apoptosis: differentiation/growth arrest primary response genes, proto-oncogenes, and tumor genes as positive and negative modulators.Oncogene 1994;9:1807–12.
Henderson S, Rowe M, Gregory C, et al. Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1.Cell 1991;65:1107–15.
Wang Y, Szekely L, Okan I, Klein G, Wiman KG. Wild-type p53 triggered apoptosis is inhibited by bcl-2 in a v-myc induced T-cell lymphoma line.Oncogene 1993;8:3427–30.
Liu YJ, Mason DY, Johnson GD, et al. Germinal center cells express bcl-2 protein after activation by signals which prevent their entry into apoptosis.Eur J Immunol 1991;21:1905–10.
Ryan JJ, Prochownik E, Gottlieb CA, Apel IJ, Merino R, Nunez G, Clarke MF. c-myc and bcl-2 modulate p53 function by altering p53 subcellular trafficking during the cell cycle.Proc Natl Acad Sci USA 1994;91:5878–82.
Author information
Authors and Affiliations
Additional information
Supported by American Cancer Society Career Development Award 93–95 and NIH U01-CA-62912.
Rights and permissions
About this article
Cite this article
Waggoner, S.E., Baunoch, D.A., Anderson, S.A. et al. Bcl-2 protein expression associated with resistance to apoptosis in clear cell adenocarcinomas of the vagina and cervix expressing wild-type p53. Annals of Surgical Oncology 5, 544–547 (1998). https://doi.org/10.1007/BF02303648
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02303648