Dynamics of the IL-33/ST2 network in the progression of human colorectal adenoma to sporadic colorectal cancer

Abstract

Most sporadic colorectal cancers (CRCs) develop from preformed adenomas. Cytokines are involved in the transition from adenoma to CRC. Interleukin-33 (IL-33) is a newly discovered proinflammatory cytokine belonging to the IL-1 cytokine family and involved in the development of chronic inflammation and cancer. The aim of this study was to evaluate the dynamics of the IL-33/ST2 axis during the sequence of progression from normal colorectum to adenoma to carcinoma and to investigate the association of IL-33 and ST2 expression with clinicopathological parameters and prognosis. The results demonstrated that the levels of IL-33 and ST2 in adenomas (n = 50), determined by real-time PCR, were significantly higher than those of normal controls (n = 30); the levels of both IL-33/ST mRNA in CRCs (n = 50) were higher than in normal controls but lower than in adenomas. Further analysis revealed that the expression level of ST2 in CRCs was associated with tumor/node/metastasis (TNM) stage. The log-rank test showed that neither the IL-33 nor the ST2 expression level was correlated with overall survival in patients with CRC. The increased expression of IL-33/ST2 in adenomas and CRC tissues was confirmed by immunohistochemistry and was observed in both the tumor stromal cells and adenomatous/cancerous cells. Notably, increased densities of IL-33-positive and ST2-positive microvessels were found in the stroma of adenomas and CRCs. In conclusion, increased expression of the IL-33/ST2 axis along the colorectal adenoma–carcinoma sequence might be involved in the neoplastic transformation via the participation of this axis in the regulation of angiogenesis.

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Abbreviations

CRC:

Colorectal cancer

CT:

Cycle threshold

IBD:

Inflammatory bowel diseases

IFN:

Interferon

IHC:

Immunohistochemistry

IL:

Interleukin

LGD:

Lower-grade dysplasia

HGD:

High-grade dysplasia

HPF:

High-power fields

MGD:

Moderate-grade dysplasia

MVD:

Microvessel densities

PCR:

Polymerase chain reaction

SEM:

Mean of standard error

Th:

T helper

TNF:

Tumor necrosis factor

TNM:

Tumor/node/metastasis

References

  1. 1.

    Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Leslie A, Carey FA, Pratt NR, Steele RJ (2002) The colorectal adenoma-carcinoma sequence. Br J Surg 89:845–860

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Khosraviani K (1996) Colorectal adenoma-carcinoma sequence. Gut 39:342

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  4. 4.

    Xie K (2001) Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev 12:375–391

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Cacev T, Radosevic S, Krizanac S, Kapitanovic S (2008) Influence of interleukin-8 and interleukin-10 on sporadic colon cancer development and progression. Carcinogenesis 29:1572–1580

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14:6735–6741

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Fantini MC, Pallone F (2008) Cytokines: from gut inflammation to colorectal cancer. Curr Drug Targets 9:375–380

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Choi JW, Liu H, Shin DH, Yu GI, Hwang JS, Kim ES, Yun JW (2013) Proteomic and cytokine plasma biomarkers for predicting progression from colorectal adenoma to carcinoma in human patients. Proteomics 13:2361–2374

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Chung YC, Chang YF (2003) Significance of inflammatory cytokines in the progression of colorectal cancer. Hepatogastroenterology 50:1910–1913

    CAS  PubMed  Google Scholar 

  10. 10.

    Kang M, Edmundson P, Araujo-Perez F, McCoy AN, Galanko J, Keku TO (2013) Association of plasma endotoxin, inflammatory cytokines and risk of colorectal adenomas. BMC Cancer 13:91

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  11. 11.

    Kim S, Keku TO, Martin C, Galanko J, Woosley JT, Schroeder JC, Satia JA, Halabi S, Sandler RS (2008) Circulating levels of inflammatory cytokines and risk of colorectal adenomas. Cancer Res 68:323–328

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  12. 12.

