BACKGROUND: Colorectal cancer (CRC) is third most commonly diagnosed cancer worldwide. The aim of the prospective study was to evaluate mitosis and apoptosis of epithelial cells at each stage of colorectal neoplasia. METHODS: A total of 61 persons were enrolled into the study: 18 patients with non-advanced colorectal adenoma (non-a-A), 13 patients with advanced colorectal adenoma (a-A), 13 patients with CRC and 17 controls: individuals with normal findings on colonoscopy. Biopsy samples were taken from pathology (patients) and healthy mucosa (patients and healthy controls). Samples were formalin-fixed paraffin-embedded and stained with haematoxylin-eosin. Mitotic and apoptotic activity were evaluated in lower and upper part of the crypts and in the superficial compartment. Apoptotic activity was also assessed using detection of activated caspase-3. RESULTS: In controls, mitotic activity was present in lower part of crypts, accompanied with low apoptotic activity. Mitotic and apoptotic activity decreased (to almost zero) in upper part of crypts. In superficial compartment, increase in apoptotic activity was observed. Transformation of healthy mucosa into non-a-A was associated with significant increase of mitotic activity in lower and upper part of the crypts and with significant increase of apoptotic activity in all three compartments; p < 0.05. Transformation of non-a-A into a-A did not lead to any further significant increase in apoptotic activity, but was related to significant increase in mitotic activity in upper part of crypts and superficial compartment. A significant decrease in apoptotic activity was detected in all three comparments of CRC samples compared to a-A; p < 0.05. No differences in mitotic and apoptotic activity between biopsies in healthy controls and biopsy samples from healthy mucosa in patients with colorectal neoplasia were observed. Detection of activated caspase-3 confirmed the above findings in apoptotic activity. CONCLUSIONS: Significant dysregulation of mitosis and apoptosis during the progression of colorectal neoplasia, corresponding with histology, was confirmed. In patients with sporadic colorectal neoplasia, healthy mucosa does not display different mitotic and apoptotic activity compared to mucosa in healthy controls and therefore adequate endoscopic/surgical removal of colorectal neoplasia is sufficient.

Charles University Faculty of Medicine in Hradec Kralove University Hospital Hradec Kralove 2nd Department of Internal Medicine Gastroenterology Sokolska 581 500 05 Hradec Kralove Czech Republic

University of Defence Faculty of Military Health Sciences Hradec Kralove Czech Republic

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Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–E386. doi: 10.1002/ijc.29210. PubMed DOI

Arora H, Qureshi R, Rizvi MA, et al. Study of apoptosis-related interactions in colorectal cancer. Tumour Biol. 2016;37(11):14415–14425. doi: 10.1007/s13277-016-5363-9. PubMed DOI

Abraha AM, Ketema EB. Apoptotic pathways as a therapeutic target for colorectal cancer treatment. World J Gastrointest Oncol. 2016;8(8):583–591. doi: 10.4251/wjgo.v8.i8.583. PubMed DOI PMC

Maskens AP, Dujardin-Loits RM. Kinetics of tissue proliferation in colorectal mucosa during post-natal growth. Cell Tissue Kinet. 1981;14(5):467–477. PubMed

Raskov H, Pommergaard HC, Burcharth J, et al. Colorectal carcinogenesis-update and perspectives. World J Gastroenterol. 2014;20(48):18151–18164. doi: 10.3748/wjg.v20.i48.18151. PubMed DOI PMC

Zhao R, Michor F. Patterns of proliferative activity in the colonic crypt determine crypt stability and rates of somatic evolution. PLoS Comput Biol. 2013;9:e1003082. doi: 10.1371/journal.pcbi.1003082. PubMed DOI PMC

Sträter J, Koretz K, Günthert AR, et al. In situ detection of enterocytic apoptosis in normal colonic mucosa and in familial adenomatous polyposis. Gut. 1995;37(6):819–825. doi: 10.1136/gut.37.6.819. PubMed DOI PMC

van der Wath RC, Gardiner BS, Burgess AW, et al. Cell organisation in the colonic crypt: a theoretical comparison of the pedigree and niche concepts. PLoS One. 2013;8(9):e73204. doi: 10.1371/journal.pone.0073204. PubMed DOI PMC

