Inflammatory Biomarkers for Cancer

  • Alexandre Corthay
  • Guttorm Haraldsen


Cancer is associated with various degrees of inflammation both locally and systemically, resulting from an immunological response towards malignant lesions. Here, we critically evaluate several inflammatory parameters as biomarkers and prognostic tools for cancer. Colorectal cancer (CRC) represents a paradigm of the causative relationship between chronic inflammatory disease and cancer development. However, close examination reveals that for CRC, risk in patients with inflammatory bowel disease (IBD) has been largely overestimated. In fact, IBD patients only have a slightly increased risk of developing CRC (standardized incidence ratio ~ 1.7), which only weakly supports the link between chronic inflammation and cancer. However, long-term immunosuppressive treatment of IBD patients is associated with an increased risk for overall cancer, particularly haematologic and skin cancers. In contrast, there is a strong association between infection with the bacterium Helicobacter pylori, gastritis, and gastric cancer. Therefore, H. pylori seropositivity or the associated gastritis may be used as predictive biomarkers for cancer, although the rate of false positives is high. We have also reviewed several cytokines of the interleukin-1 family and cytokines that converge on STAT3 signalling because they are very well suited to illustrate the multitude of cytokine actions that makes interpretation of one single cytokine as a biomarker of cancer very complex. In addition, we describe in more detail the biology of IL-33, the most recently identified member of the IL-1 family, because it has not yet been subject to review in the context of cancer immunology.


Inflammatory biomarkers Inflammation Inflammatory bowel disease Colorectal cancer Gastritis Gastric cancer Helicobacter pylori Interleukin TGF 



This work was supported by grants from the Research Council of Norway, Norway Grants 2009–2014 under project contract NFI/R/2014/051, the South-Eastern Norway Regional Health Authority, and the Norwegian Cancer Society.


  1. 1.
    Haabeth OA, Bogen B, Corthay A. A model for cancer-suppressive inflammation. Oncoimmunology. 2012;1(7):1146–55.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Danese S, Mantovani A. Inflammatory bowel disease and intestinal cancer: a paradigm of the Yin-Yang interplay between inflammation and cancer. Oncogene. 2010;29(23):3313–23.CrossRefPubMedGoogle Scholar
  3. 3.
    Jess T, Frisch M, Simonsen J. Trends in overall and cause-specific mortality among patients with inflammatory bowel disease from 1982 to 2010. Clin Gastroenterol Hepatol. 2013;11(1):43–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Farraye FA, Odze RD, Eaden J, Itzkowitz SH, McCabe RP, Dassopoulos T, et al. AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology. 2010;138(2):738–45.CrossRefPubMedGoogle Scholar
  5. 5.
    Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48(4):526–35.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Herrinton LJ, Liu L, Levin TR, Allison JE, Lewis JD, Velayos F. Incidence and mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease from 1998 to 2010. Gastroenterology. 2012;143(2):382–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Beaugerie L, Svrcek M, Seksik P, Bouvier AM, Simon T, Allez M, et al. Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease. Gastroenterology. 2013;145(1):166–75.e8.CrossRefPubMedGoogle Scholar
  8. 8.
    Jess T, Gamborg M, Matzen P, Munkholm P, Sorensen TI. Increased risk of intestinal cancer in Crohn's disease: a meta-analysis of population-based cohort studies. Am J Gastroenterol. 2005;100(12):2724–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Soderlund S, Brandt L, Lapidus A, Karlen P, Brostrom O, Lofberg R, et al. Decreasing time-trends of colorectal cancer in a large cohort of patients with inflammatory bowel disease. Gastroenterology. 2009;136(5):1561–7. quiz 818–9CrossRefPubMedGoogle Scholar
  10. 10.
    Jess T, Simonsen J, Jorgensen KT, Pedersen BV, Nielsen NM, Frisch M. Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years. Gastroenterology. 2012;143(2):375–81.e1. quiz e13–4CrossRefPubMedGoogle Scholar
  11. 11.
    Baars JE, Looman CW, Steyerberg EW, Beukers R, Tan AC, Weusten BL, et al. The risk of inflammatory bowel disease-related colorectal carcinoma is limited: results from a nationwide nested case-control study. Am J Gastroenterol. 2011;106(2):319–28.CrossRefPubMedGoogle Scholar
  12. 12.
    Brown LM. Helicobacter pylori: epidemiology and routes of transmission. Epidemiol Rev. 2000;22(2):283–97.CrossRefPubMedGoogle Scholar
  13. 13.
