Top

International Journal of Colorectal Disease

Published in:

01-02-2009 | Original Article

Molecular and clinico-pathological markers in rectal cancer: a tissue micro-array study

Authors: Annelies Debucquoy, Laurence Goethals, Louis Libbrecht, Christiaan Perneel, Karel Geboes, Nadine Ectors, William H. McBride, Karin Haustermans

Published in: International Journal of Colorectal Disease | Issue 2/2009

Abstract

Aims

The aims of the study were to study the effect of pre-operative treatment on the expression of tumour-related proteins and to correlate the expression of these proteins with response and survival of patients with advanced rectal cancer.

Materials and methods

Tissue micro-arrays from pre- and post-treatment biopsies of 99 patients with rectal cancer treated with pre-operative (chemo)radiotherapy were stained for epidermal growth factor receptor (EGFR), carbonic anhydrase IX, Ki67, vascular endothelial growth factor, cyclo-oxygenase 2 (COX-2) and cleaved cytokeratin 18 (c-CK18). Also, fibro-inflammatory alterations after treatment were evaluated.

Results

Pre-operative (chemo)radiotherapy caused fibro-inflammatory changes, a downregulation of proliferation (Ki67) and EGFR and an upregulation of apoptosis (cleaved CK18). Patients with a good regression during pre-operative treatment showed less proliferating and apoptotic cells in the resection specimen. Multivariate analysis showed that T downstaging, fibro-inflammatory changes in the resection specimen and COX-2 expression in the biopsy correlated with overall survival.

Conclusions

Pre-operative treatment has an effect on proliferation, apoptosis, inflammation and EGFR expression. The classical clinical parameters as well as fibro-inflammatory changes and COX-2 expression seem most valuable as predictors for survival.

Adam IJ, Mohamdee MO, Martin IG, Scott N, Finan PJ, Johnston D, Dixon MF, Quirke P (1994) Role of circumferential margin involvement in the local recurrence of rectal cancer. Lancet 344:707–711PubMedCrossRef

Heald RJ, Moran BJ, Ryall RD, Sexton R, MacFarlane JK (1998) Rectal cancer: the Basingstoke experience of total mesorectal excision, 1978–1997. Arch Surg 133:894–899PubMedCrossRef

Wibe A, Eriksen MT, Syse A, Myrvold HE, Soreide O (2003) Total mesorectal excision for rectal cancer—what can be achieved by a national audit? Colorectal Disease 5:471–477PubMedCrossRef

Hermanek P, Hermanek PJ (2000) Role of the surgeon as a variable in the treatment of rectal cancer. Semin Surg Oncol 19:329–335PubMedCrossRef

Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, Rutten HJ, Pahlman L, Glimelius B, van Krieken JH et al (2001) Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638–646PubMedCrossRef

Krook JE, Moertel CG, Gunderson LL, Wieand HS, Collins RT, Beart RW, Kubista TP, Poon MA, Meyers WC, Mailliard JA (1991) Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324:709–715PubMed

Lee JH, Lee JH, Ahn JH, Bahng H, Kim TW, Kang YK, Lee KH, Kim JC, Yu CS, Kim JH et al (2002) Randomized trial of postoperative adjuvant therapy in stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: a preliminary report. J Clin Oncol 20:1751–1758PubMedCrossRef

O’Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG, Mayer RJ, Gunderson LL, Rich TA (1994) Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331:502–507PubMedCrossRef

Stockholm Rectal Cancer Study Group (1990) Preoperative short-term radiation therapy in operable rectal carcinoma. A prospective randomized trial. Cancer 66:49–55CrossRef

10.

Tepper JE, O’Connell MJ, Petroni GR, Hollis D, Cooke E, Benson AB III, Cummings B, Gunderson LL, Macdonald JS, Martenson JA (1997) Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114. J Clin Oncol 15:2030–2039PubMed

11.

Thomas PR, Lindblad AS (1988) Adjuvant postoperative radiotherapy and chemotherapy in rectal carcinoma: a review of the Gastrointestinal Tumor Study Group experience. Radiother Oncol 13:245–252PubMedCrossRef

12.

Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC (2006) Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355:1114–1123PubMedCrossRef

13.

