High iNOS and IL-1β immunoreactivity are features of colitis-associated colorectal cancer tumors, but fail to predict 5-year survival
Keywords:
Colorectal cancer, colitisassociated colorectal cancer, Interleukin-1β, inducible nitric oxide synthase, inflammatory bowel disease, tumor biology
Abstract
Background: Inflammatory bowel disease (IBD; mainly ulcerative colitis and Crohn’s disease) is associated with the development of colorectal cancer (CRC) referred to as colitis-associated colorectal cancer (CAC). In inflammatory flares of IBD, the production of luminal nitric oxide (NO) increases due to the increased inducible nitric oxide synthase (iNOS) activity in inflamed tissue. It is believed that iNOS parallels pro-inflammatory interleukin-1β (IL-1β). How these biomarkers relate to CAC pathogenesis or survival is unknown.
Aim: The primary aim of this study was to investigate iNOS and IL-1β immunoreactivity in CAC tumors in comparison with CRC and normal colonic mucosa, and the secondary aim was to determine if immunoreactivity correlates with 5-year survival of CAC.
Methods: Immunohistochemistry was performed on tissue sections as follows: CAC (n = 59); sporadic CRC (sCRC) (n = 12); colonic mucosa >2 cm outside sCRC margin (normal mucosa) (n = 22); paracancerous IBD (pIBD) (n = 12). The expression of iNOS and IL-1β was quantified separately for epithelium and stroma. Data were evaluated using the Mann-Whitney U-test and the log-rank test for 5-year Kaplan-Meier survival curves. Results were compared with online mRNA databases.
Results: Immunoreactivity occurred predominantly in epithelial cells and to lesser extent in stroma. Compared with normal mucosa, immunoreactivity for iNOS (P < 0.01) and IL-1β (P < 0.005) was higher in CAC epithelium. In CAC stroma, iNOS immunoreactivity was lower than normal mucosa (P < 0.001), whereas IL-1β was higher (P < 0.05). Immunoreactivity differences of iNOS or IL-1β among CAC patients failed to correlate with 5-year survival. These findings were supported by online mRNA databases.
Conclusion: Consistent with high NO production in IBD, there is more iNOS in CAC epithelium, albeit not in stroma. This immunoreactivity difference exists for IL-1β in both epithelium and stroma. The intervention of arginine or iNOS activity for CAC chemotherapy is not straightforward.
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References
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51. Gonzalez FJ. Role of HNF4α in the superinduction of the IL-1β-activated iNOS gene by oxidative stress. Biochem J. 2006;394:e3. doi: 10.1042/BJ20060005
2. Sjöberg D, Holmström T, Larsson M, Nielsen A-L, Holmquist L, Ekbom A, et al. Incidence and clinical course of Crohn’s disease during the first year – results from the IBD Cohort of the Uppsala Region (ICURE) of Sweden 2005–2009. J Crohns Colitis. 2014;8:215–22. doi: 10.1016/j.crohns.2013.08.009
3. Ekbom A, Helmick C, Zack M, Adami H-O. Ulcerative colitis and colorectal cancer. N Engl J Med. 1990;323:1228–33. doi: 10.1056/NEJM199011013231802
4. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526–35.
5. Gillen CD, Andrews HA, Prior P, Allan RN. Crohn’s disease and colorectal cancer. Gut. 1994;35:651–5.
6. Olén O, Erichsen R, Sachs MC, Pedersen L, Halfvarson J, Askling J, et al. Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study. Lancet. 2020;395(10218):123–31. doi: 10.1016/S0140-6736(19)32545-0
7. Nieminen U, Jussila A, Nordling S, Mustonen H, Färkkilä MA. Inflammation and disease duration have a cumulative effect on the risk of dysplasia and carcinoma in IBD: a case-control observational study based on registry data. Int J Cancer J Int Cancer. 2014;134:189–96. doi: 10.1002/ijc.28346
8. Gupta RB, Harpaz N, Itzkowitz S, Hossain S, Matula S, Kornbluth A, et al. Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology. 2007;133:1099–105; quiz 1340–1. doi: 10.1053/j.gastro.2007.08.001
9. Jess T, Loftus EV Jr, Velayos FS, Winther KV, Tremaine WJ, Zinsmeister AR, et al. Risk factors for colorectal neoplasia in inflammatory bowel disease: a nested case-control study from Copenhagen county, Denmark and Olmsted county, Minnesota. Am J Gastroenterol. 2007;102:829–36. doi: 10.1111/j.1572-0241.2007.01070.x
10. Bonovas S, Fiorino G, Lytras T, Nikolopoulos G, Peyrin-Biroulet L, Danese S. Systematic review with meta-analysis: use of 5-aminosalicylates and risk of colorectal neoplasia in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45:1179–92. doi: 10.1111/apt.14023
11. Bewtra M, Kaiser LM, TenHave T, Lewis JD. Crohn’s disease and ulcerative colitis are associated with elevated standardized mortality ratios: a meta-analysis. Inflamm Bowel Dis. 2013;19:599–613. doi: 10.1097/MIB.0b013e31827f27ae
12. Jussila A, Virta LJ, Pukkala E, Färkkilä MA. Mortality and causes of death in patients with inflammatory bowel disease: a nationwide register study in Finland. J Crohns Colitis. 2014;8:1088–96. doi: 10.1016/j.crohns.2014.02.015
13. Ljung T, Lundberg S, Varsanyi M, Johansson C, Schmidt PT, Herulf M, et al. Rectal nitric oxide as biomarker in the treatment of inflammatory bowel disease: responders versus nonresponders. World J Gastroenterol. 2006;12:3386–92.
