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
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References
Cameron DA, Keen JC, Dixon JM, Bellamy C, Hanby A, Anderson TJ and Miller WR (2000) Effective tamoxifen therapy of breast cancer involves both antiproliferative and pro-apoptotic changes. Eur J Cancer 36: 845–851
Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U and Stein H (1984) Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunology 133: 1710–1715
Giatromanolaki A, Koukourakis MI, Georgoulias V, Gatter KC, Harris AL and Fountzilas G (1999) Angiogenesis vs. response after combined chemoradiotherapy of squamous cell head and neck cancer. Int J Cancer 80: 810–817
Hockenbery D, Nunez G, Milliman C, Schreiber RD and Korsmeyer SJ (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348: 334–336
Ikeguchi M, Saito H, Katano K, Tsujitani S, Maeta M and Kaibara N (1997) 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 185: 398–403
Inada T, Ichikawa A, Igarashi S, Kubota T and Ogata Y (1997) Effect of preoperative 5-fluorouracil on apoptosis of advanced gastric cancer. J Surg Oncol 65: 106–110
Kagawa S, Fujiwara T, Hizuta A, Yasuda T, Zhang WW, Roth JA and Tanaka N (1997) p53 expression overcomes p21WAF1/CIP1-mediated G1 arrest and induced apoptosis in human cancer cells. Oncogene 15: 1903–1909
Katada N, Hinder RA, Smyrk TC, Hirabayashi N, Perdikis G, Lund RJ, Woodward T and Klingler PJ (1997) Apoptosis is inhibited early in the dysplasia-carcinoma sequence of Barrett esophagus. Arch Surg 132: 728–733
Kerr JFR, Wyllie AH and Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implication in tissue kinetics. Br J Cancer 26: 239–257
Kollmannsberger C, Quietzch D, Haag C, Lingenfelser T, Schroeder M, Hartmann JT, Baronius W, Hempel V, Clemens M, Kanz L and Bokemeyer C (2000) 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 83: 458–462
Koshiji M, Adachi Y, Taketani S, Takeuchi K, Hioki K and Ikehara S (1997) Mechanism underlying apoptosis induced by combination of 5-fluorouracil and interferon-gamma. Biochem Biophys Res Commun 52: 376–381
Kupryjanczky J, Dansonka MA, Szymanska T, Karpinska G, Rembiszewska A, Rusin M, Konopinski R, Kraszewska E, Timorek A, Yandell DW and Stelmachow J (2000) Spontaneous apoptosis in ovarian carcinomas: a positive association with p53 gene mutation is dependent on growth fraction. Br J Cancer 82: 579–583
Lane DP (1992) p53, guardian of the genome. Nature 358: 15–16
Leland HH and Kastan MB (1994) Cell cycle control and cancer. Science 266: 1821–1828
Levin AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88: 323–331
Liu YJ, Mason DY, Johnson GD, Abbot S, Gregory CD, Hardie DL, Gordon J and MacLennan IC (1991) Germinal center cells express bcl-2 protein after activation by signals which prevent their entry into apoptosis. Eur J Immunol 21: 1905–1910
Longsdon MD, Meyn RE Jr., Besa PC, Pugh WC, Stephens LC, Peter LJ, Milas L, Cox JD, Cabanillas F, Brisbay S, Andersen M and McDonnell TJ (1999) 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 44: 19–29
Luo D, Cheng CS and Xie Y (1999) Expression of bcl-2 family proteins during chemotherapeutic agents-induced apoptosis in the hepatoblastoma HepG2 cell line. Br J Bio Science 56: 114–122
Miyake H, Hanada N, Nakamura H, Kagawa S, Fujiwara T, Hara I, Eto H, Gohji K, Arakawa S, Kamidono S and Saya H (1998) Overexpression of bcl-2 in bladder cancer cells inhibits apoptosis induced by cisplatin and adenoviral-medioated p53 gene transfer. Oncogene 16: 933–943
Oltvai ZN, Milliman CL and Korsmeyer SJ (1993) Bcl-2 heterodimerizes in vivo with a conserved homology, Bax, that accelerates programmed cell death. Cell 74: 609–619
Ozer E, Canda T and Kuyucuodlu F (1998) p53 mutations in bilateral breast carcinoma. Correlation with Ki-67 expression and the mean nuclear volume. Cancer Lett 122: 101–106
Paules RS, Levedakou EN, Wilson SJ, Innes CL, Rhodes N, Tlsty TD, Galloway DA, Donehower LA, Tainsky MA and Kaufmann WK (1995) Defective G2 checkpoint function in cells from individuals with familial cancer syndromes. Cancer Res 55: 1763–1773
Reed JC (1994) Bcl-2 and the regulation of programmed cell death. J Cell Biol 124: 1–6
Rey A, Lara PC, Redondo E, Valdés E and Apolinario R (1997) Overexpression of p53 in Transitional Cell Carcinoma of the Renal Pelvis and Ureter: relation to Tumor Proliferation and Survival. Cancer 79: 2178–2185
Rodel C, Grabenbauer GG, Rodel F, Birkenhake S, Kuhn R, Martus P, Zorcher T, Fursich D, Papadopoulos T, Dunst J, Schrott KM and Sauer R (2000) 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 46: 1213–1221
Rupnow BA, Murtha AD, Alarcon RM, Giaccia AJ and Knox SJ (1998) Direct evidence that apoptosis enhances tumour responses to fractionated radiotherapy. Cancer Res 58: 1779–1784
Sato T, Hanada M, Bodrug S, Irie S, Iwama N, Boise LH, Thompson CB, Golemis E, Fong L, Wang HG and Reed JC (1994) Interaction among members of the Bcl-2 protein family analyzed with a yeast two-hybrid system. Proc Natl Acad Sci USA 91: 9238–9242
Scott N, Hale A, Deakin M, Hand P, Adab FA, Hall C, Williams GT and Elder JB (1998) A histopathological assessment of the response or rectal adenocarcinoma to combination chemo-radiotherapy: relationship to apoptotic activity, p53 and bcl-2 expression. Eur J Surg Oncol 24: 169–173
Slootweg PJ, Koole R and Hordijk GJ (1994) 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 30B: 138–141
Sugamura K, Makino M and Kaibara N (1998) Apoptosis as a prognostic factor in colorectal carcinoma. Surg Today 28: 145–150
Suto T, Sugai T, Nakamura S, Funato O, Nitta H, Sasaki R, Kanno S and Saito K (1998) Assessment of the Expression of p53, MIB-1 (KI-67 Antigen), and Argyrophilic Nucleolar Organizer Regions in Carcinoma of the Extrahepatic Bile Duct. Cancer 82: 86–95
Vaux DL, Cory S and Adams JM (1988) Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335: 440–442
Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N and Hennessy TPJ (1996) A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. The New England Journal of Medicine 335: 462–467
Xie X, Clausen OP, De Angelis P and Boysen M (1999) The proqnostic value of spontaneous apoptosis, bax, bcl-2, and p53 in oral squamous cell carcinoma of the tongue. Cancer 86: 913–920
Zhang GJ, Kimijima I, Onda M, Kanno M, Sato H, Watanabe T, Tsuchiya A, Abe R and Takenoshita S (1999) 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 5: 2971–2977
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Raouf, A., Evoy, D., Carton, E. et al. Spontaneous and inducible apoptosis in oesophageal adenocarcinoma. Br J Cancer 85, 1781–1786 (2001). https://doi.org/10.1054/bjoc.2001.2084
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DOI: https://doi.org/10.1054/bjoc.2001.2084
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