Role of Th17 lymphocytes in pathogenesis of colorectal cancer
Jacek Karczewski 1 , Małgorzata Mazur 1 , Anna Rychlewska-Hańczewska 1 , Zygmunt Adamski 1Abstract
Colorectal cancer (CRC) is estimated to be the first leading cause of death from cancer among men and women in the EU. Every year in Poland, 15,254 cases of CRC are diagnosed, and 10,501 patients die of the disease, making it the second leading cause of death from cancer. In more than 90% of cases, the disease begins as adenomatous polyps with epithelial dysplasia as a common feature. Inflammatory bowel diseases (IBD), a group of chronic inflammatory diseases of the gastrointestinal tract characterized by remissions and relapses, constitute an independent risk factor of CRC development. CRC developing in IBD patients, however, has features distinct from sporadic cancer, suggesting the influence of unique factors. The high risk of CRC in IBD patients probably results from chronic inflammation. In most cases, neoplastic lesions arise within the inflamed gastrointestinal mucosa during the process of re-epithelization, which is a healing response to ulceration. The recently discovered Th17 lymphocytes, which demonstrate strong pro-inflammatory capabilities, might link the two diseases. Th17 lymphocytes produce a number of pro-inflammatory cytokines, such as interleukin (IL)-17A, IL-17F, IL-21, IL-22 and tumor necrosis factor (TNF)-a, and play a key role in mucosal defense against various pathogens. Numerous observations suggest that Th17 lymphocytes are involved in pathogenesis of different autoimmune diseases and pathologic inflammatory states. Mounting evidence suggests that Th17 cells contribute to the pathogenesis of IBD and CRC. However, their precise role in both diseases is unknown.
References
- 1. Abraham C., Cho J.: Interleukin-23/Th17 pathways and inflammatorybowel disease. Inflamm. Bowel Dis., 2009; 15: 1090-1100
Google Scholar - 2. Baltgalvis K.A., Berger F.G., Pena M.M., Davis J.M., Muga S.J., CarsonJ.A.: Interleukin-6 and cachexia in ApcMin/+ mice. Am. J. Physiol.Regul. Integr. Comp. Physiol., 2008; 294: R393-R401
Google Scholar - 3. Becker C., Fantini M.C., Schramm C., Lehr H.A., Wirtz S., NikolaevA., Burg J., Strand S., Kiesslich R., Huber S., Ito H., NishimotoN., Yoshizaki K., Kishimoto T., Galle P.R. i wsp.: TGF-beta suppressestumor progression in colon cancer by inhibition of IL-6 trans-signaling.Immunity, 2004; 21: 491-501
Google Scholar - 4. Beriou G., Costantino C.M., Ashley C.W., Yang L., Kuchroo V.K., Baecher-AllanC., Hafler D.A.: IL-17-producing human peripheral regulatoryT cells retain suppressive function. Blood, 2009; 113: 4240-4249
Google Scholar - 5. Bettelli E., Carrier Y., Gao W., Korn T., Strom T.B., Oukka M., WeinerH.L., Kuchroo V.K.: Reciprocal developmental pathways forthe generation of pathogenic effector TH17 and regulatory T cells.Nature, 2006; 441: 235-238
Google Scholar - 6. Brand S.: Crohn’s disease: Th1, Th17 or both? The change of aparadigm: new immunological and genetic insights implicate Th17cells in the pathogenesis of Crohn’s disease. Gut, 2009; 58: 1152-1167
Google Scholar - 7. Chung Y.C., Chang Y.F.: Serum interleukin-6 levels reflect thedisease status of colorectal cancer. J. Surg. Oncol., 2003; 83: 222-226
