Abstract
An imbalance between apoptotic and proliferative processes is believed to underlie colorectal neoplasia. We evaluated the expression of bcl-2, p53, mdm2 proteins, and apoptosis in colorectal neoplasms, as well as their correlation with clinico-pathological parameters, using image analysis. Biopsies from 46 colorectal cancers, 121 adenomas, and 25 controls were studied using monoclonal antibodies against p53, bcl-2, mdm2 and the terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) method for apoptosis. P53 and bcl2 protein expression was higher in adenomas ≥1 cm (P < 0.03) and tubulovillous-villous adenomas (P < 0.03), and correlated with dysplasia (P < 0.03). In Cox regression analysis, Dukes’ stage was the most significant independent prognostic indicator of a worse survival (P < 0.019), whereas when stage was eliminated, bcl-2 expression was also a powerful predictor for bad prognosis (P = 0.02).
In conclusion, both bcl-2 and p53 immunohistochemical profiles may be useful adjuncts in detecting adenomas with a malignant potential, whereas bcl-2 could be used in combination with Dukes’ stage as a predictor of prognosis in colorectal cancer.
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References
Sternberg SS (1997) Apoptosis. In: Thaw VE, Hummel JE, Bass LB, Josephson D, (eds) Histology for pathologists. Lippincott Williams & Wilkins, Philadelphia, pp 3–21
Mignotte B, Vayssiere JL (1998) Mitochondria and apoptosis. Eur J Biochem 252:1–15
Schmitt CA, Lowe SW (1999) Apoptosis and therapy. J Pathol 187:127–137
Butler LM, Hewett PJ, Fitridge RA, Cowled PA (1999) Deregulation of apoptosis in colorectal carcinoma: theoretical and therapeutic implications. Aust NZ J Surg 69:88–94
Elkablawy MA, Maxwell P, Williamson K, Anderson N, Hamilton PW (2001) Apoptosis and cell-cycle regulatory proteins in colorectal carcinoma: relationship to tumour stage and patient survival. J Pathol 194:436–443
Maritsi D, Stagikas D, Charalabopoulos K, Batistatou A (2006) What’s new in p53. Hippokratia 10:116–119
Broll R, Stark A, Windhovel U, Best R, Strik MW, Schimmelpenning H, Schwandner O, Kujath P, Bruch HP, Duchrow M (1999) Expression of p53 and mdm2 mRNA and protein in colorectal carcinomas. Eur J Cancer 35:1083–1088
Paradiso A, Ranieri G, Simone G, Silvestris N, Costa A, De Lena M, Leone A, Vallejo C, Lacava J (2002) mdm2-p53 interaction: lack of correlation with the response to 5-Fluorouracil in advanced colorectal cancer. Oncology 62:278–285
Montgomery EA (2006) Colon: polyps, tumors, and tumefactions. In: Pine JW, Jacobs AE (eds) Biopsy interpretation of the gastrointestinal tract mucosa, Lippincott Williams & Wilkins, Philadelphia, pp 269–316
Fenoglio-Preiser CM (1999) Carcinomas and other epithelial and neuroendocrine tumors of the large intestine. In: AS Patterson M Iannuzzi L Carita (eds) Gastrointestinal pathology: an atlas and text. Lippincott Williams & Wilkins, Philadelphia, pp 909–1068
Watson AJ, Merritt AJ, Jones LS, Askew JN, Anderson E, Becciolini A, Balzi M, Potten CS, Hickman JA (1996) Evidence of reciprocity of bcl-2 and p53 expression in human colorectal adenomas and carcinomas. Br J Cancer 73:889–895
Hao X, Du M, Bishop AE, Talbot IC (1998) Imbalance between proliferation and apoptosis in the development of colorectal carcinoma. Virchows Arch 433:523–527
Saleh HA, Jackson H, Banerjee M (2000) Immunohistochemical expression of bcl-2 and p53 oncoproteins: correlation with Ki67 proliferation index and prognostic histopathologic parameters in colorectal neoplasia. Appl Immunohistochem Mol Morphol 8:175–182
