Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
International Journal of Colorectal Disease
Published in: International Journal of Colorectal Disease 3/2006

01-04-2006 | Original Article

Analysis of neuroendocrine differentiation and the p53/BAX pathway in UICC stage III colorectal carcinoma identifies patients with good prognosis

Authors: Patricia Grabowski, Isrid Sturm, Katharina Schelwies, Kerstin Maaser, Heinz-Johannes Buhr, Bernd Dörken, Martin Zeitz, Peter T. Daniel, Hans Scherübl

Published in: International Journal of Colorectal Disease | Issue 3/2006

Login to get access

Abstract

Background and aims

Neuroendocrine differentiation is an independent prognostic factor in colorectal cancer. Moreover, an altered p53/BAX pathway is associated with a poor clinical outcome in Union Internationale Contre le Cancer (UICC) stage III disease. Because these markers are involved in different genetic events disrupted in colorectal cancer, we investigated the prognostic power of a multimarker analysis.

Patients and methods

Specimens were analyzed from 59 patients with UICC stage III disease who underwent surgery for colorectal adenocarcinoma at our institution and were followed up for 5 years or until death. Tumors were studied for both p53 mutation and BAX protein expression as well as for the expression of neuroendocrine markers. Statistical analysis of each marker alone or in combination was performed.

Results

p53 status/BAX expression and neuroendocrine differentiation are not correlated in stage III colorectal cancers. However, the combination of both independent events identified a subgroup of patients with an excellent prognosis: Patients whose tumors were neuroendocrine marker-negative and who exhibited an intact p53/BAX pathway lived longer (mean survival, 93 months; range, 82–104 months) than patients whose tumors were either neuroendocrine marker-positive or whose tumors had a completely disrupted apoptotic pathway (41 months; range, 26–57 months; p<0.00001). In multivariate regression analysis, neuroendocrine marker-positive, p53 mutated, low-BAX-expressing tumors revealed an almost fivefold higher risk for earlier death (p<0.0001).