    Linz B, Balloux F, Moodley Y, Manica A, Liu H, Roumagnac P, et al. An African origin for the intimate association between humans and Helicobacter pylori. Nature. 2007;445(7130):915–8.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Maixner F, Krause-Kyora B, Turaev D, Herbig A, Hoopmann MR, Hallows JL, et al. The 5300-year-old Helicobacter pylori genome of the Iceman. Science. 2016;351(6269):162–5.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Warren JR. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet. 1983;1(8336):1273–5.PubMedGoogle Scholar
  16. 16.
    Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;1(8390):1311–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Fiocca R, Villani L, Turpini F, Turpini R, Solcia E. High incidence of Campylobacter-like organisms in endoscopic biopsies from patients with gastritis, with or without peptic ulcer. Digestion. 1987;38(4):234–44.CrossRefPubMedGoogle Scholar
  18. 18.
    Niemela S, Karttunen T, Lehtola J. Campylobacter-like organisms in patients with gastric ulcer. Scand J Gastroenterol. 1987;22(4):487–90.CrossRefPubMedGoogle Scholar
  19. 19.
    Nomura A, Stemmermann GN, Chyou PH, Kato I, Perez-Perez GI, Blaser MJ. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med. 1991;325(16):1132–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991;325(16):1127–31.CrossRefPubMedGoogle Scholar
  21. 21.
    Enomoto H, Watanabe H, Nishikura K, Umezawa H, Asakura H. Topographic distribution of Helicobacter pylori in the resected stomach. Eur J Gastroenterol Hepatol. 1998;10(6):473–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Hansen S, Melby KK, Aase S, Jellum E, Vollset SE. Helicobacter pylori infection and risk of cardia cancer and non-cardia gastric cancer. A nested case-control study. Scand J Gastroenterol. 1999;34(4):353–60.CrossRefPubMedGoogle Scholar
  23. 23.
    Sasazuki S, Inoue M, Iwasaki M, Otani T, Yamamoto S, Ikeda S, et al. Effect of Helicobacter pylori infection combined with CagA and pepsinogen status on gastric cancer development among Japanese men and women: a nested case-control study. Cancer Epidemiol Biomark Prev. 2006 Jul;15(7):1341–7.CrossRefGoogle Scholar
  24. 24.
    Infection with Helicobacter Pylori. World health organization, international agency for research on cancer. IARC Monogr Eval Carcinog Risks Hum. 1994;61:177–240.Google Scholar
  25. 25.
    Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345(11):784–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Watabe H, Mitsushima T, Yamaji Y, Okamoto M, Wada R, Kokubo T, et al. Predicting the development of gastric cancer from combining Helicobacter pylori antibodies and serum pepsinogen status: a prospective endoscopic cohort study. Gut. 2005;54(6):764–8.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kokkola A, Kosunen TU, Puolakkainen P, Sipponen P, Harkonen M, Laxen F, et al. Spontaneous disappearance of Helicobacter pylori antibodies in patients with advanced atrophic corpus gastritis. APMIS. 2003;111(6):619–24.CrossRefPubMedGoogle Scholar
  28. 28.
    Dinarello CA. Why not treat human cancer with interleukin-1 blockade? Cancer Metastasis Rev. 2010;29(2):317–29.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    O'Neill LA. The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunol Rev. 2008;226:10–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317(5834):121–4.CrossRefPubMedGoogle Scholar
  31. 31.
    Swann JB, Vesely MD, Silva A, Sharkey J, Akira S, Schreiber RD, et al. Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc Natl Acad Sci U S A. 2008;105(2):652–6.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Rakoff-Nahoum S, Medzhitov R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science. 2007;317(5834):124–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Uronis JM, Muhlbauer M, Herfarth HH, Rubinas TC, Jones GS, Jobin C. Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS One. 2009;4(6):e6026.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Salcedo R, Worschech A, Cardone M, Jones Y, Gyulai Z, Dai RM, et al. MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J Exp Med. 2010;207(8):1625–36.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Mager LF, Riether C, Schurch CM, Banz Y, Wasmer MH, Stuber R, et al. IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms. J Clin Invest. 2015;125(7):2579–91.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Haabeth OA, Lorvik KB, Hammarstrom C, Donaldson IM, Haraldsen G, Bogen B, et al. Inflammation driven by tumour-specific Th1 cells protects against B-cell cancer. Nat Commun. 2011;2:240.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Corthay A. Does the immune system naturally protect against cancer? Front Immunol. 2014;5:197.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015 Jul;21(7):677–87.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Dupaul-Chicoine J, Yeretssian G, Doiron K, Bergstrom KS, McIntire CR, LeBlanc PM, et al. Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity. 2010;32(3):367–78.CrossRefPubMedGoogle Scholar
  40. 40.
