Skip to main content
Journal of Cancer Research and Clinical Oncology logoLink to Journal of Cancer Research and Clinical Oncology
. 1995 Jun;121(6):357–363. doi: 10.1007/BF01225688

Bcl-2 expression and its association with cell kinetics in human gastric carcinomas and intestinal metaplasia

Makoto Saegusa 1,, Yasuo Takano 1, Isao Okayasu 1
PMCID: PMC12201682  PMID: 7797601

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.

Key words: bcl-2, Ki-67, Apoptosis, p53, Gastric carcinoma, Intestinal metaplasia

Abbreviation

IM

intestinal metaplasia

References

  1. 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 [PMC free article] [PubMed] [Google Scholar]
  2. 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 [DOI] [PubMed] [Google Scholar]
  3. 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 [PMC free article] [PubMed] [Google Scholar]
  4. 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 [PubMed] [Google Scholar]
  5. 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 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Correa P (1988) A human model of gastric carcinogenesis. Cancer Res 48: 3554–3560 [PubMed] [Google Scholar]
  7. 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 [PubMed] [Google Scholar]
  8. 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 [PMC free article] [PubMed] [Google Scholar]
  9. 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 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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 [PMC free article] [PubMed] [Google Scholar]
  11. 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 [PubMed] [Google Scholar]
  12. 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 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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 [DOI] [PubMed] [Google Scholar]
  14. 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 [DOI] [PubMed] [Google Scholar]
  15. Korsmeyer SJ (1992) Bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood 80: 879–886 [PubMed] [Google Scholar]
  16. LeBrun DP, Warnke RA, Cleary ML (1993) Expression ofbcl-2 in fetal tissues suggests a role in morphogenesis. Am J Pathol 142: 743–753 [PMC free article] [PubMed] [Google Scholar]
  17. 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 [DOI] [PubMed] [Google Scholar]
  18. Martin HM, Filipe MI, Morris RW, Lane DP, Silvestre F (1992) p53 expression and prognosis in gastric carcinoma. Int J Cancer 50: 859–862 [DOI] [PubMed] [Google Scholar]
  19. 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 [DOI] [PubMed] [Google Scholar]
  20. 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 [PubMed] [Google Scholar]
  21. 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 [PubMed] [Google Scholar]
  22. 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 [DOI] [PubMed] [Google Scholar]
  23. Novack DV, Korsmeyer SJ (1994) Bcl-2 protein expression during murine development. Am J Pathol 145: 61–73 [PMC free article] [PubMed] [Google Scholar]
  24. 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 [PMC free article] [PubMed] [Google Scholar]
  25. 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 [DOI] [PubMed] [Google Scholar]
  26. 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 [PubMed] [Google Scholar]
  27. 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 [DOI] [PubMed] [Google Scholar]
  28. 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 [DOI] [PubMed] [Google Scholar]
  29. 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 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sugano H, Nakamura K, Kato Y (1982) Pathological studies of human gastric cancer. Acta Pathol Jpn 32: 329–347 [PubMed] [Google Scholar]
  31. 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 [PMC free article] [PubMed] [Google Scholar]
  32. 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 [DOI] [PubMed] [Google Scholar]
  33. 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 [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. 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 [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cancer Research and Clinical Oncology are provided here courtesy of Springer

RESOURCES