Google Scholar - 8. Cobrin G.M., Abreu M.T.: Defects of mucosal immunity leadingto Crohn’s disease. Immunol. Rev., 2005; 206: 277-295
Google Scholar - 9. Deknuydt F., Bioley G., Valmori D., Ayyoub M.: IL-1β and IL-2 converthuman Treg into TH17 cells. Clin. Immunol., 2009; 131: 298-307
Google Scholar - 10. Didkowska J., Wojciechowska U., Zatoński W.: Nowotwory zło-śliwe w Polsce w 2009 roku. Warszawa: Centrum Onkologii Instytutim. M. Skłodowskiej-Curie, 2011
Google Scholar - 11. Dubin P.J., Kolls J.K.: Th17 cytokines and mucosal immunity.Immunol. Rev., 2008; 226: 160-171
Google Scholar - 12. Esplugues E., Huber S., Gagliani N., Hauser A.E., Town T., WanY.Y., O’Connor W. Jr., Rongvaux A., Van Rooijen N., Haberman A.M.,Iwakura Y., Kuchroo V.K., Kolls J.K., Bluestone J.A., Herold K.C., FlawellR.A.: Control of TH17 cells occurs in the small intestine. Nature,2011; 475: 514-518
Google Scholar - 13. Farraye F.A., Odze R.D., Eaden J., Itzkovitz S.H.: AGA technicalreview on the diagnosis and management of colorectal neoplasia ininflammatory bowel disease. Gastroenterology, 2010; 138: 746-774
Google Scholar - 14. Gabrilovich D.I., Hurwitz A.A.: Tumor-induced immune suppression.Mechanisms and therapeutic reversal. Springer, New York 2008
Google Scholar - 15. Grivennikov S., Karin E., Terzic J., Mucida D., Yu G.Y., VallabhapurapuS., Scheller J., Rose-John S., Cheroutre H., Eckmann L.,Karin M.: IL-6 and Stat3 are required for survival of intestinal epithelialcells and development of colitis-associated cancer. CancerCell, 2009; 15: 103-113
Google Scholar - 16. Gupta R.B., Harpaz N., Itzkowitz S., Hossain S., Matula S., KornbluthA., Bodian C., Ullman T.: Histologic inflammation is a risk factorfor progression to colorectal neoplasia in ulcerative colitis: a cohortstudy. Gastroenterology, 2007; 133: 1099-1105
Google Scholar - 17. Hölttä V., Klemetti P., Sipponen T., Westerholm-Ormio M., KociubinskiG., Salo H., Räsänen L., Kolho K.L., Färkkilä M., Savilahti E.,Vaarala O.: IL-23/IL-17 immunity as a hallmark of Crohn’s disease.Inflamm. Bowel Dis., 2008; 14: 1175-1184
Google Scholar - 18. Hueber W., Sands B.E., Lewitzky S., Vandemeulebroecke M.,Reinisch W., Higgins P.D., Wehkamp J., Feagan B.G., Yao M.D., KarczewskiM., Karczewski J., Pezous N., Bek S., Bruin G., Mellgard B. iwsp.: Secukinumab, a human anti-IL-17A monoclonal antibody, formoderate to severe Crohn’s disease: unexpected results of a randomised,double-blind placebo-controlled trial. Gut, 2012; 61: 1693-1700
Google Scholar - 19. Hus I., Maciąg E., Roliński J.: Znaczenie limfocytów Th17 w odpornościprzeciwnowotworowej. Postępy Hig. Med. Dośw., 2010;64: 244-250
Google Scholar - 20. Itzkowitz S.H., Yio X.: Inflammation and cancer IV. Colorectalcancer in inflammatory bowel disease: the role of inflammation. Am.J. Physiol. Gastrointest. Liver Physiol., 2004; 287: G7-G17
Google Scholar - 21. Jankowski J.A.: Inflammation and Gastrointestinal Cancers,Springer-Verlag, Berlin Heidelberg, 2011
Google Scholar - 22. Ji Y., Zhang W.: Th17 cells: positive or negative role in tumor?Cancer Immunol. Immunother., 2010; 59: 979-987
Google Scholar - 23. Karczewski J., Karczewski M.: Immunoregulatory defect in patientswith active Crohn’s disease. Inflamm. Bowel Dis., 2013; 19: E2-E4