    Krzystek-Korpacka M, Diakowska D, Kapturkiewicz B, Bebenek M, Gamian A (2013) Profiles of circulating inflammatory cytokines in colorectal cancer (CRC), high cancer risk conditions, and health are distinct. Possible implications for CRC screening and surveillance. Cancer Lett 337:107–114

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Cui G, Goll R, Olsen T, Steigen SE, Husebekk A, Vonen B, Florholmen J (2007) Reduced expression of microenvironmental Th1 cytokines accompanies adenomas-carcinomas sequence of colorectum. Cancer Immunol Immunother 56:985–995

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Cui G, Yuan A, Goll R, Vonen B, Florholmen J (2009) Dynamic changes of interleukin-8 network along the colorectal adenoma-carcinoma sequence. Cancer Immunol Immunother 58:1897–1905

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Oliveira Frick V, Rubie C, Ghadjar P, Faust SK, Wagner M, Graber S, Schilling MK (2011) Changes in CXCL12/CXCR4-chemokine expression during onset of colorectal malignancies. Tumour Biol 32:189–196

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Pellegrini P, Berghella AM, Contasta I, Del Beato T, Adorno D (2006) The study of a patient’s immune system may prove to be a useful noninvasive tool for stage classification in colon cancer. Cancer Biother Radiopharm 21:443–467

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Liew FY (2012) IL-33: a Janus cytokine. Ann Rheum Dis 71(Suppl 2):i101–i104

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Beltran CJ, Nunez LE, Diaz-Jimenez D, Farfan N, Candia E, Heine C, Lopez F, Gonzalez MJ, Quera R, Hermoso MA (2010) Characterization of the novel ST2/IL-33 system in patients with inflammatory bowel disease. Inflamm Bowel Dis 16:1097–1107

    PubMed  Article  Google Scholar 

  19. 19.

    Milovanovic M, Volarevic V, Radosavljevic G, Jovanovic I, Pejnovic N, Arsenijevic N, Lukic ML (2012) IL-33/ST2 axis in inflammation and immunopathology. Immunol Res 52:89–99

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Kobori A, Yagi Y, Imaeda H, Ban H, Bamba S, Tsujikawa T, Saito Y, Fujiyama Y, Andoh A (2010) Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis. J Gastroenterol 45:999–1007

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Jovanovic IP, Pejnovic NN, Radosavljevic GD, Arsenijevic NN, Lukic ML (2012) IL-33/ST2 axis in innate and acquired immunity to tumors. Oncoimmunology 1:229–231

    PubMed Central  PubMed  Article  Google Scholar 

  22. 22.

    Eiwegger T, Akdis CA (2011) IL-33 links tissue cells, dendritic cells and Th2 cell development in a mouse model of asthma. Eur J Immunol 41:1535–1538

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Schmieder A, Multhoff G, Radons J (2012) Interleukin-33 acts as a pro-inflammatory cytokine and modulates its receptor gene expression in highly metastatic human pancreatic carcinoma cells. Cytokine 60:514–521

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Chen SF, Nieh S, Jao SW, Wu MZ, Liu CL, Chang YC, Lin YS (2013) The paracrine effect of cancer-associated fibroblast-induced interleukin-33 regulates the invasiveness of head and neck squamous cell carcinoma. J Pathol 231:180–189

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Zhang P, Liu XK, Chu Z, Ye JC, Li KL, Zhuang WL, Yang DJ, Jiang YF (2012) Detection of interleukin-33 in serum and carcinoma tissue from patients with hepatocellular carcinoma and its clinical implications. J Int Med Res 40:1654–1661

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Hu LA, Fu Y, Zhang DN, Zhang J (2013) Serum IL-33 as a diagnostic and prognostic marker in non- small cell lung cancer. Asian Pac J Cancer Prev 14:2563–2566

    PubMed  Article  Google Scholar 

  27. 27.

    Sun P, Ben Q, Tu S, Dong W, Qi X, Wu Y (2011) Serum interleukin-33 levels in patients with gastric cancer. Dig Dis Sci 56:3596–3601

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Musolino C, Allegra A, Profita M, Alonci A, Saitta S, Russo S, Bonanno A, Innao V, Gangemi S (2013) Reduced IL-33 plasma levels in multiple myeloma patients are associated with more advanced stage of disease. Br J Heamatol 160:709–710

    CAS  Article  Google Scholar 

  29. 29.

    Seidelin JB, Rogler G, Nielsen OH (2011) A role for interleukin-33 in T(H)2-polarized intestinal inflammation? Mucosal Immunol 4:496–502

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Cui G, Olsen T, Christiansen I, Vonen B, Florholmen J, Goll R (2006) Improvement of real-time polymerase chain reaction for quantifying TNF-alpha mRNA expression in inflamed colorectal mucosa: an approach to optimize procedures for clinical use. Scand J Clin Lab Inv 66:249–259

    CAS  Article  Google Scholar 

  31. 31.