Goussia AC, Ioachim E, Agnantis NJ, Mahera M, Tsianos EV (2000) Bcl-2 expression in colorectal tumours. Correlation with p53, mdm-2, Rb proteins and proliferation indices. Histol Histopathol 15:667–672
Han HS, Park YM, Hwang TS (2006) Differential expression of BCL-2, Bcl-XL and p53 in colorectal cancer. J Gastroenterol Hepatol 21:1108–1114
Scopa CD, Tsamandas AC, Zolota V, Kalofonos HP, Batistatou A, Vagianos C (2003) Potential role of bcl-2 and Ki-67 expression and apoptosis in colorectal carcinoma: a clinicopathologic study. Dig Dis Sci 48:1990–1997
Bhatavdekar JM, Patel DD, Ghosh N, Chikhlikar PR, Trivedi TI, Suthar TP, Doctor SS, Shah NG, Balar DB (1997) Co-expression of bcl-2, c-Myc and p53 oncoproteins as prognostic discriminants in patients with colorectal carcinoma. Dis Colon Rectum 40:785–790
Srivastava S, Verma M, Henson DE (2001) Biomarkers for early detection of colon cancer. Clin Cancer Res 7:1118–1126
Sinicrope FA, Hart J, Michelassi F, Lee JJ (1995) Prognostic value of bcl-2 oncoprotein expression in stage II colon carcinoma. Clin Cancer Res 1:1103–1110
Kouvidou C, Stefanaki K, Dai Y, Tzardi M, Koutsoubi K, Darivianaki , Karidi E, Rontogianni D, Zois E, Kakolyris S, Georgoulias V, Delides G, Kanavaros P (1997) P21/waf1 protein expression in nasopharyngeal carcinoma. Comparative study with PCNA, p53 and MDM-2 protein expression. Anticancer Res 17:2615–2619
Kaklamanis L, Savage A, Mortensen N, Tsiotos P, Doussis-Anagnostopoulou I, Biddolph S, Whitehouse R, Harris AL, Gatter KC (1996) Early expression of bcl-2 protein in the adenoma-carcinoma sequence. J Pathol 179:10–14
Bosari S, Moneghini L, Graziani D, Lee AK, Murray JJ, Coggi G, Viale G (1995) Bcl-2 oncoprotein in colorectal hyperplastic polyps, adenomas, and adenocarcinomas. Hum Pathol 26:534–540
Watson NF, Madjd Z, Scrimegour D, Spendlove I, Ellis IO, Scholefield JH, Durrant LG (2005) Evidence that the p53 negative/Bcl-2 positive phenotype is an independent indicator of good prognosis in colorectal cancer: a tissue microarray study of 460 patients. World J Surg Oncol 3:47–57
Yang HB, Chow NH, Sheu BS, Chan SH, Chien CH, Su IJ (1999) The role of bcl-2 in the progression of the colorectal adenoma-carcinoma sequence. Anticancer Res 19:727–730
Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed JC (1994) Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vivo and in vitro. Oncogene 9:1799–1805
Haldar S, Negrini M, Monne M, Sabbioni S, Crose CM (1994) Down-regulation of bcl-2 by p53 in breast cancer cells. Cancer Res 54:2095–2097
Geske FJ, Gerschenson LE (2001) The biology of apoptosis. Hum Pathol 32:1029–1038,
Hao XP, Ilyas M, Talbot IC (1997) Expression of Bcl-2 and p53 in the colorectal adenoma-carcinoma sequence. Pathobiology 65:140–145
Miyashita T, Harigai M, Hanada M, Reed JC (1994) Identification of a p53 dependent negative response element in the bcl-2 gene. Cancer Res 54:3131–3135
Jen J, Kim H, Piantadosi S, Liu ZF, Levitt RC, Sistonen P, Kinzler KW, Vogelstein B, Hamilton SR (1994) Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 331:213–221
Ayhan A, Yasui W, Yokozaki H, Seto M, Ueda R, Tahara E (1994) Loss of heterozygosity at the bcl-2 gene locus and expression of bcl-2 in human gastric and colorectal carcinomas. Jpn J Cancer Res 85:584–591
Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bcl-2 heterodimerises in vivo with a conserved homolog, Bax, that accelerates programed cell death. Cell 74:609–619