Potten CS, Kellett M, Roberts SA, et al. Measurement of in vivo proliferation in human colorectal mucosa using bromodeoxyuridine. Gut. 1992;33(1):71–78. doi: 10.1136/gut.33.1.71. PubMed DOI PMC

Karoui M, Tresallet C, Brouquet A, et al. Colorectal carcinogenesis. 1. Hereditary predisposition and colorectal cancer. J Chir (Paris) 2007;144(1):13–18. doi: 10.1016/S0021-7697(07)89450-6. PubMed DOI

Kohoutova D, Smajs D, Moravkova P, et al. Escherichia coli strains of phylogenetic group B2 and D and bacteriocin production are associated with advanced colorectal neoplasia. BMC Infect Dis. 2014;14:733. doi: 10.1186/s12879-014-0733-7. PubMed DOI PMC

Pejchal J, Pejchal J, Novotný J, et al. Activation of p38 MAPK and expression of TGF-β1 in rat colon enterocytes after whole body γ-irradiation. Int J Radiat Biol. 2012;88(4):348–358. doi: 10.3109/09553002.2012.654044. PubMed DOI

Kohoutova D, Pejchal J, Cyrany J et al. Apoptosis in the development of colorectal neoplasia. Gastroenterol and Hepatol. 2016;70(4):313–318. [Article in Czech].

Hassan M, Watari H, AbuAlmaaty A, et al. Apoptosis and molecular targeting therapy in cancer. Biomed Res Int. 2014;2014:150845. PubMed PMC

Leiszter K, Galamb O, Sipos F, et al. Sporadic colorectal cancer development shows rejuvenescence regarding epithelial proliferation and apoptosis. PLoS One. 2013;8(10):e74140. doi: 10.1371/journal.pone.0074140. PubMed DOI PMC

Plati J, Bucur O, Khosravi-Far R. Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb) 2011;3(4):279–296. doi: 10.1039/c0ib00144a. PubMed DOI PMC

Koehler BC, Jäger D, Schulze-Bergkamen H. Targeting cell death signaling in colorectal cancer: current strategies and future perspectives. World J Gastroenterol. 2014;20(8):1923–1934. doi: 10.3748/wjg.v20.i8.1923. PubMed DOI PMC

Wang H, Sun X, Li M. Apoptosis-induction is a novel therapeutic strategy for gastrointestinal and liver cancers. Curr Gene Ther. 2015;15(2):193–200. doi: 10.2174/1566523214666141224100801. PubMed DOI

Lockshin RA, Williams CM. Programmed cell death - II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths. J Ins Physiol. 1964;10:643–649. doi: 10.1016/0022-1910(64)90034-4. DOI

Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239–257. doi: 10.1038/bjc.1972.33. PubMed DOI PMC

Harfouche G, Martin MT. Response of normal stem cells to ionizing radiation: a balance between homeostasis and genomic stability. Mutat Res. 2010;704:167–174. doi: 10.1016/j.mrrev.2010.01.007. PubMed DOI

Umar S. Intestinal stem cells. Curr Gastroenterol Rep. 2010;12:340–348. doi: 10.1007/s11894-010-0130-3. PubMed DOI PMC

Dhawan P, Ahmad R, Srivastava AS, et al. Cancer stem cells and colorectal cancer: an overview. Curr Top Med Chem. 2011;11(13):1592–1598. doi: 10.2174/156802611796117694. PubMed DOI

Roostaee A, Benoit YD, Boudjadi S, et al. Epigenetics in intestinal epithelial cell renewal. J Cell Physiol. 2016;231(11):2361–2367. doi: 10.1002/jcp.25401. PubMed DOI PMC