14. Douki T, Cadet J. Peroxynitrite mediated oxidation of purine bases of nucleosides and isolated DNA. Free Radic Res. 1996;24:369–80. doi: 10.3109/10715769609088035
15. Lao-Sirieix P, Fitzgerald RC. Role of the micro-environment in Barrett’s carcinogenesis. Biochem Soc Trans. 2010;38:327–30. doi: 10.1042/BST0380327
16. Sherman MP, Aeberhard EE, Wong VZ, Simmons MS, Roth MD, Tashkin DP. Effects of smoking marijuana, tobacco or cocaine alone or in combination on DNA damage in human alveolar macrophages. Life Sci. 1995;56:2201–7. doi: 10.1016/0024-3205(95)00208-N
17. Takasawa S, Tsuchida C, Sakuramoto-Tsuchida S, Takeda M, Itaya-Hironaka A, Yamauchi A, et al. Expression of human REG family genes in inflammatory bowel disease and their molecular mechanism. Immunol Res. 2018;66:800–5. doi: 10.1007/s12026-019-9067-2
18. Wang C, Gong G, Sheh A, Muthupalani S, Bryant EM, Puglisi DA, et al. Interleukin-22 drives nitric oxide-dependent DNA damage and dysplasia in a murine model of colitis-associated cancer. Mucosal Immunol. 2017;10:1504–17. doi: 10.1038/mi.2017.9
19. Dabrowska M, Uram L, Zielinski Z, Rode W, Sikora E. Oxidative stress and inhibition of nitric oxide generation underlie methotrexate-induced senescence in human colon cancer cells. Mech Ageing Dev. 2018;170:22–9. doi: 10.1016/j.mad.2017.07.006
20. Zhang R, Ma A, Urbanski SJ, McCafferty D-M. Induction of inducible nitric oxide synthase: a protective mechanism in colitis-induced adenocarcinoma. Carcinogenesis. 2007;28:1122–30. doi: 10.1093/carcin/bgl224
21. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–7. doi: 10.1038/nature01322
22. Conti J, Thomas G. The role of tumour stroma in colorectal cancer invasion and metastasis. Cancers. 2011;3:2160–8. doi: 10.3390/cancers3022160
23. Baghban R, Roshangar L, Jahanban-Esfahlan R, Seidi K, Ebrahimi-Kalan A, Jaymand M, et al. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun Signal. 2020;18:59. doi: 10.1186/s12964-020-0530-4
24. Zhu Y, Zhu M, Lance P. iNOS signaling interacts with COX-2 pathway in colonic fibroblasts. Exp Cell Res. 2012;318:2116–27. doi: 10.1016/j.yexcr.2012.05.027
25. Zhu Y, Zhu M, Lance P. IL1β-mediated Stromal COX-2 signaling mediates proliferation and invasiveness of colonic epithelial cancer cells. Exp Cell Res. 2012;318:2520–30. doi: 10.1016/j.yexcr.2012.07.021
26. McEntee CP, Finlay CM, Lavelle EC. Divergent roles for the IL-1 family in gastrointestinal homeostasis and inflammation. Front Immunol. 2019;10:1266. doi: 10.3389/fimmu.2019.01266
27. Reimund J-M, Wittersheim C, Dumont S, Muller CD, Baumann R, Poindron P, et al. Mucosal inflammatory cytokine production by intestinal biopsies in patients with ulcerative colitis and Crohn’s disease. J Clin Immunol. 1996;16:144–50. doi: 10.1007/BF01540912
28. McAlindon ME, Hawkey CJ, Mahida YR. Expression of interleukin 1β and interleukin 1β converting enzyme by intestinal macrophages in health and inflammatory bowel disease. Gut. 1998;42:214–9. doi: 10.1136/gut.42.2.214
29. Apte RN, Krelin Y, Song X, Dotan S, Recih E, Elkabets M, et al. Effects of micro-environment- and malignant cell-derived interleukin-1 in carcinogenesis, tumour invasiveness and tumour–host interactions. Eur J Cancer. 2006;42:751–9. doi: 10.1016/j.ejca.2006.01.010
30. Song X, Voronov E, Dvorkin T, Fima E, Cagnano E, Benharroch D, et al. Differential effects of IL-1α and IL-1β on tumorigenicity patterns and invasiveness. J Immunol. 2003;171:6448–56. doi: 10.4049/jimmunol.171.12.6448
31. Chen Y, Yang Z, Deng B, Wu D, Quan Y, Min Z. Interleukin 1β/1RA axis in colorectal cancer regulates tumor invasion, proliferation and apoptosis via autophagy. Oncol Rep. 2020;43:908–18. doi: 10.3892/or.2020.7475
32. Sands BE. From symptom to diagnosis: clinical distinctions among various forms of intestinal inflammation. Gastroenterology. 2004;126:1518–32. doi: 10.1053/j.gastro.2004.02.072
33. Galamb O, Györffy B, Sipos F, Spisák S, Németh AM, Miheller P, et al. Inflammation, adenoma and cancer: objective classification of colon biopsy specimens with gene expression signature. Dis Markers. United States. 2008;25:1–16. doi: 10.1155/2008/586721
34. Watanabe T, Kobunai T, Toda E, Kanazawa T, Kazama Y, Tanaka J, et al. Gene expression signature and the prediction of ulcerative colitis-associated colorectal cancer by DNA microarray. Clin Cancer Res Off J Am Assoc Cancer Res. United States. 2007;13(2 Pt 1):415–20. doi: 10.1158/1078-0432.CCR-06-0753
35. Weinstein JN, Collisson EA, Mills GB, Shaw KRM, Ozenberger BA, Ellrott K, et al. The cancer genome atlas pan-cancer analysis project. Nat Genet. 2013;45:1113–20. doi: 10.1038/ng.2764
36. Liu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, et al. An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell. 2018;173:400–16.e11. doi: 10.1016/j.cell.2018.02.052
37. Swedish colorectal cancer registry (colon). Available from: https://statistik.incanet.se/kolorektal/kolon/ [cited 8 Jun 2023].