Google Scholar - 24. Karczewski J., Karczewski M.: Possible defect of regulatory Tcells in patients with ulcerative colitis. Cent. Eur. J. Immunol., 2011;36: 254-255
Google Scholar - 25. Karczewski J., Mazur M., Karczewski M.: Dual role of Th17 cellsin Crohn’s disease. Cent. Eur. J. Immunol., 2012; 37: 286-289
Google Scholar - 26. Kim Y.J., Hong K.S., Chung J.W., Kim J.H., Hahm K.B.: Preventionof colitis-associated carcinogenesis with infliximab. Cancer Prev.Res., 2010; 3: 1314-1333
Google Scholar - 27. Koenen H.J., Smeets R.L., Vink P.M., van Rijssen E., Boots A.M.,Joosten I.: Human CD25highFoxp3pos regulatory T cells differentiateinto IL-17-producing cells. Blood, 2008; 112: 2340-2352
Google Scholar - 28. Kryczek I., Banerjee M., Cheng P., Vatan L., Szeliga W., Wei S.,Huang E., Finlayson E., Simeone D., Welling T.H., Chang A., Coukos G.,Liu R., Zou W.: Phenotype, distribution, generation, and functionaland clinical relevance of Th17 cells in the human tumor environments.Blood, 2009; 114: 1141-1149
Google Scholar - 29. Kryczek I., Wei S., Zou L., Altuwaijri S., Szeliga W., Kolls J., ChangA., Zou W.: Cutting edge: Th17 and regulatory T cell dynamics andthe regulation by IL-2 in the tumor microenvironment. J. Immunol.,2007; 178: 6730-6733
Google Scholar - 30. Langowski J.L., Zhang X., Wu L., Mattson J.D., Chen T., Smith K.,Basham B., McClanahan T., Kastelein R.A., Oft M.: IL-23 promotestumour incidence and growth. Nature, 2006; 442: 461-465
Google Scholar - 31. Le Gouvello S., Bastuji-Garin S., Aloulou N., Mansour H., ChaumetteM.T., Berrehar F., Seikour A., Charachon A., Karoui M., LeroyK., Farcet J.P., Sobhani I.: High prevalence of Foxp3 and IL17 in MMR–proficient colorectal carcinomas. Gut, 2008; 57: 772-779
Google Scholar - 32. Lee J.W., Wang P., Kattah M.G., Youssef S., Steinman L., DeFea K.,Straus D.S.: Differential regulation of chemokines by IL-17 in colonicepithelial cells. J. Immunol., 2008; 181: 6536-6545
Google Scholar - 33. Lee Y.K., Mukasa R., Hatton R.D., Weaver C.T.: Developmental plasticityof Th17 and Treg cells. Curr. Opin. Immunol., 2009; 21: 274-280
Google Scholar - 34. Li Y., de Haar C., Chen M., Deuring J., Gerrits M.M., Smits R.,Xia B., Kuipers E.J., van der Woude C.J.: Disease-related expressionof the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitisand ulcerative colitis-related carcinogenesis. Gut, 2010; 59: 227-235
Google Scholar - 35. Mangan P.R., Harrington L.E., O’Quinn D.B., Helms W.S., BullardD.C., Elson C.O., Hatton R.D., Wahl S.M., Schoeb T.R., Weaver C.T.:Transforming growth factor-β induces development of the TH17lineage. Nature, 2006; 441: 231-234
Google Scholar - 36. Markowitz S.D., Bertagnolli M.M.: Molecular origins of cancer:molecular basis of colorectal cancer. N. Engl. J. Med., 2009; 361:2449-2460
Google Scholar - 37. Maul J., Loddenkemper C., Mundt P., Berg E., Giese T., StallmachA., Zeitz M., Duchmann R.: Peripheral and intestinal regulatoryCD4+CD25high T cells in inflammatory bowel disease. Gastroenterology,2005; 128: 1868-1878
Google Scholar - 38. O’Connor W.Jr., Kamanaka M., Booth C.J., Town T., Nakae S.,Iwakura Y., Kolls J.K., Flavell R.A.: A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat. Immunol.,2009; 10: 603-609
Google Scholar - 39. O’Quinn D.B., Palmer M.T., Lee Y.K., Weaver C.T.: Emergenceof the Th17 pathway and its role in host defense. Adv. Immunol.,2008; 99: 115-163