Dannenberg AJ, Lippman SM, Mann JR, Subbaramaiah K, DuBois RN (2005) Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention. J Clin Oncol 23:254–266PubMedCrossRef

14.

Willett CG, Kozin SV, Duda DG, di TE, Kozak KR, Boucher Y, Jain RK (2006) Combined vascular endothelial growth factor-targeted therapy and radiotherapy for rectal cancer: theory and clinical practice. Semin Oncol 33:S35–S40PubMedCrossRef

15.

Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H (1984) Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 133:1710–1715PubMed

16.

Brown DC, Gatter KC (2002) Ki67 protein: the immaculate deception? Histopathology 40:2–11PubMedCrossRef

17.

Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70PubMedCrossRef

18.

Hu W, Kavanagh JJ (2003) Anticancer therapy targeting the apoptotic pathway. Lancet Oncol 4:721–729PubMedCrossRef

19.

Leers MP, Kolgen W, Bjorklund V, Bergman T, Tribbick G, Persson B, Bjorklund P, Ramaekers FC, Bjorklund B, Nap M et al (1999) Immunocytochemical detection and mapping of a cytokeratin 18 neo-epitope exposed during early apoptosis. J Pathol 187:567–572PubMedCrossRef

20.

Duan WR, Garner DS, Williams SD, Funckes-Shippy CL, Spath IS, Blomme EA (2003) Comparison of immunohistochemistry for activated caspase-3 and cleaved cytokeratin 18 with the TUNEL method for quantification of apoptosis in histological sections of PC-3 subcutaneous xenografts. J Pathol 199:221–228PubMedCrossRef

21.

de Bruin EC, vand V, van de PS, Nagtegaal ID, van Krieken JH, Gosens MJ, Peltenburg LT, Medema JP, Marijnen CA (2006) Prognostic value of apoptosis in rectal cancer patients of the Dutch total mesorectal excision trial: radiotherapy is redundant in intrinsically high-apoptotic tumors. Clin Cancer Res 12:6432–6436PubMedCrossRef

22.

Marijnen CA, Nagtegaal ID, Mulder-Stapel AA, Schrier PI, van,d V, van Krieken JH, Peltenburg LT (2003) High intrinsic apoptosis, but not radiation-induced apoptosis, predicts better survival in rectal carcinoma patients. Int J Radiat Oncol Biol Phys 57:434–443

23.

Ivanov S, Liao SY, Ivanova A, Danilkovitch-Miagkova A, Tarasova N, Weirich G, Merrill MJ, Proescholdt MA, Oldfield EH, Lee J et al (2001) Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 158:905–919PubMed

24.

Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH et al (2000) Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60:7075–7083PubMed

25.

Saarnio J, Parkkila S, Parkkila AK, Haukipuro K, Pastorekova S, Pastorek J, Kairaluoma MI, Karttunen TJ (1998) Immunohistochemical study of colorectal tumors for expression of a novel transmembrane carbonic anhydrase, MN/CA IX, with potential value as a marker of cell proliferation. Am J Pathol 153:279–285PubMed

26.

Dworak O, Keilholz L, Hoffmann A (1997) Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 12:19–23PubMedCrossRef

27.

Shia J, Guillem JG, Moore HG, Tickoo SK, Qin J, Ruo L, Suriawinata A, Paty PB, Minsky BD, Weiser MR et al (2004) Patterns of morphologic alteration in residual rectal carcinoma following preoperative chemoradiation and their association with long-term outcome. Am J Surg Pathol 28:215–223PubMedCrossRef

28.

Pastorekova S, Zavadova Z, Kostal M, Babusikova O, Zavada J (1992) A novel quasi-viral agent, MaTu, is a two-component system. Virology 187:620–626PubMedCrossRef

29.

Rau B, Sturm I, Lage H, Berger S, Schneider U, Hauptmann S, Wust P, Riess H, Schlag PM, Dorken B, Daniel PT (2003) Dynamic expression profile of p21WAF1/CIP1 and Ki-67 predicts survival in rectal carcinoma treated with preoperative radiochemotherapy. J Clin Oncol 21:3391–3401PubMedCrossRef

30.