Conclusion

Disruption of the p53/BAX pathway is not pathognomonic for colorectal cancers with neuroendocrine differentiation. Both represent independent prognostic markers in UICC stage III disease. Therefore, the combined analysis of p53 status, BAX expression and neuroendocrine differentiation allows one to identify subgroups of patients with either very good or very poor prognosis.
Literature
1.
Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ (2004) Cancer statistics, 2004. CA Cancer J Clin 54:8–29PubMed
2.
Grizzle WE, Manne U, Jhala NC, Weiss HL (2001) Molecular characterization of colorectal neoplasia in translational research. Arch Pathol Lab Med 125:91–98PubMed
3.
Midgley R, Kerr D (2001) Conventional cytotoxic and novel therapeutic concepts in colorectal cancer. Expert Opin Investig Drugs 10:1011–1019CrossRefPubMed
4.
Compton CC, Fielding LP, Burgart LJ, Conley B, Cooper HS, Hamilton SR, Hammond ME, Henson DE, Hutter RV, Nagle RB, Nielsen ML, Sargent DJ, Taylor CR, Welton M, Willett C (2000) Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 124:979–994PubMed
5.
McLeod HL, Murray GI (1999) Tumour markers of prognosis in colorectal cancer. Br J Cancer 79:191–203PubMed
6.
Staib L, Link KH, Blatz A, Beger HG (2002) Surgery of colorectal cancer: surgical morbidity and five- and ten-year results in 2400 patients—monoinstitutional experience. World J Surg 26:59–66CrossRefPubMed
7.
Cohen AM, Tremiterra S, Candela F, Thaler HT, Sigurdson ER (1991) Prognosis of node-positive colon cancer. Cancer 67:1859–1861
8.
Grabowski P, Mann B, Mansmann U, Lovin N, Foss HD, Berger G, Scherübl H, Riecken EO, Buhr HJ, Hanski C (2000) Expression of SIALYL-Le(x) antigen defined by MAb AM-3 is an independent prognostic marker in colorectal carcinoma patients. Int J Cancer 88:281–286
9.
Maaser K, Grabowski P, Sutter AP, Höpfner M, Foss HD, Stein H, Berger G, Gavish M, Zeitz M, Scherübl H (2002) Overexpression of the peripheral benzodiazepine receptor is a relevant prognostic factor in stage III colorectal cancer. Clin Cancer Res 8:3205–3209PubMed
10.
Schelwies K, Sturm I, Grabowski P, Scherübl H, Schindler I, Hermann S, Stein H, Buhr HJ, Riecken EO, Zeitz M, Dörken B, Daniel PT (2002) Analysis of p53/BAX in primary colorectal carcinoma: low BAX protein expression is a negative prognostic factor in UICC stage III tumors. Int J Cancer 99:589–596
11.
Paradiso A, Simone G, Lena MD, Leone B, Vallejo C, Lacava J, Dellapasqua S, Daidone MG, Costa A (2001) Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer. Br J Cancer 84:651–658CrossRefPubMed
12.
Giatromanolaki A, Sivridis E, Stathopoulos GP, Fountzilas G, Kalofonos HP, Tsamandas A, Vrettou E, Scopa C, Polychronidis A, Simopoulos K, Koukourakis MI (2001) Bax protein expression in colorectal cancer: association with p53, bcl-2 and patterns of relapse. Anticancer Res 21:253–259
13.
Bondi J, Bukholm G, Nesland JM, Bukholm IR (2004) Expression of non-membranous beta-catenin and gamma-catenin, c-Myc and cyclin D1 in relation to patient outcome in human colon adenocarcinomas. APMIS 112:49–56CrossRefPubMed
14.
Rau B, Sturm I, Lage H, Berger S, Schneider U, Hauptmann S, Wust P, Riess H, Schlag PM, Dörken 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 21:3391–3401CrossRefPubMed
15.
Yang JL, Ow KT, Russell PJ, Ham JM, Crowe PJ (1996) Higher expression of oncoproteins c-myc, c-erb B-2/neu, PCNA, and p53 in metastasizing colorectal cancer than in nonmetastasizing tumors. Ann Surg Oncol 3:574–579PubMed
16.
Bhatavdekar JM, Patel DD, Chikhlikar PR, Shah NG, Vora HH, Ghosh N, Trivedi TI (2001) Molecular markers are predictors of recurrence and survival in patients with Dukes B and Dukes C colorectal adenocarcinoma. Dis Colon Rectum 44:523–533PubMed
17.