Singh N. Apoptosis in health and disease and modulation of apoptosis for therapy: an overview. Indian J Clin Biochem. 2007;22(2):6–16. doi: 10.1007/BF02913307. PubMed DOI PMC

Garg H, Suri P, Gupta JC, et al. Survivin: a unique target for tumor therapy. Cancer Cell Int. 2016;16:49. doi: 10.1186/s12935-016-0326-1. PubMed DOI PMC

Søreide K, Gudlaugsson E, Skaland I, et al. Metachronous cancer development in patients with sporadic colorectal adenomas-multivariate risk model with independent and combined value of hTERT and survivin. Int J Color Dis. 2008;23(4):389–400. doi: 10.1007/s00384-007-0424-6. PubMed DOI

Hernandez JM, Farma JM, Coppola D, et al. Expression of the antiapoptotic protein survivin in colon cancer. Clin Colorectal Cancer. 2011;10(3):188–193. doi: 10.1016/j.clcc.2011.03.014. PubMed DOI PMC

Konturek PC, Rembiasz K, Burnat G, et al. Effects of cyclooxygenase-2 inhibition on serum and tumor gastrins and expression of apoptosis-related proteins in colorectal cancer. Dig Dis Sci. 2006;51(4):779–787. doi: 10.1007/s10620-006-3206-z. PubMed DOI

Cai Y, Ma W, Huang X, et al. Effect of survivin on tumor growth of colorectal cancer in vivo. Int J Clin Exp Pathol. 2015;8(10):13267–13272. PubMed PMC

Pennati M, Folini M, Zaffaroni N. Targeting survivin in cancer therapy: fulfilled promises and open questions. Carcinogenesis. 2007;28(6):1133–1139. doi: 10.1093/carcin/bgm047. PubMed DOI

Bordonaro M, Drago E, Atamna W, et al. Comprehensive suppression of all apoptosis-induced proliferation pathways as a proposed approach to colorectal cancer prevention and therapy. PLoS One. 2014;9(12):e115068. doi: 10.1371/journal.pone.0115068. PubMed DOI PMC

Davie JR. Inhibition of histone deacetylase activity by butyrate. J Nutr. 2003;133(7 Suppl):2485S–2493S. doi: 10.1093/jn/133.7.2485S. PubMed DOI

Candido EP, Reeves R, Davie JR. Sodium butyrate inhibits histone deacetylation in cultured cells. Cell. 1978;14(1):105–113. doi: 10.1016/0092-8674(78)90305-7. PubMed DOI

Csordas A. Butyrate, aspirin and colorectal cancer. Eur J Cancer Prev. 1996;5(4):221–231. doi: 10.1097/00008469-199608000-00002. PubMed DOI

Bultman SJ. Molecular pathways: gene-environment interactions regulating dietary fiber induction of proliferation and apoptosis via butyrate for cancer prevention. Clin Cancer Res. 2014;20(4):799–803. doi: 10.1158/1078-0432.CCR-13-2483. PubMed DOI PMC

Kikuchi Y, Dinjens WN, Bosman FT. Proliferation and apoptosis in proliferative lesions of the colon and rectum. Virchows Arch. 1997;431:111–117. doi: 10.1007/s004280050076. PubMed DOI

Hong MY, Turner ND, Murphy ME, et al. In vivo regulation of colonic cell proliferation, differentiation, apoptosis, and P27Kip1 by dietary fish oil and butyrate in rats. Cancer Prev Res (Phila) 2015;8(11):1076–1083. doi: 10.1158/1940-6207.CAPR-15-0147. PubMed DOI PMC

Drago E, Bordonaro M, Lee S, et al. Propolis augments apoptosis induced by butyrate via targeting cell survival pathways. PLoS One. 2013;8(9):e73151. doi: 10.1371/journal.pone.0073151. PubMed DOI PMC

Escherichia coli from biopsies differ in virulence genes between patients with colorectal neoplasia and healthy controls

Tissue mRNA for S100A4, S100A6, S100A8, S100A9, S100A11 and S100P Proteins in Colorectal Neoplasia: A Pilot Study