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. 2001 Nov;85(11):1781–1786. doi: 10.1054/bjoc.2001.2084

Spontaneous and inducible apoptosis in oesophageal adenocarcinoma

A Raouf 1, D Evoy 1, E Carton 1, E Mulligan 1, M Griffin 2, E Sweeney 2, J V Reynolds 1
PMCID: PMC2363994  PMID: 11742502

Abstract

The use of neoadjuvant chemoradiotherapy prior to surgery in the treatment of oesophageal adenocarcinoma has increased in recent years, and up to 25% of patients will have a complete pathological response to the neoadjuvant therapy. Many patients will not respond, however, and the knowledge of molecular factors predicting response or resistance to chemoradiotherapy is required to enhance treatment results. An understanding of apoptosis and cell proliferation may be relevant and this study focused on apoptotic indices and cell-cycle related (Ki-67, p53 and bcl-2) protein expression in a cohort of 42 patients with primary oesophageal adenocarcinoma. We documented that apoptosis occurs among viable (proliferating) tumour cells in all adenocarcinoma cases examined in this study. Pre-operative chemoradiotherapy significantly increased apoptosis and significantly decreased cell proliferation (estimated by Ki-67 expression). Immunohistochemically detected p53 and bcl-2 gene products had no regulatory role in the apoptotic process. The cumulative expression of p53 protein is significantly associated with increasing proliferation activity. Evaluation of apoptosis in pre-treatment specimens may have potential utility in predicting the efficacy of treatment. Assessment of the tumours proliferation activity by Ki-67 expression might identify patients who are at risk of developing metastastic disease. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: oesophagus, adenocarcinoma, apoptosis, Ki-67, p53, bcl-2