    Cui G, Koh TJ, Chen D, Zhao CM, Takaishi S, Dockray GJ, Varro A, Rogers AB, Fox JG, Wang TC (2004) Overexpression of glycine-extended gastrin inhibits parietal cell loss and atrophy in the mouse stomach. Cancer Res 64:8160–8166

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Cui J, Xu G, Liu J, Pang Z, Florholmen J, Cui G (2013) The expression of non-mast histamine in tumor associated microvessels in human colorectal cancers. Pathol Oncol Res 19:311–316

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Jovanovic IP, Pejnovic NN, Radosavljevic GD, Pantic JM, Milovanovic MZ, Arsenijevic NN, Lukic ML (2014) Interleukin-33/ST2 axis promotes breast cancer growth and metastases by facilitating intratumoral accumulation of immunosuppressive and innate lymphoid cells. Int J Cancer 134:1669–1682

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Kuchler AM, Pollheimer J, Balogh J, Sponheim J, Manley L, Sorensen DR, De Angelis PM, Scott H, Haraldsen G (2008) Nuclear interleukin-33 is generally expressed in resting endothelium but rapidly lost upon angiogenic or proinflammatory activation. Am J Pathol 173:1229–1242

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  35. 35.

    Contasta I, Berghella AM, Pellegrini P, Adorno D (2003) Passage from normal mucosa to adenoma and colon cancer: alteration of normal sCD30 mechanisms regulating TH1/TH2 cell functions. Cancer Biother Radiopharm 18:549–557

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Marvie P, Lisbonne M, L’Helgoualc’h A, Rauch M, Turlin B, Preisser L, Bourd-Boittin K, Theret N, Gascan H, Piquet-Pellorce C, Samson M (2010) Interleukin-33 overexpression is associated with liver fibrosis in mice and humans. J Cell Mol Med 14:1726–1739

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Meephansan J, Tsuda H, Komine M, Tominaga S, Ohtsuki M (2012) Regulation of IL-33 expression by IFN-gamma and tumor necrosis factor-alpha in normal human epidermal keratinocytes. J Invest Dermatol 132:2593–2600

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Byrne SN, Beaugie C, O’Sullivan C, Leighton S, Halliday GM (2011) The immune-modulating cytokine and endogenous Alarmin interleukin-33 is upregulated in skin exposed to inflammatory UVB radiation. Am J Pathol 179:211–222

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  39. 39.

    Seltmann J, Werfel T, Wittmann M (2013) Evidence for a regulatory loop between IFN-gamma and IL-33 in skin inflammation. Exp Dermatol 22:102–107

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Gschwantler M, Kriwanek S, Langner E, Goritzer B, Schrutka-Kolbl C, Brownstone E, Feichtinger H, Weiss W (2002) High-grade dysplasia and invasive carcinoma in colorectal adenomas: a multivariate analysis of the impact of adenoma and patient characteristics. Eur J Gastroenterol Hepatol 14:183–188

    PubMed  Article  Google Scholar 

  41. 41.

    Ajdukovic J, Tonkic A, Salamunic I, Hozo I, Simunic M, Bonacin D (2010) Interleukins IL-33 and IL-17/IL-17A in patients with ulcerative colitis. Hepatogastroenterology 57:1442–1444

    CAS  PubMed  Google Scholar 

  42. 42.

    Seidelin JB, Bjerrum JT, Coskun M, Widjaya B, Vainer B, Nielsen OH (2010) IL-33 is upregulated in colonocytes of ulcerative colitis. Immunol Lett 128:80–85

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Choi YS, Choi HJ, Min JK, Pyun BJ, Maeng YS, Park H, Kim J, Kim YM, Kwon YG (2009) Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. Blood 114:3117–3126

    CAS  PubMed  Article  Google Scholar 

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Acknowledgments

This research was supported by grants from the Medical Research Program of Northern Norway Regional Health Authority (Grant No. SFP-44-04) and the National Natural Science Foundation of China (Grant No. 81071969).

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All authors declare no conflicts of interest.

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Correspondence to Guanglin Cui.

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Cui, G., Qi, H., Gundersen, M.D. et al. Dynamics of the IL-33/ST2 network in the progression of human colorectal adenoma to sporadic colorectal cancer. Cancer Immunol Immunother 64, 181–190 (2015). https://doi.org/10.1007/s00262-014-1624-x

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Keywords

  • Adenoma–carcinoma transition
  • Colorectal cancer
  • Interleukin-33
  • ST2