Grabowski P, Schindler I, Anagnostopoulos I, Foss HD, Riecken EO, Mansmann U, Stein H, Berger G, Buhr HJ, Scherübl H (2001) Neuroendocrine differentiation is a relevant prognostic factor in stage III–IV colorectal cancer. Eur J Gastroenterol Hepatol 13:405–411CrossRefPubMed
18.
Grabowski P, Schönfelder J, Ahnert-Hilger G, Foss HD, Heine B, Schindler I, Stein H, Berger G, Zeitz M, Scherübl H (2002) Expression of neuroendocrine markers: a signature of human undifferentiated carcinoma of the colon and rectum. Virchows Arch 441:256–263CrossRefPubMed
19.
Hamada Y, Oishi A, Shoji T, Takada H, Yamamura M, Hioki K, Yamamoto M (1992) Endocrine cells and prognosis in patients with colorectal carcinoma. Cancer 69:2641–2646
20.
Mori M, Mimori K, Kamakura T, Adachi Y, Ikeda Y, Sugimachi K (1995) Chromogranin positive cells in colorectal carcinoma and transitional mucosa. J Clin Pathol 48:754–758PubMed
21.
Foley EF, Gaffey MJ, Frierson HF Jr (1998) The frequency and clinical significance of neuroendocrine cells within stage III adenocarcinomas of the colon. Arch Pathol Lab Med 122:912–914PubMed
22.
Le Douarin NM (1995) From the APUD to the neuroendocrine system: a developmental perspective. In: Scherübl H, Hescheler J (eds) The electrophysiology of neuroendocrine cells. CRC, Boca Raton, pp 3–10
23.
Brittan M, Wright NA (2004) Stem cell in gastrointestinal structure and neoplastic development. Gut 53:899–910CrossRefPubMed
24.
Johnson LR (1988) Regulation of gastrointestinal mucosal growth. Physiol Rev 68:456–502PubMed
25.
Güner D, Sturm I, Hemmati P, Hermann S, Hauptmann S, Wurm R, Budach V, Dörken B, Lorenz M, Daniel PT (2003) Multigene analysis of Rb pathway and apoptosis control in esophageal squamous cell carcinoma identifies patients with good prognosis. Int J Cancer 103:445–454
26.
Miyashita T, Reed JC (1995) Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80:293–299CrossRefPubMed
27.
Daniel PT, Schulze-Osthoff K, Belka C, Güner D (2003) Guardians of cell death: the Bcl-2 family proteins. Essays Biochem 39:73–88PubMed
28.
29.
Daniel PT, Wieder T, Sturm I, Schulze-Osthoff K (2001) The kiss of death: promises and failures of death receptors and ligands in cancer therapy. Leukemia 15:1022–1032CrossRefPubMed
30.
Friedrich K, Wieder T, Von Haefen C, Radetzki S, Janicke R, Schulze-Osthoff K, Dörken B, Daniel PT (2001) Overexpression of caspase-3 restores sensitivity for drug-induced apoptosis in breast cancer cell lines with acquired drug resistance. Oncogene 20:2749–2760CrossRefPubMed
31.
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489CrossRefPubMed
32.
Sturm I, Köhne CH, Wolff G, Petrowsky H, Hillebrand T, Hauptmann S, Lorenz M, Dörken B, Daniel PT (1999) Analysis of the p53/BAX pathway in colorectal cancer: low BAX is a negative prognostic factor in patients with resected liver metastases. J Clin Oncol 17:1364–1374PubMed
33.
Hamilton SR, Aaltonen LA (2000) Pathology and genetics of tumours of the digestive system. World Health Organization classification of tumours. IARC, Lyon
34.
Sturm I, Papadopoulos S, Hillebrand T, Benter T, Luck HJ, Wolff G, Dörken B, Daniel PT (2000) Impaired BAX protein expression in breast cancer: mutational analysis of the BAX and the p53 gene. Int J Cancer 87:517–521
35.
Grizzle WE, Manne U, Weiss HL, Jhala N, Talley L (2002) Molecular staging of colorectal cancer in African-American and Caucasian patients using phenotypic expression of p53, Bcl-2, MUC-1 AND p27(kip-1). Int J Cancer 97:403–409
36.
Sturm I, Petrowsky H, Volz R, Lorenz M, Radetzki S, Hillebrand T, Wolff G, Hauptmann S, Dörken B, Daniel PT (2001) Analysis of p53/BAX/p16(ink4a/CDKN2) in esophageal squamous cell carcinoma: high BAX and p16(ink4a/CDKN2) identifies patients with good prognosis. J Clin Oncol 19:2272–2281PubMed
37.
de Bruine AP, Wiggers T, Beek C, Volovics A, von Meyenfeldt M, Arends JW, Bosman FT (1993) Endocrine cells in colorectal adenocarcinomas: incidence, hormone profile and prognostic relevance. Int J Cancer 54:765–771
38.