Google Scholar - 40. Popivanova B.K., Kitamura K., Wu Y., Kondo T., Kagaya T., KanekoS., Oshima M., Fujii C., Mukaida N.: Blocking TNF-α in mice reducescolorectal carcinogenesis associated with chronic colitis. J. Clin.Invest.; 2008; 118: 560-570
Google Scholar - 41. Rutter M., Saunders B., Wilkinson K., Rumbles S., Schofield G.,Kamm M., Williams C., Price A., Talbot I., Forbes A.: Severity of inflammationis a risk factor for colorectal neoplasia in ulcerativecolitis. Gastroenterology, 2004; 126: 451-459
Google Scholar - 42. Saruta M., Yu Q.T., Fleshner P.R., Mantel P.Y., Schmidt-Weber C.B.,Banham A.H., Papadakis K.A.: Characterization of FOXP3+ CD4+ regulatoryT cells in Crohn’s disease. Clin. Immunol., 2007; 125: 281-290
Google Scholar - 43. Strober W., Fuss I.J.: Proinflammatory cytokines in the pathogenesisof inflammatory bowel diseases. Gastroenterology, 2011;140: 1756-1767
Google Scholar - 44. Targan S.R., Shanahan F., Karp L.C.: Inflammatory Bowel Disease:Translating basic science into clinical practice. 5 ed: BlackwellPublishing Ltd., 2010
Google Scholar - 45. Tosolini M., Kirilovsky A., Mlecnik B., Fredriksen T., Mauger S.,Bindea G., Berger A., Bruneval P., Fridman W.H., Pagès F., Galon J.:Clinical impact of different classes of infiltrating T cytotoxic andhelper cells (Th1, th2, treg, th17) in patients with colorectal cancer.Cancer Res., 2011; 71: 1263-1271
Google Scholar - 46. Ullman T.A., Itzkowitz S.H.: Intestinal inflammation and cancer.Gastroenterology, 2011; 140: 1807-1816
Google Scholar - 47. Velayos F.S., Terdiman J.P., Walsh J.M.: Effect of 5-aminosalicylateuse on colorectal cancer and dysplasia risk: a systematic reviewand metaanalysis of observational studies. Am. J. Gastroenterol.,2005; 100: 1345-1353
Google Scholar - 48. Voo K.S., Wang Y.H., Santori F.R., Boggiano C., Wang Y.H., ArimaK., Bover L., Hanabuchi S., Khalili J., Marinova E., Zheng B., LittmanD.R., Liu Y.J.: Identification of IL-17-producing FOXP3+ regulatoryT cells in humans. Proc. Natl. Acad. Sci. USA, 2009; 106: 4793-4798
Google Scholar - 49. Weaver C.T., Hatton R.D., Mangan P.R., Harrington L.E.: IL-17family cytokines and the expanding diversity of effector T cell lineages.Annu. Rev. Immunol., 2007; 25: 821-852
Google Scholar - 50. Wei E.K., Giovannucci E., Wu K., Rosner B., Fuchs C.S., WillettW.C., Colditz G.A.: Comparison of risk factors for colon and rectalcancer. Int. J. Cancer, 2004; 108: 433-442
Google Scholar - 51. Witowski J., Ksiazek K., Jörres A.: Interleukin-17: a mediator ofinflammatory responses. Cell. Mol. Life Sci., 2004; 61: 567-579
Google Scholar - 52. Wu S., Rhee K.J., Albesiano E., Rabizadeh S., Wu X., Yen H.R.,Huso D.L., Brancati F.L., Wick E., McAllister F., Housseau F., PardollD.M., Sears C.L.: A human colonic commensal promotes colon tumorigenesisvia activation of T helper type 17 T cell responses. Nat.Med., 2009; 15: 1016-1022
Google Scholar - 53. Ye J., Su X., Hsueh E.C., Zhang Y., Koenig J.M., Hoft D.F., Peng G.:Human tumor-infiltrating Th17 cells have the capacity to differentiateinto IFN-γ+ and FOXP3+ T cells with potent suppressive function.Eur. J. Immunol., 2011; 41: 936-951
Google Scholar - 54. Zou W., Restifo N.P.: TH17 cells in tumour immunity and immunotherapy.Nat. Rev. Immunol., 2010; 10: 248-256
Google Scholar