Dent P, Reardon DB, Park JS, Bowers G, Logsdon C, Valerie K, Schmidt-Ullrich R (1999) Radiation-induced release of transforming growth factor alpha activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death. Mol Biol Cell 10:2493–2506PubMed

31.

Ruifrok AC, Mason KA, Lozano G, Thames HD (1997) Spatial and temporal patterns of expression of epidermal growth factor, transforming growth factor alpha and transforming growth factor beta 1–3 and their receptors in mouse jejunum after radiation treatment. Radiat Res 147:1–12PubMedCrossRef

32.

Schmidt-Ullrich RK, Valerie KC, Chan W, McWilliams D (1994) Altered expression of epidermal growth factor receptor and estrogen receptor in MCF-7 cells after single and repeated radiation exposures. Int J Radiat Oncol Biol Phys 29:813–819PubMed

33.

Steinauer KK, Gibbs I, Ning S, French JN, Armstrong J, Knox SJ (2000) Radiation induces upregulation of cyclooxygenase-2 (COX-2) protein in PC-3 cells. Int J Radiat Oncol Biol Phys 48:325–328PubMed

34.

Gosens MJ, Klaassen RA, Tan-Go I, Rutten HJ, Martijn H, van den Brule AJ, Nieuwenhuijzen GA, van Krieken JH, Nagtegaal ID (2007) Circumferential margin involvement is the crucial prognostic factor after multimodality treatment in patients with locally advanced rectal carcinoma. Clin Cancer Res 13:6617–6623PubMedCrossRef

35.

Theodoropoulos G, Wise WE, Padmanabhan A, Kerner BA, Taylor CW, Aguilar PS, Khanduja KS (2002) T-level downstaging and complete pathologic response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival. Dis Colon Rectum 45:895–903PubMedCrossRef

36.

Jass JR (1987) The pathological classification of colorectal cancer. Ann Acad Med Singapore 16:469–473PubMed

37.

Fux R, Schwab M, Thon KP, Gleiter CH, Fritz P (2005) Cyclooxygenase-2 expression in human colorectal cancer is unrelated to overall patient survival. Clin Cancer Res 11:4754–4760PubMedCrossRef

38.

Konno H, Baba M, Shoji T, Ohta M, Suzuki S, Nakamura S (2002) Cyclooxygenase-2 expression correlates with uPAR levels and is responsible for poor prognosis of colorectal cancer. Clin Exp Metastasis 19:527–534PubMedCrossRef

39.

Masunaga R, Kohno H, Dhar DK, Ohno S, Shibakita M, Kinugasa S, Yoshimura H, Tachibana M, Kubota H, Nagasue N (2000) Cyclooxygenase-2 expression correlates with tumor neovascularization and prognosis in human colorectal carcinoma patients. Clin Cancer Res 6:4064–4068PubMed

40.

Sheehan KM, Sheahan K, O’Donoghue DP, MacSweeney F, Conroy RM, Fitzgerald DJ, Murray FE (1999) The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA 282:1254–1257PubMedCrossRef

41.

Soumaoro LT, Uetake H, Higuchi T, Takagi Y, Enomoto M, Sugihara K (2004) Cyclooxygenase-2 expression: a significant prognostic indicator for patients with colorectal cancer. Clin Cancer Res 10:8465–8471PubMedCrossRef

42.

Tomozawa S, Tsuno NH, Sunami E, Hatano K, Kitayama J, Osada T, Saito S, Tsuruo T, Shibata Y, Nagawa H (2000) Cyclooxygenase-2 overexpression correlates with tumour recurrence, especially haematogenous metastasis, of colorectal cancer. Br J Cancer 83:324–328PubMedCrossRef

43.

Joo YE, Kim HS, Min SW, Lee WS, Park CH, Park CS, Choi SK, Rew JS, Kim SJ (2002) Expression of cyclooxygenase-2 protein in colorectal carcinomas. Int J Gastrointest Cancer 31:147–154PubMedCrossRef

44.

Petersen S, Haroske G, Hellmich G, Ludwig K, Petersen C, Eicheler W (2002) COX-2 expression in rectal carcinoma: immunohistochemical pattern and clinical outcome. Anticancer Res 22:1225–1230PubMed

45.