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Selected References

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  1. Cameron D. A., Keen J. C., Dixon J. M., Bellamy C., Hanby A., Anderson T. J., Miller W. R. Effective tamoxifen therapy of breast cancer involves both antiproliferative and pro-apoptotic changes. Eur J Cancer. 2000 May;36(7):845–851. doi: 10.1016/s0959-8049(00)00013-7. [DOI] [PubMed] [Google Scholar]
  2. Gerdes J., Lemke H., Baisch H., Wacker H. H., Schwab U., Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984 Oct;133(4):1710–1715. [PubMed] [Google Scholar]
  3. Giatromanolaki A., Koukourakis M. I., Georgoulias V., Gatter K. C., Harris A. L., Fountzilas G. Angiogenesis vs. response after combined chemoradiotherapy of squamous cell head and neck cancer. Int J Cancer. 1999 Mar 15;80(6):810–817. doi: 10.1002/(sici)1097-0215(19990315)80:6<810::aid-ijc3>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  4. Hartwell L. H., Kastan M. B. Cell cycle control and cancer. Science. 1994 Dec 16;266(5192):1821–1828. doi: 10.1126/science.7997877. [DOI] [PubMed] [Google Scholar]
  5. Hockenbery D., Nuñez G., Milliman C., Schreiber R. D., Korsmeyer S. J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990 Nov 22;348(6299):334–336. doi: 10.1038/348334a0. [DOI] [PubMed] [Google Scholar]
  6. Ikeguchi M., Saito H., Katano K., Tsujitani S., Maeta M., Kaibara N. Clinicopathologic significance of the expression of mutated p53 protein and the proliferative activity of cancer cells in patients with esophageal squamous cell carcinoma. J Am Coll Surg. 1997 Oct;185(4):398–403. [PubMed] [Google Scholar]
  7. Inada T., Ichikawa A., Igarashi S., Kubota T., Ogata Y. Effect of preoperative 5-fluorouracil on apoptosis of advanced gastric cancer. J Surg Oncol. 1997 Jun;65(2):106–110. doi: 10.1002/(sici)1096-9098(199706)65:2<106::aid-jso6>3.0.co;2-b. [DOI] [PubMed] [Google Scholar]
  8. Kagawa S., Fujiwara T., Hizuta A., Yasuda T., Zhang W. W., Roth J. A., Tanaka N. p53 expression overcomes p21WAF1/CIP1-mediated G1 arrest and induces apoptosis in human cancer cells. Oncogene. 1997 Oct 16;15(16):1903–1909. doi: 10.1038/sj.onc.1201362. [DOI] [PubMed] [Google Scholar]
  9. Katada N., Hinder R. A., Smyrk T. C., Hirabayashi N., Perdikis G., Lund R. J., Woodward T., Klingler P. J. Apoptosis is inhibited early in the dysplasia-carcinoma sequence of Barrett esophagus. Arch Surg. 1997 Jul;132(7):728–733. doi: 10.1001/archsurg.1997.01430310042007. [DOI] [PubMed] [Google Scholar]
  10. Kerr J. F., Wyllie A. H., Currie A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4):239–257. doi: 10.1038/bjc.1972.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kollmannsberger C., Quietzsch D., Haag C., Lingenfelser T., Schroeder M., Hartmann J. T., Baronius W., Hempel V., Clemens M., Kanz L. A phase II study of paclitaxel, weekly, 24-hour continous infusion 5-fluorouracil, folinic acid and cisplatin in patients with advanced gastric cancer. Br J Cancer. 2000 Aug;83(4):458–462. doi: 10.1054/bjoc.2000.1295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Koshiji M., Adachi Y., Taketani S., Takeuchi K., Hioki K., Ikehara S. Mechanisms underlying apoptosis induced by combination of 5-fluorouracil and interferon-gamma. Biochem Biophys Res Commun. 1997 Nov 17;240(2):376–381. doi: 10.1006/bbrc.1997.7657. [DOI] [PubMed] [Google Scholar]
  13. Kupryjańczyk J., Dansonka-Mieszkowska A., Szymańska T., Karpińska G., Rembiszewska A., Rusin M., Konopiński R., Kraszewska E., Timorek A., Yandell D. W. Spontaneous apoptosis in ovarian carcinomas: a positive association with p53 gene mutation is dependent on growth fraction. Br J Cancer. 2000 Feb;82(3):579–583. doi: 10.1054/bjoc.1999.0967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lane D. P. Cancer. p53, guardian of the genome. Nature. 1992 Jul 2;358(6381):15–16. doi: 10.1038/358015a0. [DOI] [PubMed] [Google Scholar]
  15. Liu Y. J., Mason D. Y., Johnson G. D., Abbot S., Gregory C. D., Hardie D. L., Gordon J., MacLennan I. C. Germinal center cells express bcl-2 protein after activation by signals which prevent their entry into apoptosis. Eur J Immunol. 1991 Aug;21(8):1905–1910. doi: 10.1002/eji.1830210819. [DOI] [PubMed] [Google Scholar]
  16. Logsdon M. D., Meyn R. E., Jr, Besa P. C., Pugh W. C., Stephens L. C., Peters L. J., Milas L., Cox J. D., Cabanillas F., Brisbay S. Apoptosis and the Bcl-2 gene family -- patterns of expression and prognostic value in stage I and II follicular center lymphoma. Int J Radiat Oncol Biol Phys. 1999 Apr 1;44(1):19–29. doi: 10.1016/s0360-3016(98)00455-6. [DOI] [PubMed] [Google Scholar]
  17. Luo D., Cheng S. C., Xie Y. Expression of Bcl-2 family proteins during chemotherapeutic agents-induced apoptosis in the hepatoblastoma HepG2 cell line. Br J Biomed Sci. 1999;56(2):114–122. [PubMed] [Google Scholar]
