Abstract
Thebcl-2 protooncogene was initially discovered at the t(14;18) chromosomal breakpoint in follicular lymphomas. It has been demonstrated thatbcl-2 protein (Bcl-2) expression blocks apoptosis and plays an important role in cell development and maturation. In the present study, Bcl-2 expression was immunohistochemically examined in 103 cases of gastric carcinoma, as well as 64 cases of non-carcinous gastric mucosa, and its correlation with apoptosis, cell proliferation and p53 immunoreactivity was investigated. Bcl-2 was detected in 18.0% of differentiatedtype gastric carcinomas (9 of 50) and 7.5% of the undifferentiated type (4 of 53). In adjacent intestinal metaplastic gastric epithelium, the incidence of Bcl-2 positivity in the incomplete type (21/23, 91.3%) was significantly higher than in the complete type (23/41, 56.1%) (P<0.04). Double immunostaining for Bcl-2 and Ki-67 clearly revealed the majority of Bcl-2-positive cancer cells to be in a nonproliferating state, although some cancer cells expressed both proteins together. Statistical assessment demonstrated that the average Ki-67 labeling index and apoptotic labeling index in Bcl-2-positive foci were significantly lower than in Bcl-2-negative foci (P<0.0001,P<0.0003). In addition, a significant dissociation between Bcl-2 and p53 immunoreactivity was found in cancer tissues. These results indicate that aberrant Bcl-2 expression in gastric carcinomas possibly originates from intestinal metaplastic epithelium, and suggest a possible role in tumor development and growth.
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Abbreviations
- IM :
-
intestinal metaplasia
References
Arends MJ, McGregor AH, Wyllie AH (1994) Apoptosis is inversely related to necrosis and determines net growth in tumors bearing constitutively expressedmyc, ras, and HPV oncogenes. Am J Pathol 144:1045–1057
Baas IO, Muldder J-WR, Offerhaus JA, vogelstein B, Hamilton SR (1994) An evaluation of six antibodies for immunohistochemistry of mutant p53 gene product in archival colorectal neoplasms. J Pathol 172: 5–12
Charlotte F, L'Hermine A, Martin N, Geleyn Y, Nollet M, Gaulard P, Zafrani ES (1994) Immunohistochemical detection ofbcl-2 protein in normal and pathological human liver. Am J Pathol 144: 460–465
Chleq-Deschamps CM, LeBrun DP, Huie P, Besnier DP, Warnke RA, Sibley RK, Cleary ML (1993) Topographical dissociation ofbcl-2 messenger RNA and protein expression in human lymphoid tissues. Blood 81: 293–298
Cleary ML, Sklar J (1985) Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome, 18. Proc Natl Acad Sci USA 82: 7437–7443
Correa P (1988) A human model of gastric carcinogenesis. Cancer Res 48: 3554–3560
Correa P (1992) Human gastric carcinogenesis: a multistep and multifactorial process. First American Cancer Society Award lecture on cancer epidemiology and prevention. Cancer Res 52: 6735–6740
Gaulard P, Peuchmaur M-F d'Agay, Brousse N Gisselbrecht C, SolalCeligny P, Diebold J, Mason DY (1992) Expression of thebcl-2 gene product in follicular lymphoma. Am J Pathol 140: 1089–1095
Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119: 493–501
Gompel A, Sabourin JC, Martin A, Yaneva H, Audouin, J, Decroix Y, Poitout P (1994) Bcl-2 expression in normal endometrium during the menstrual cycle. Am J Pathol 144: 1195–1202
Haldar S, Negrini M, Monne M, Sabbioni S, Croce CM (1994) Downregulation of bcl-2 by p53 in breast cancer cells. Cancer Res 54: 2095–2097
Hockenbery DM, Zutter M, Hickey W, Nahm M, Korsmeyer SJ (1991) Bcl2 protein is topographically restricted in tissues characterized by apototic cell death. Proc Natl Acad Sci USA 88: 6961–6965
Iida F, Kusama J (1982) Gastric carcinoma and intestinal metaplasia. Significance of type of intestinal metaplasia upon development of gastric carcinoma. Cancer 50: 2854–2858