    Allen IC, TeKippe EM, Woodford RM, Uronis JM, Holl EK, Rogers AB, et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med. 2010;207(5):1045–56.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Zaki MH, Vogel P, Body-Malapel M, Lamkanfi M, Kanneganti TD. IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. J Immunol. 2010;185(8):4912–20.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Lee JK, Kim SH, Lewis EC, Azam T, Reznikov LL, Dinarello CA. Differences in signaling pathways by IL-1beta and IL-18. Proc Natl Acad Sci U S A. 2004;101(23):8815–20.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Krelin Y, Voronov E, Dotan S, Elkabets M, Reich E, Fogel M, et al. Interleukin-1beta-driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors. Cancer Res. 2007;67(3):1062–71.CrossRefPubMedGoogle Scholar
  44. 44.
    Hitzler I, Sayi A, Kohler E, Engler DB, Koch KN, Hardt WD, et al. Caspase-1 has both proinflammatory and regulatory properties in Helicobacter infections, which are differentially mediated by its substrates IL-1beta and IL-18. J Immunol. 2012;188(8):3594–602.CrossRefPubMedGoogle Scholar
  45. 45.
    Haabeth OA, Lorvik KB, Yagita H, Bogen B, Corthay A. Interleukin-1 is required for cancer eradication mediated by tumor-specific Th1 cells. OncoImmunology. 2016;5(1):e1039763.CrossRefPubMedGoogle Scholar
  46. 46.
    Lust JA, Lacy MQ, Zeldenrust SR, Dispenzieri A, Gertz MA, Witzig TE, et al. Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1{beta}-induced interleukin 6 production and the myeloma proliferative component. Mayo Clin Proc. 2009;84(2):114–22.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Hong DS, Hui D, Bruera E, Janku F, Naing A, Falchook GS, et al. MABp1, a first-in-class true human antibody targeting interleukin-1alpha in refractory cancers: an open-label, phase 1 dose-escalation and expansion study. Lancet Oncol. 2014;15(6):656–66.CrossRefPubMedGoogle Scholar
  48. 48.
    Fabbi M, Carbotti G, Ferrini S. Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP. J Leukoc Biol. 2015;97(4):665–75.CrossRefPubMedGoogle Scholar
  49. 49.
    Oertli M, Sundquist M, Hitzler I, Engler DB, Arnold IC, Reuter S, et al. DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection. J Clin Invest. 2012;122(3):1082–96.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Nishio S, Yamada N, Ohyama H, Yamanegi K, Nakasho K, Hata M, et al. Enhanced suppression of pulmonary metastasis of malignant melanoma cells by combined administration of alpha-galactosylceramide and interleukin-18. Cancer Sci. 2008;99(1):113–20.PubMedGoogle Scholar
  51. 51.
    Osaki T, Peron JM, Cai Q, Okamura H, Robbins PD, Kurimoto M, et al. IFN-gamma-inducing factor/IL-18 administration mediates IFN-gamma- and IL-12-independent antitumor effects. J Immunol. 1998;160(4):1742–9.PubMedGoogle Scholar
  52. 52.
    Coughlin CM, Salhany KE, Gee MS, LaTemple DC, Kotenko S, Ma X, et al. Tumor cell responses to IFNgamma affect tumorigenicity and response to IL-12 therapy and antiangiogenesis. Immunity. 1998;9(1):25–34.CrossRefPubMedGoogle Scholar
  53. 53.
    Wong JL, Mailliard RB, Moschos SJ, Edington H, Lotze MT, Kirkwood JM, et al. Helper activity of natural killer cells during the dendritic cell-mediated induction of melanoma-specific cytotoxic T cells. J Immunother. 2011;34(3):270–8.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Orengo AM, Fabbi M, Miglietta L, Andreani C, Bruzzone M, Puppo A, et al. Interleukin (IL)-18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor. Int J Cancer. 2011;129(5):1116–25.CrossRefPubMedGoogle Scholar
  55. 55.
    Fujita K, Ewing CM, Isaacs WB, Pavlovich CP. Immunomodulatory IL-18 binding protein is produced by prostate cancer cells and its levels in urine and serum correlate with tumor status. Int J Cancer. 2011;129(2):424–32.CrossRefPubMedGoogle Scholar
  56. 56.
    Carbotti G, Barisione G, Orengo AM, Brizzolara A, Airoldi I, Bagnoli M, et al. The IL-18 antagonist IL-18-binding protein is produced in the human ovarian cancer microenvironment. Clin Cancer Res. 2013;19(17):4611–20.CrossRefPubMedGoogle Scholar
  57. 57.
    Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23(5):479–90.CrossRefPubMedGoogle Scholar
  58. 58.
    Tominaga S. A putative protein of a growth specific cDNA from BALB/c-3T3 cells is highly similar to the extracellular portion of mouse interleukin 1 receptor. FEBS Lett. 1989;258(2):301–4.CrossRefPubMedGoogle Scholar
  59. 59.
    Onda H, Kasuya H, Takakura K, Hori T, Imaizumi T, Takeuchi T, et al. Identification of genes differentially expressed in canine vasospastic cerebral arteries after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 1999;19(11):1279–88.CrossRefPubMedGoogle Scholar
  60. 60.
    Kuchler AM, Pollheimer J, Balogh J, Sponheim J, Manley L, Sorensen DR, et al. Nuclear interleukin-33 is generally expressed in resting endothelium but rapidly lost upon angiogenic or proinflammatory activation. Am J Pathol. 2008;173(4):1229–42.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Moussion C, Ortega N, Girard JP. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘alarmin’? PLoS One. 2008;3(10):e3331.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Sundnes O, Pietka W, Loos T, Sponheim J, Rankin AL, Pflanz S, et al. Epidermal expression and regulation of interleukin-33 during homeostasis and inflammation: strong species differences. J Invest Dermatol. 2015;135(7):1771–80.CrossRefPubMedGoogle Scholar
  63. 63.
    Pollheimer J, Bodin J, Sundnes O, Edelmann RJ, Skanland SS, Sponheim J, et al. Interleukin-33 drives a proinflammatory endothelial activation that selectively targets nonquiescent cells. Arterioscler Thromb Vasc Biol. 2013;33(2):e47–55.CrossRefPubMedGoogle Scholar
  64. 64.
    Hu LA, Fu Y, Zhang DN, Zhang J. Serum IL-33 as a diagnostic and prognostic marker in non- small cell lung cancer. Asian Pac J Cancer Prev. 2013;14(4):2563–6.CrossRefPubMedGoogle Scholar
  65. 65.
    Liu J, Shen JX, JL H, Huang WH, Zhang GJ. Significance of interleukin-33 and its related cytokines in patients with breast cancers. Front Immunol. 2014;5:141.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Yu XX, Hu Z, Shen X, Dong LY, Zhou WZ, Hu WH. IL-33 promotes gastric cancer cell invasion and migration via ST2-ERK1/2 pathway. Dig Dis Sci. 2015;60(5):1265–72.CrossRefPubMedGoogle Scholar
  67. 67.
    Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Cespedes MV, et al. Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012;22(5):571–84.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Bergis D, Kassis V, Ranglack A, Koeberle V, Piiper A, Kronenberger B, et al. High serum levels of the interleukin-33 receptor soluble ST2 as a negative prognostic factor in hepatocellular carcinoma. Transl Oncol. 2013;6(3):311–8.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    DP L, Zhou XY, Yao LT, Liu CG, Ma W, Jin F, et al. Serum soluble ST2 is associated with ER-positive breast cancer. BMC Cancer. 2014;14:198.CrossRefGoogle Scholar
  70. 70.
    Ishikawa K, Yagi-Nakanishi S, Nakanishi Y, Kondo S, Tsuji A, Endo K, et al. Expression of interleukin-33 is correlated with poor prognosis of patients with squamous cell carcinoma of the tongue. Auris Nasus Larynx. 2014;41(6):552–7.CrossRefPubMedGoogle Scholar
  71. 71.
    Brunner SM, Rubner C, Kesselring R, Martin M, Griesshammer E, Ruemmele P, et al. Tumor-infiltrating, interleukin-33-producing effector-memory CD8(+) T cells in resected hepatocellular carcinoma prolong patient survival. Hepatology. 2015;61(6):1957–67.CrossRefPubMedGoogle Scholar
  72. 72.
    Chen SF, Nieh S, Jao SW, MZ W, Liu CL, Chang YC, et al. The paracrine effect of cancer-associated fibroblast-induced interleukin-33 regulates the invasiveness of head and neck squamous cell carcinoma. J Pathol. 2013;231(2):180–9.CrossRefPubMedGoogle Scholar
  73. 73.
    Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an oncogene. Cell. 1999;98(3):295–303.CrossRefPubMedGoogle Scholar
  74. 74.
    Taniguchi K, Karin M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol. 2014;26(1):54–74.CrossRefPubMedGoogle Scholar
  75. 75.