  18. Miyake H., Hanada N., Nakamura H., Kagawa S., Fujiwara T., Hara I., Eto H., Gohji K., Arakawa S., Kamidono S. Overexpression of Bcl-2 in bladder cancer cells inhibits apoptosis induced by cisplatin and adenoviral-mediated p53 gene transfer. Oncogene. 1998 Feb 19;16(7):933–943. doi: 10.1038/sj.onc.1201602. [DOI] [PubMed] [Google Scholar]
  19. Oltvai Z. N., Milliman C. L., Korsmeyer S. J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993 Aug 27;74(4):609–619. doi: 10.1016/0092-8674(93)90509-o. [DOI] [PubMed] [Google Scholar]
  20. Ozer E., Canda T., Kuyucuodlu F. p53 mutations in bilateral breast carcinoma. Correlation with Ki-67 expression and the mean nuclear volume. Cancer Lett. 1998 Jan 9;122(1-2):101–106. doi: 10.1016/s0304-3835(97)00374-1. [DOI] [PubMed] [Google Scholar]
  21. Paules R. S., Levedakou E. N., Wilson S. J., Innes C. L., Rhodes N., Tlsty T. D., Galloway D. A., Donehower L. A., Tainsky M. A., Kaufmann W. K. Defective G2 checkpoint function in cells from individuals with familial cancer syndromes. Cancer Res. 1995 Apr 15;55(8):1763–1773. [PubMed] [Google Scholar]
  22. Reed J. C. Bcl-2 and the regulation of programmed cell death. J Cell Biol. 1994 Jan;124(1-2):1–6. doi: 10.1083/jcb.124.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Rey A., Lara P. C., Redondo E., Valdés E., Apolinario R. Overexpression of p53 in transitional cell carcinoma of the renal pelvis and ureter. Relation to tumor proliferation and survival. Cancer. 1997 Jun 1;79(11):2178–2185. doi: 10.1002/(sici)1097-0142(19970601)79:11<2178::aid-cncr16>3.0.co;2-t. [DOI] [PubMed] [Google Scholar]
  24. Rupnow B. A., Murtha A. D., Alarcon R. M., Giaccia A. J., Knox S. J. Direct evidence that apoptosis enhances tumor responses to fractionated radiotherapy. Cancer Res. 1998 May 1;58(9):1779–1784. [PubMed] [Google Scholar]
  25. Rödel C., Grabenbauer G. G., Rödel F., Birkenhake S., Kühn R., Martus P., Zörcher T., Fürsich D., Papadopoulos T., Dunst J. Apoptosis, p53, bcl-2, and Ki-67 in invasive bladder carcinoma: possible predictors for response to radiochemotherapy and successful bladder preservation. Int J Radiat Oncol Biol Phys. 2000 Mar 15;46(5):1213–1221. doi: 10.1016/s0360-3016(99)00544-1. [DOI] [PubMed] [Google Scholar]
  26. Sato T., Hanada M., Bodrug S., Irie S., Iwama N., Boise L. H., Thompson C. B., Golemis E., Fong L., Wang H. G. Interactions among members of the Bcl-2 protein family analyzed with a yeast two-hybrid system. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9238–9242. doi: 10.1073/pnas.91.20.9238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Scott N., Hale A., Deakin M., Hand P., Adab F. A., Hall C., Williams G. T., Elder J. B. A histopathological assessment of the response of rectal adenocarcinoma to combination chemo-radiotherapy: relationship to apoptotic activity, p53 and bcl-2 expression. Eur J Surg Oncol. 1998 Jun;24(3):169–173. doi: 10.1016/s0748-7983(98)92861-x. [DOI] [PubMed] [Google Scholar]
  28. Slootweg P. J., Koole R., Hordijk G. J. The presence of p53 protein in relation to Ki-67 as cellular proliferation marker in head and neck squamous cell carcinoma and adjacent dysplastic mucosa. Eur J Cancer B Oral Oncol. 1994;30B(2):138–141. doi: 10.1016/0964-1955(94)90066-3. [DOI] [PubMed] [Google Scholar]
  29. Sugamura K., Makino M., Kaibara N. Apoptosis as a prognostic factor in colorectal carcinoma. Surg Today. 1998;28(2):145–150. doi: 10.1007/s005950050096. [DOI] [PubMed] [Google Scholar]
  30. Suto T., Sugai T., Nakamura S., Funato O., Nitta H., Sasaki R., Kanno S., Saito K. Assessment of the expression of p53, MIB-1 (Ki-67 antigen), and argyrophilic nucleolar organizer regions in carcinoma of the extrahepatic bile duct. Cancer. 1998 Jan 1;82(1):86–95. [PubMed] [Google Scholar]
  31. Vaux D. L., Cory S., Adams J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988 Sep 29;335(6189):440–442. doi: 10.1038/335440a0. [DOI] [PubMed] [Google Scholar]
  32. Walsh T. N., Noonan N., Hollywood D., Kelly A., Keeling N., Hennessy T. P. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996 Aug 15;335(7):462–467. doi: 10.1056/NEJM199608153350702. [DOI] [PubMed] [Google Scholar]
  33. Xie X., Clausen O. P., De Angelis P., Boysen M. The prognostic value of spontaneous apoptosis, Bax, Bcl-2, and p53 in oral squamous cell carcinoma of the tongue. Cancer. 1999 Sep 15;86(6):913–920. doi: 10.1002/(sici)1097-0142(19990915)86:6<913::aid-cncr4>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  34. Zhang G. J., Kimijima I., Onda M., Kanno M., Sato H., Watanabe T., Tsuchiya A., Abe R., Takenoshita S. Tamoxifen-induced apoptosis in breast cancer cells relates to down-regulation of bcl-2, but not bax and bcl-X(L), without alteration of p53 protein levels. Clin Cancer Res. 1999 Oct;5(10):2971–2977. [PubMed] [Google Scholar]

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