Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.727
Index Copernicus  – 166.39
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2006, vol. 15, nr 6, November-December, p. 983–988

Publication type: original article

Language: English

Colonic Carcinogenesis in an Experimental Model of Chronic Colitis in Rats

Proces karcynogenezy w doświadczalnym modelu przewlekłego zapalenia okrężnicy u szczurów

Romualda Wojczys1,, Wiktor Bednarz1,, Janusz Dawiskiba1,, Grzegorz Bielicki1,

1 1st Department of General, Gastroenterological, and Endocrine Surgery, Silesian Piasts University of Medicine in Wrocław, Poland

Abstract

Background. The study of the adenoma−carcinoma sequence in an animal model of chronic colitis resembling human ulcerative colitis is essential to understand the pathogenesis of the process and to allow the testing cancer chemopreventive agents.
Objectives. The aim was to establish a model of chronic colitis to study the relationship between inflammation and cancer development as well as to elucidate the adenoma−to−carcinoma cascade demonstrated by the p53 and Ki67 markers and dysplastic lesions (high and low grade). Additionally, the metastatic affection of liver tissue was investigated.
Material and Methods. An experimental model of colitis and carcinogenesis in 50 two−month−old Wistar rats was used. First colitis was induced using acetic acid and histologically proved, then carcinogenesis in two groups of animals (healthy and with induced colitis) was studied. Azoxymethane was used as the carcinogen.
Results. Colonic adenocarcinoma developed in 30% of the colitis−induced group and in 20% of the group without induced colitis but receiving the carcinogen. Dysplasia preceded the development of colonic adenocarcinoma. Ki67 and p53 positivity was an early sign of colonic malignancy in both dysplastic (mostly high grade) and carcinoma lesions. Liver tissue was affected by metastatic carcinoma only in those animals with chronic colitis.
Conclusion. Chronic colitis resembling human ulcerative colitis leads to the development of colonic adenocarcinoma. In the colitis−induced group the process of carcinogenesis was more frequent and expansive than in the healthy animals.

Streszczenie

Wprowadzenie. Badania dotyczą zwierzęcego modelu przewlekłego zapalenia okrężnicy odpowiadającego ludzkiemu wrzodziejącemu zapaleniu jelita grubego. Poglądy na temat karcynogenezy u pacjentów z zapalnymi chorobami jelit są dotychczas nieustalone i kontrowersyjne.
Cel pracy. Zbadanie karcynogenezy na eksperymentalnym modelu zapalenia jelita grubego u szczura.
Materiał i metody. Do badań użyto 50 2−miesięcznych szczurów szczepu Wistar. Doświadczenie podzielono na dwa etapy. Pierwszy to indukcja zapalenia jelita grubego przez doodbytnicze podanie kwasu octowego, a drugi to karcynogeneza wywołana dootrzewnowym podaniem azoksymetanu: w pierwszej grupie przy zmienionym zapalnie jelicie, w drugiej przy jelicie zdrowym. Metodą immunohistochemiczną oceniono p53 i Ki67. Dodatkowo uwzględniono zmiany o charakterze dysplazji (low and high grade). Oceniono także tkankę wątrobową pod względem zmian o charakterze przerzutowym.
Wyniki. W obu grupach poddanych działaniu karcynogenu nowotwory rozwinęły się odpowiednio w 30 i 20% (o 10% częściej w grupie zwierząt cierpiących na zapalenie okrężnicy). Zmiany histopatologiczne (dysplazja high and low grade) wyprzedzały rozwój nowotworu. Reakcje Ki67 i p53 były dodatnie w zmianach dysplastycznych (high grade) i nowotworowych. U zwierząt z przewlekłym procesem zapalnym w jelicie dodatkowo wystąpiły zmiany o charakterze przerzutowym do wątroby.
Wnioski. Przewlekły proces zapalny o charakterze colitis, odpowiadający wrzodziejącemu zapaleniu okrężnicy u ludzi, pobudza rozwój raka jelita grubego. W grupie zwierząt chorych na zapalenie okrężnicy proces ten jest częstszy i bardziej ekspansywny.