Iida F, Murata F, Nagata T (1978) Histochemical studies of mucosubstances in metaplastic epithelium of the stomach, with special reference to the development of intestinal metaplasia. Histochemistry 56: 229–237
Korsmeyer SJ (1992) Bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood 80: 879–886
LeBrun DP, Warnke RA, Cleary ML (1993) Expression ofbcl-2 in fetal tissues suggests a role in morphogenesis. Am J Pathol 142: 743–753
Lu Q-L, Poulsom R, Wong L, Hanby A (1993) Bcl-2 expression in adult and embryonic non-hematopoietic tissues. J Pathol 169: 431–437
Martin HM, Filipe MI, Morris RW, Lane DP, Silvestre F (1992) p53 expression and prognosis in gastric carcinoma. Int J Cancer 50: 859–862
McDonnell TJ, Korsmeyer SJ (1991) Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature 349: 254–256
McDonnell TJ, Troncoso P Logothetis C, Chung LWK, Hsieh J-T, Tu S-M, Campbell ML (1992) Expression of the protooncogenebcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res 52: 6940–6944
Miyashita T, Harigai M, Hanada M, Reed JC-l (1994) Identification of a p53-dependent negative response element in thebcl-2 gene. Cancer Res 54: 3131–3135
Monaghan P, Robertson D, Amos TAS, Dyer MJS, Mason DY, Greaves MF (1992) Ultrastructural localization of Bcl-2 protein. J Histochem Cytochem 40: 1819–1825
Novack DV, Korsmeyer SJ (1994) Bcl-2 protein expression during murine development. Am J Pathol 145: 61–73
Pezzella F, Tse AGD, Cordell JL, Pulford KAF, Gatter KC, Mason DY (1990) Expression of thebcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am J Pathol 137: 225–232
Pezzella F, Turley H, Kuzu I, Tungekar MF, Dunnill MS, Pierce CB, Harris A, Gatter KC Mason DY (1993) Bcl-2 protein in non-small-cell lung carcinoma. N Engl J Med 329: 690–694
Pietenpol JA, Papadopoulos N, Markowitz S, Willson JKV, Kinzler KW, Vogelstein B (1994) Paradoxical inhibition of solid tumor cell growth by bcl2. Cancer Res 54: 3714–3717
Pilotti S, Collini P, Rilke F, Cattoretti G, Bo RD, Pierotti MA (1994) Bcl-2 protein expression in carcinomas originating from the follicular epithelium of the thyroid gland. J Pathol 172: 337–342
Reed JC, Tsujimoto Y, Alpers JD, Croce CM, Nowell PC (1987) Regulation ofbcl-2 proto-oncogene expression during normal human lymphocyte proliferation. Science 236: 1295–1297
Starzynska T, Bromley M, Ghosh A, Stern PL (1992) Prognostic significance of p53 overexpression in gastric and colorectal carcinoma. Br J Cancer 66: 558–562
Sugano H, Nakamura K, Kato Y (1982) Pathological studies of human gastric cancer. Acta Pathol Jpn 32: 329–347
Toth K, Vaughan MM, Slocum HK, Arredondo MA, Takita H, Baker RM, Rustum YM (1994) New immunohistochemical “sandwich” staining method formdr1 P-glycoprotein detection with JSB-1 monoclonal antibody in formalin-fixed, paraffin-embedded human tissues. Am J Pathol 144: 227–236
Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM (1984) Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 226: 1097–1099
Umekita Y, Kobayashi K, Saheki T, Yosida H (1994) Nuclear accumulation of p53 protein correlates with mutations in the p53 gene on archival paraffin-embedded tissues of human breast cancer. Jpn J Cancer Res 85: 825–830
Veis DJ, Sorenson CM, Shutter JR Korsmeyer SJ (1993) Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75: 229–240
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Saegusa, M., Takano, Y. & Okayasu, I. Bcl-2 expression and its association with cell kinetics in human gastric carcinomas and intestinal metaplasia. J Cancer Res Clin Oncol 121, 357–363 (1995). https://doi.org/10.1007/BF01225688
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DOI: https://doi.org/10.1007/BF01225688