Vortmeyer AO, Lubensky IA, Merino MJ, Wang CY, Pham T, Furth EE, Zhuang Z (1997) Concordance of genetic alterations in poorly differentiated colorectal neuroendocrine carcinomas and associated adenocarcinomas. J Natl Cancer Inst 89:1448–1453CrossRefPubMed
39.
Reubi JC (2003) Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev 24:389–427CrossRefPubMed
40.
Öberg K (1994) Expression of growth factors and their receptors in neuroendocrine gut and pancreatic tumors, and prognostic factors for survival. Ann N Y Acad Sci 733:46–55PubMed
41.
Wulbrand U, Wied M, Zofel P, Göke B, Arnold R, Fehmann H (1998) Growth factor receptor expression in human gastroenteropancreatic neuroendocrine tumours. Eur J Clin Invest 28:1038–1049CrossRefPubMed
42.
Nilsson O, Wangberg B, McRae A, Dahlstrom A, Ahlman H (1993) Growth factors and carcinoid tumours. Acta Oncol 32:115–124PubMed
43.
von Wichert G, Jehle PM, Hoeflich A, Koschnick S, Dralle H, Wolf E, Wiedenmann B, Boehm BO, Adler G, Seufferlein T (2000) Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. Cancer Res 60:4573–4581
44.
Nilsson O, Wangberg B, Kolby L, Schultz GS, Ahlman H (1995) Expression of transforming growth factor alpha and its receptor in human neuroendocrine tumours. Int J Cancer 60:645–651
45.
Terris B, Scoazec JY, Rubbia L, Bregeaud L, Pepper MS, Ruszniewski P, Belghiti J, Flejou J, Degott C (1998) Expression of vascular endothelial growth factor in digestive neuroendocrine tumours. Histopathology 32:133–138PubMed
46.
Gilmore AP, Valentijn AJ, Wang P, Ranger AM, Bundred N, O’Hare MJ, Wakeling A, Korsmeyer SJ, Streuli CH (2002) Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor. J Biol Chem 277:27643–27650CrossRefPubMed
47.
Ahmad T, Farnie G, Bundred NJ, Anderson NG (2004) The mitogenic action of insulin-like growth factor I in normal human mammary epithelial cells requires the epidermal growth factor receptor tyrosine kinase. J Biol Chem 279:1713–1719CrossRefPubMed
48.
Höpfner M, Sutter AP, Gerst B, Zeitz M, Scherübl H (2003) A novel approach in the treatment of neuroendocrine gastrointestinal tumours. Targeting the epidermal growth factor receptor by gefitinib (ZD1839). Br J Cancer 89:1766–1775CrossRefPubMed
49.
50.
Lohmann DR, Funk A, Niedermeyer HP, Haupel S, Hofler H (1993) Identification of p53 gene mutations in gastrointestinal and pancreatic carcinoids by nonradioisotopic SSCA. Virchows Arch B Cell Pathol Incl Mol Pathol 64:293–296PubMed
Metadata
Title
Analysis of neuroendocrine differentiation and the p53/BAX pathway in UICC stage III colorectal carcinoma identifies patients with good prognosis
Authors
Patricia Grabowski
Isrid Sturm
Katharina Schelwies
Kerstin Maaser
Heinz-Johannes Buhr
Bernd Dörken
Martin Zeitz
Peter T. Daniel
Hans Scherübl
Publication date
01-04-2006
Publisher
Springer-Verlag
Published in
International Journal of Colorectal Disease / Issue 3/2006
Print ISSN: 0179-1958
Electronic ISSN: 1432-1262
DOI
https://doi.org/10.1007/s00384-005-0779-5

Other articles of this Issue 3/2006

International Journal of Colorectal Disease 3/2006 Go to the issue

Letter to the Editor

Perineal resection of a sigmoid tumour presenting as colorectoanal intussusception: report of a case and review of the literature

Letter to the Editor

Locally recurrent rectal cancer: when should radiofrequency ablation be used?

Original Article

Endorectal ultrasound-directed biopsy: a useful technique to detect local recurrence of rectal cancer

Original Article

Thymidine phosphorylase, dihydropyrimidine dehydrogenase and thymidylate synthase mRNA expression in primary colorectal tumors—correlation to tumor histopathology and clinical follow-up

Original Article

Hypoxia, angiogenesis and apoptosis markers in locally advanced rectal cancer

Case Report

Selective effect of infliximab on the inflammatory component of a colonic stricture in Crohn’s disease