Hao XP, Frayling IM, Sgouros JG, Du MQ, Willcocks TC, Talbot IC, Tomlinson IP (2002) The spectrum of p53 mutations in colorectal adenomas differs from that in colorectal carcinomas. Gut 50:834–839
Silvestrini R, Veneroni S, Daidone MG, Benini E, Boracchi P, Mezzetti M, Di Fronzo G, Rilke F, Veronesi U (1994) The Bcl-2 protein: a prognostic indicator strongly related to p53 protein in lymph node-negative breast cancer patients. J Natl Cancer Inst 86:499–504
Joensuu H, Pylkkanen L, Toikkanen S (1994) Bcl-2 protein expression and long-term survival in breast cancer. Am J Pathol 145:1191–1198
Nakamura S, Akazawa K, Kinukawa N, Yao T, Tsuneyoshi M (1996) Inverse correlation between the expression of bcl-2 and p53 proteins in primary gastric lymphoma. Hum Pathol 27:225–233
Hussein MR, Al-Sabae TM, Georgis MN (2004) Analysis of Bcl-2 and p53 protein expression in non-Hodgin’s lymphoma. Ann Oncol 12:1849–1850
Klobusicka M, Kusenda J, Babusikova O (2002) Immunocytochemical detection of bcl-2 and p53 proteins in B-chronic lymphocytic leukemia patients. Neoplasma 49:387–393
Hao XP, Gunther T, Roessner A, Price AB, Talbot IC (1998) Expression of mdm2 and p53 in epithelial neoplasms of the colorectum. Mol Pathol 51:26–29
Abdel-Fattah G, Yoffe B, Krishnan B, Khaoustov V, Itani K (2000) Mdm2/p53 protein expression in the development of colorectal adenocarcinoma. J Gastrointest Surg 4:109–114
Ofner D, Maier H, Reidmann B (1995) Histochemically detectable p53 and mdm2 oncoprotein expression in colorectal carcinoma: prognostic significance. J Clin Pathol 48:12–16
Theodorakis P, D’Sa-Eipper C, Subramanian T, Chinnadurai G (1996) Unmasking of a proliferation-restraining activity of the antiapoptosis protein EBV BHRF1. Oncogene 12:1707–1713
Tsutsui S, Yasuda K, Suzuki K, Takeuchi H, Nishizaki T, Higashi H, Era S (2006) Bcl-2 protein expression is associated with p27 and p53 protein expressions and MIB-1 counts in breast cancer. BMC Cancer 6:187–193
Papatheodoridis GV, Triantafyllou K, Tzouvala M, Paspatis G, Xourgias V, Karamanolis DG (1996) Characteristics of rectosigmoid adenomas as predictors of synchronous advanced proximal colon neoplasms. Am J Gastroenterol 91:1809–1813
Gondal G, Grotmol T, Hofstad B, Bretthauer M, Eide TJ, Hoff G (2003) Grading of distal colorectal adenomas as predictors for proximal colonic neoplasia and choice of endoscope in population screening: prevention study (NORCCAP) experience from the Norwegian Colorectal Cancer. Gut 52:398–403
Atkin WS, Morson BC, Cuzick J (1992) Long-term risk of colorectal cancer after excision of rectosigmoid adenomas. N Engl J Med 326:658–662
Dave S, Hui S, Kroenke K, Imperiale TF (2003) Is the distal hyperplastic polyps a marker for proximal neoplasia? a systematic review. J Gen Intern Med 18:128–137
Lewis JD, Ng K, Hung KE, Bilker WB, Berlin JA, Brensinger C, Rustgi AK (2003) Detection of proximal adenomatous polyps with screening sigmoidoscopy: a systemic review and meta-analysis of screening colonoscopy. Arch Intern Med 163:413–420
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Tzouvala, M., Lazaris, A.C., Papatheodoridis, G.V. et al. Potential Role of Apoptosis and Apoptotic Regulatory Proteins in Colorectal Neoplasia: Correlations with Clinico-Pathological Parameters and Survival. Dig Dis Sci 53, 451–460 (2008). https://doi.org/10.1007/s10620-007-9857-6
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DOI: https://doi.org/10.1007/s10620-007-9857-6