Wu AW, Gu J, Ji JF, Li ZF, Xu GW (2003) Role of COX-2 in carcinogenesis of colorectal cancer and its relationship with tumor biological characteristics and patients’ prognosis. World J Gastroenterol 9:1990–1994PubMed

46.

Zhang H, Sun XF (2002) Overexpression of cyclooxygenase-2 correlates with advanced stages of colorectal cancer. Am J Gastroenterol 97:1037–1041PubMedCrossRef

47.

Palmqvist R, Sellberg P, Oberg A, Tavelin B, Rutegard JN, Stenling R (1999) Low tumour cell proliferation at the invasive margin is associated with a poor prognosis in Dukes’ stage B colorectal cancers. Br J Cancer 79:577–581PubMedCrossRef

48.

Chen YT, Henk MJ, Carney KJ, Wong WD, Rothenberger DA, Zheng T, Feygin M, Madoff RD (1997) Prognostic significance of tumor markers in colorectal cancer patients: DNA index, S-phase fraction, p53 expression, and Ki-67 index. J Gastrointest Surg 1:266–272PubMedCrossRef

49.

Sato T, Nishimura G, Fushida S, Fujimura T, Yonemura Y, Nonomura A, Miwa K, Miyazaki I (1998) Evaluation of p53, Ki-67 and DNA ploidy in both primary rectal carcinomas and locally recurrent tumors. Oncol Rep 5:1225–1229PubMed

50.

Hoos A, Nissan A, Stojadinovic A, Shia J, Hedvat CV, Leung DH, Paty PB, Klimstra D, Cordon-Cardo C, Wong WD (2002) Tissue microarray molecular profiling of early, node-negative adenocarcinoma of the rectum: a comprehensive analysis. Clin Cancer Res 8:3841–3849PubMed

51.

Allegra CJ, Parr AL, Wold LE, Mahoney MR, Sargent DJ, Johnston P, Klein P, Behan K, O’Connell MJ, Levitt R et al (2002) Investigation of the prognostic and predictive value of thymidylate synthase, p53, and Ki-67 in patients with locally advanced colon cancer. J Clin Oncol 20:1735–1743PubMedCrossRef

52.

Jansson A, Sun XF (1997) Ki-67 expression in relation to clinicopathological variables and prognosis in colorectal adenocarcinomas. APMIS 105:730–734PubMedCrossRef

53.

Rosati G, Chiacchio R, Reggiardo G, De SD, Manzione L (2004) Thymidylate synthase expression, p53, bcl-2, Ki-67 and p27 in colorectal cancer: relationships with tumor recurrence and survival. Tumour Biol 25:258–263PubMedCrossRef

Title: Molecular and clinico-pathological markers in rectal cancer: a tissue micro-array study
Authors: Annelies Debucquoy
Laurence Goethals
Louis Libbrecht
Christiaan Perneel
Karel Geboes
Nadine Ectors
William H. McBride
Karin Haustermans
Publication date: 01-02-2009
Publisher: Springer-Verlag
Published in: International Journal of Colorectal Disease / Issue 2/2009
Print ISSN: 0179-1958
Electronic ISSN: 1432-1262
DOI: https://doi.org/10.1007/s00384-008-0608-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Molecular and clinico-pathological markers in rectal cancer: a tissue micro-array study

Abstract

Aims

Materials and methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Aims

Materials and methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 2/2009

Cranial mesohepatectomy: a challenging parenchyma-preserving operation for colorectal liver metastases

Prolapse of the rectum, long-term results of surgical treatment

The predictive value of metabolic response to preoperative radiochemotherapy in locally advanced rectal cancer measured by PET/CT

Vitamin D receptor poly(A) microsatellite and colorectal cancer risk in Caucasians

Evaluation of novel histone deacetylase inhibitors as therapeutic agents for colorectal adenocarcinomas compared to established regimens with the histoculture drug response assay

Lactobacillus suntoryeus inhibits pro-inflammatory cytokine expression and TLR-4-linked NF-κB activation in experimental colitis