Key words

colitis, dysplasia, colonic carcinogenesis, rats

Słowa kluczowe

zapalenie okrężnicy, dysplazja, karcynogeneza, szczury

References (18)

  1. Munkholm P: Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther 2003, 18, 2, 1–5.
  2. Lashner BA, Provencher KS, Bozdech JM, Brzeziński A: Worsening risk for the development of dysplasia or cancer in patients with chronic ulcerative colitis. Am J Gastroenterol 1995, 30, 377–380.
  3. Ishitsuka T, Kashiwagi H, Konishi F: Microsatellite instability in inflamed and neoplastic epithelium in ulcerative colitis. J Clin Pathol 2001, l54, 526–533.
  4. Yin J, Harpaz N, Tong Y, Huang Y, Laurin J, Greenwald BD, Hontanosas M, Newkirk C, Meltzer SJ: P53 point mutations in dysplastic and cancerous ulcerative colitis lesions. Gastroenterology 1993, 104, 1633–1639.
  5. Vetuschi A: Increased proliferation and apoptosis of colonic epithelial cells in dextran sulfate sodium−induced colitis in rats. Dig Dis Sci 2002, 47, 1447–1457.
  6. Bansal P, Sonnenberg A: Risk factors of colorectal cancer in inflammatory bowel disease. Am J Gastroenterol 1966, 91, 44–48.
  7. Elson ChO, Sartor RB, Tennyson GS, Ridell RH: Experimental models of inflammatory bowel disease. Gastroenterology 1995, 109, 1344–1367.
  8. Iseki K, Tatsuta M, Uehara H, Iishi H Yano H, Sakai N, Ishiguro S: Inhibition of angiogenesis as a mechanism for inhibition by 1 alpha−hydroxyvitamin D3 and 1,25−dihydroxyvitamin D3 of colon carcinogenesis induced by azoxymethane in Wistar rats. Int J Cancer 1999, 81, 730–733.
  9. Matthews J, Cooke T: Changes in crypt cell DNA content during experimental colonic carcinogenesis. Br J Cancer 1986, 53, 787–791.
  10. McCue JL, Sheffield JP, Uff C, Philips RK: Experimental carcinogenesis at sutured and sutureless colonic anastomoses. Dis Colon Rectum 1992, 35, 902–909.
  11. Gillen CD, Walmsley RS, Prior P, Andrews HA, Allan RN: Ulcerative colitis and Crohn’s disease: a comparison of the colorectal cancer risk in extensive colitis. Gut 1994, 35, 1590–1592.
  12. Langholz E, Munkholm P, Dawidsen M, Binder V: Colorectal cancer risk and mortality in patients with ulcerative colitis. Gastroenterology 1993, 104(4), 1241–1242.
  13. Winther KV, Jess T, Langholtz E, Mungholm P, Binder V: Survival and cause−specific mortality in ulcerative colitis: follow up of a population−based cohort in Copenhagen County. Gastroenterology 2003, 125(6), 1881–1883.
  14. Solomon MJ, Schnitzel M: Cancer and inflammatory bowel disease: bias, epidemiology, surveillance and treatment. World J Surg 1998, 22, 352–358.
  15. Pasz−Walczak G, Szybka M, Kordek R: Comparative analysis of microsatellite instability and expression of MLH1, MSH2, P21(WAF1), P53 proteins in colorectal cancer and estimation of their clinico−pathological significance. Pol J Pathol 2004, 2, 39.
  16. Leslie A, Carey FA, Pratt NR, Steele RJC: The colorectal adenoma−carcinoma sequence. Br J Surg 2002, 89, 845–860.
  17. Heushen UA, Heuschen G, Autsbach F, Allemeyer EH, Herfarth C: Adenocarcinoma in the ileal pouch: late risk of cancer after restorative proctocolectomy. Int J Colorectal Dis 2001, 16, 126–130.
  18. Conell WR, Talbot IC, Harpaz N, Britto N, Wilkonson KH, Kamm MA, Lennard−Jones JE: Clinicopathological characteristic of colorectal carcinoma complicating ulcerative colitis. Gut 1994, 35, 1419–1423.