Apoptosis in the development of colorectal neoplasia
Darina Kohoutová1, Jaroslav Pejchal Orcid.org 2, Jiří Cyrany1,3, Paula Morávková1, Stanislav Rejchrt Orcid.org 1, Jan Bureš Orcid.org 4
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Summary
Background: The Czech Republic has one of the highest incidence rates of colorectal cancer. Cell proliferation, differentiation, and apoptosis play a key role in the development of this disease. The aim of our study was to assess the level of apoptosis at each stage of colorectal neoplasia. Methodology: Apoptosis was evaluated by examining mucosal biopsies of colorectal neoplasm and normal mucosa. This was performed in 20 patients with non-advanced adenoma, 20 patients with advanced adenoma, 20 patients with colorectal carcinoma, and 20 individuals with normal colorectal findings. The grade of apoptosis was assessed after hematoxylin-eosin staining (in three compartments: the superficial compartment and the upper and lower parts of the crypts) and by immunohistochemical methods (by detection of activated-caspase-3). Results: Apoptotic activity was reported as an apoptotic index. In healthy colorectal mucosa, low apoptotic activity was observed in the lower part of the crypts. In the upper part of the crypts, apoptotic activity decreased (to almost zero) and in the superficial compartment, there was an increase in apoptotic activity. Transformation of healthy mucosa into non-advanced colorectal adenoma was associated with a statistically significant increase in apoptotic activity in all three compartments (p ≤ 0.05), with the biggest increase in the upper part of the crypts. Transformation of non-advanced adenoma into advanced adenoma was related to further increases in apoptotic activity, again, mainly in the upper part of the crypts. There was a statistically significant decrease in apoptotic activity in all three comparments of carcinoma samples compared to advanced adenoma (p ≤ 0.05). Results of immunohistochemical methods confirmed this trend. Conclusions: We have shown deregulation of apoptosis during the development of colorectal neoplasia. Being able to influence the degree of apoptosis, especially during the transformation of an advanced adenoma into a carcinoma, would have beneficial consequences in clinical practice.
Keywords
apoptosis, colorectal adenoma, colorectal cancerTo read this article in full, please register for free on this website.
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Literature
2. Epidemiologie zhoubných nádorů v České republice. [online]. Dostupné z: www.svod.cz.
3. Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet 2014; 383 (9927): 1490–1502. doi: 10.1016/S0140-6736 (13) 61649-9.
4. Fearon E, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61 (5): 759–767.
5. Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology 2010; 138 (6): 2059–2072. doi: 10.1053/j.gastro.2009.12.065.
6. 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.
7. 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.007 3204.
8. 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.
9. 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.
10. 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 (6): e1003082. doi: 10.1371/journal.pcbi.1003082.
11. 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.
12. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. J Cancer 1972; 26 (4): 239–257.
13. Pejchal J, Novotný J, Mařák V 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.
14. 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.
15. 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.
16. 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.
17. Baig S, Seevasant I, Mohamad J et al. Potential of apoptotic pathway-targeted cancer therapeutic research: where do we stand? Cell Death Dis 2016; 7: e2058. doi: 10.1038/cddis.2015.275.
18. Lavrik IN. Systems biology of apoptosis signaling networks. Curr Opin Biotechnol 2010; 21 (4): 551–555. doi: 10.1016/j.copbio.2010.07.001.
19. Lavrik IN, Golks A, Krammer PH. Caspases: pharmacological manipulation of cell death. J Clin Invest 2005; 115 (10): 2665–2672.
20. Czabotar PE, Lessene G, Strasser A et al. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 2014; 15 (1): 49–63. doi: 10.1038/nrm3722.
21. Wang K, Lin B. Inhibitor of apoptosis proteins (IAPs) as regulatory factors of hepatic apoptosis. Cell Signal 2013; 25 (10): 1970–1980. doi: 10.1016/j.cellsig.2013. 06.003.
22. Salvesen GS, Duckett CS. IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 2002; 3 (6): 401–410.
23. Kelly PN, Strasser A. The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy. Cell Death Differ 2011; 18 (9): 1414–1424. doi: 10.1038/cdd.2011.1.
24. Juin P, Geneste O, Gautier F et al. Decoding and unlocking theBCL-2 dependency of cancer cells. Nat Rev Cancer 2013; 13 (7): 455–465. doi: 10.1038/nrc3538.
25. 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.
26. Pennati M, Folini M, Zaffaroni N. Targeting survivin in cancer therapy: fulfilled promises and open questions. Carcinogenesis 2007; 28 (6): 1133–1139.
27. 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 Colorectal Dis 2008; 23 (4): 389–400. doi: 10.1007/s00384-007-0424-6.
28. 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.
29. Candido EP, Reeves R, Davie JR. Sodium butyrate inhibits histone deacetylation in cultured cells. Cell 1978; 14 (1): 105–113.
30. Andoh A. Physiological role of gut microbiota for maintaining human health. Digestion 2016; 93 (3): 176–181. doi: 10.1159/000444066.
31. Cummings JH, Pomare EW, Branch WJ et al. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 1987; 28 (10): 1221–1227.
32. Donohoe DR, Garge N, Zhang X et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab 2011; 13 (5): 517–526. doi: 10.1016/j.cmet.2011.02. 018.
33. 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.
34. Donohoe DR, Collins LB, Wali A et al. The Warburg effect dictates the mechanism of butyrate-mediated histone acety- lation and cell proliferation. Mol Cell 2012; 48 (4): 612–626. doi: 10.1016/j.molcel.2012.08.033.
35. Kikuchi Y, Dinjens WN, Bosman FT. Proliferation and apoptosis in proliferative lesions of the colon and rectum. Virchows Arch 1997; 431 (12): 111–117.
36. 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.
37. Ryoo HD, Gorenc T, Steller H. Apoptotic cells can induce compensatory cell proliferation through the JNK and the Wingless signaling pathways. Dev Cell 2004; 7 (4): 491–501.
38. Fan Y, Bergmann A. Apoptosis-induced compensatory proliferation. The Cell is dead. Long live the Cell! Trends Cell Biol 2008; 18 (10): 467–473. doi: 10.1016/j.tcb.2008. 08.001.