38. Swedish colorectal cancer registry (rectum). Available from: https://statistik.incanet.se/kolorektal/rektum/ [cited 8 Jun 2023].
39. Nath N, Kashfi K. Tumor associated macrophages and ‘NO’. Biochem Pharmacol. 2020;176:113899. doi: 10.1016/j.bcp.2020.113899
40. Murray PJ. Macrophage polarization. Annu Rev Physiol. 2017;79:541–66. doi: 10.1146/annurev-physiol-022516-034339
41. Fearon ER, Wicha MS. KRAS and cancer stem cells in APC-mutant colorectal cancer. J Natl Cancer Inst. 2014;106:djt444. doi: 10.1093/jnci/djt444
42. Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182:311–22. doi: 10.1002/(SICI)1097-4652(200003)182:3<311::AID-JCP1>3.0.CO;2-9
43. Saraggi D, Fassan M, Mescoli C, Scarpa M, Valeri N, Michielan A, et al. The molecular landscape of colitis-associated carcinogenesis. Dig Liver Dis. 2017;49:326–30. doi: 10.1016/j.dld.2016.12.011
44. Shi F, Wei B, Lan T, Xiao Y, Quan X, Chen J, et al. Low NLRP3 expression predicts a better prognosis of colorectal cancer. Biosci Rep. 2021;41:BSR20210280. doi: 10.1042/BSR20210280
45. Olesen M, Middelveld R, Bohr J, Tysk C, Lundberg S, Eriksson JON, et al. Luminal nitric oxide and epithelial expression of inducible and endothelial nitric oxide synthase in collagenous and lymphocytic colitis. Scand J Gastroenterol. 2003;38:66–72. doi: 10.1080/00365521.2018.12027890
46. Perner A, Andresen L, Normark M, Rask-Madsen J. Constitutive expression of inducible nitric oxide synthase in the normal human colonic epithelium. Scand J Gastroenterol. 2002;37:944–8.
47. Leonard N, Bishop AE, Polak JM, Talbot IC. Expression of nitric oxide synthase in inflammatory bowel disease is not affected by corticosteroid treatment. J Clin Pathol. 1998;51:750–3. doi: 10.1136/jcp.51.10.750
48. Ekmekcioglu S, Grimm EA, Roszik J. Targeting iNOS to increase efficacy of immunotherapies. Hum Vaccines Immunother. 2017;13:1105–8. doi: 10.1080/21645515.2016.1276682
49. Mintz J, Vedenko A, Rosete O, Shah K, Goldstein G, Hare JM, et al. Current advances of nitric oxide in cancer and anticancer therapeutics. Vaccines. 2021;9:94. doi: 10.3390/vaccines9020094
50. Amiot A, Laharie D, Malamut G, Serrero M, Poullenot F, Peyrin-Biroulet L, et al. Management of immune checkpoint inhibitor in patients with cancer and pre-existing inflammatory bowel disease: recommendations from the GETAID. Dig Liver Dis. 2022;54:1162–7. doi: 10.1016/j.dld.2022.06.020
51. Gonzalez FJ. Role of HNF4α in the superinduction of the IL-1β-activated iNOS gene by oxidative stress. Biochem J. 2006;394:e3. doi: 10.1042/BJ20060005
Published
2024-01-02
How to Cite
Björner K., Chen W.-N., Gannavarapu V. R., Axling F., Gulyas M., Halim M. A., Webb D.-L., & Hellström P. M. (2024). High iNOS and IL-1β immunoreactivity are features of colitis-associated colorectal cancer tumors, but fail to predict 5-year survival. Upsala Journal of Medical Sciences, 128(1). https://doi.org/10.48101/ujms.v128.10241
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