    Belluco C, Nitti D, Frantz M, Toppan P, Basso D, Plebani M, et al. Interleukin-6 blood level is associated with circulating carcinoembryonic antigen and prognosis in patients with colorectal cancer. Ann Surg Oncol. 2000;7(2):133–8.CrossRefPubMedGoogle Scholar
  76. 76.
    Putoczki TL, Thiem S, Loving A, Busuttil RA, Wilson NJ, Ziegler PK, et al. Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell. 2013;24(2):257–71.CrossRefPubMedGoogle Scholar
  77. 77.
    Musolino C, Allegra A, Profita M, Alonci A, Saitta S, Russo S, et al. Reduced IL-33 plasma levels in multiple myeloma patients are associated with more advanced stage of disease. Br J Haematol. 2013;160(5):709–10.CrossRefPubMedGoogle Scholar
  78. 78.
    Tseng-Rogenski SS, Hamaya Y, Choi DY, Carethers JM. Interleukin 6 alters localization of hMSH3, leading to DNA mismatch repair defects in colorectal cancer cells. Gastroenterology. 2015;148(3):579–89.CrossRefPubMedGoogle Scholar
  79. 79.
    He B, You L, Uematsu K, Zang K, Xu Z, Lee AY, et al. SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci U S A. 2003;100(24):14133–8.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Rebouissou S, Amessou M, Couchy G, Poussin K, Imbeaud S, Pilati C, et al. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature. 2009;457(7226):200–4.CrossRefPubMedGoogle Scholar
  81. 81.
    Rutz S, Wang X, Ouyang W. The IL-20 subfamily of cytokines—from host defence to tissue homeostasis. Nat Rev Immunol. 2014 Dec;14(12):783–95.CrossRefPubMedGoogle Scholar
  82. 82.
    McGee HM, Schmidt BA, Booth CJ, Yancopoulos GD, Valenzuela DM, Murphy AJ, et al. IL-22 promotes fibroblast-mediated wound repair in the skin. J Invest Dermatol. 2013;133(5):1321–9.CrossRefPubMedGoogle Scholar
  83. 83.
    Liao C, ZB Y, Meng G, Wang L, Liu QY, Chen LT, et al. Association between Th17-related cytokines and risk of non-small cell lung cancer among patients with or without chronic obstructive pulmonary disease. Cancer. 2015;121(Suppl 17):3122–9.CrossRefPubMedGoogle Scholar
  84. 84.
    Wu T, Cui L, Liang Z, Liu C, Liu Y, Li J. Elevated serum IL-22 levels correlate with chemoresistant condition of colorectal cancer. Clin Immunol. 2013;147(1):38–9.CrossRefPubMedGoogle Scholar
  85. 85.
    Wu T, Wang Z, Liu Y, Mei Z, Wang G, Liang Z, et al. Interleukin 22 protects colorectal cancer cells from chemotherapy by activating the STAT3 pathway and inducing autocrine expression of interleukin 8. Clin Immunol. 2014;154(2):116–26.CrossRefPubMedGoogle Scholar
  86. 86.
    Nardinocchi L, Sonego G, Passarelli F, Avitabile S, Scarponi C, Failla CM, et al. Interleukin-17 and interleukin-22 promote tumor progression in human nonmelanoma skin cancer. Eur J Immunol. 2015;45(3):922–31.CrossRefPubMedGoogle Scholar
  87. 87.
    Kirchberger S, Royston DJ, Boulard O, Thornton E, Franchini F, Szabady RL, et al. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J Exp Med. 2013;210(5):917–31.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Park O, Wang H, Weng H, Feigenbaum L, Li H, Yin S, et al. In vivo consequences of liver-specific interleukin-22 expression in mice: Implications for human liver disease progression. Hepatology. 2011;54(1):252–61.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Massague J. TGFbeta in cancer. Cell. 2008;134(2):215–30.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 2013;14(6):e218–28.CrossRefPubMedGoogle Scholar
  91. 91.
    Principe DR, Doll JA, Bauer J, Jung B, Munshi HG, Bartholin L, et al. TGF-beta: duality of function between tumor prevention and carcinogenesis. J Natl Cancer Inst. 2014;106(2):djt369.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Itatani Y, Kawada K, Fujishita T, Kakizaki F, Hirai H, Matsumoto T, et al. Loss of SMAD4 from colorectal cancer cells promotes CCL15 expression to recruit CCR1+ myeloid cells and facilitate liver metastasis. Gastroenterology. 2013;145(5):1064–75.e11.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Department of PathologyOslo University HospitalOsloNorway

Personalised recommendations