Inflammation, cytokines, the IL-17/IL-6/STAT3/NF-κB axis, and tumorigenesis
Authors Chen X, Zhou S
Received 27 April 2015
Accepted for publication 28 April 2015
Published 8 June 2015 Volume 2015:9 Pages 2941—2946
Checked for plagiarism Yes
Xiao-Wu Chen,1 Shu-Feng Zhou2
1Department of General Surgery, The First People’s Hospital of Shunde, Southern Medical University, Shunde, Foshan, Guangdong, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
In the recently published paper by Xie et al1 in the journal of Drug Design, Development and Therapy, the authors have evaluated interleukin (IL)-17–driven inflammatory responses in 17 cases of human colon adenocarcinomas, 16 cases of human normal colon tissues adjacent to the resected colon adenocarcinomas, ten cases of human ulcerative colitis tissues from biopsies, and eight cases of human benign colon polyps. The authors have observed that human colon adenocarcinomas contained the highest levels of IL-17, which was significantly higher than the IL-17 level in the adenomas, ulcerative colitis, and normal colon tissues (P<0.01). The levels of IL-17 receptor A (IL-17RA) were also the highest in human colon adenocarcinomas, followed by adenomas and ulcerative colitis. The increased level of IL-17 and IL-17RA was accompanied with increased IL-17–driven inflammatory responses, including activation of extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase pathways, increased expression of matrix metalloproteinase (MMP)-9, MMP-7, MMP-2, B-cell lymphoma, and cyclin D1, decreased expression of Bcl-2-associated X protein, and increased expression of vascular endothelial growth factor (VEGF) and VEGF receptor expression that were associated with increased angiogenesis.1 These data suggest that IL-17–driven inflammatory responses contribute to the initiation, growth, development, and metastasis of colon cancer. IL-17 and its related signaling pathways may serve as promising novel targets in the development of drugs for the prevention and treatment of colon cancer.
The authors have no conflicts of interest in this work.
Xie Z, Qu Y, Leng Y, et al. Human colon carcinogenesis is associated with increased interleukin-17-driven inflammatory responses. Drug Des Devel Ther. 2015;9:1679–1689.
Tartour E, Fossiez F, Joyeux I, et al. Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Res. 1999;59(15):3698–3704.
Iwakura Y, Ishigame H, Saijo S, Nakae S. Functional specialization of interleukin-17 family members. Immunity. 2011;34(2):149–162.
Yang B, Kang H, Fung A, Zhao H, Wang T, Ma D. The role of interleukin 17 in tumour proliferation, angiogenesis, and metastasis. Mediators Inflamm. 2014;2014:623759.
Chang SH, Dong C. Signaling of interleukin-17 family cytokines in immunity and inflammation. Cell Signal. 2011;23(7):1069–1075.
Xu S, Cao X. Interleukin-17 and its expanding biological functions. Cell Mol Immunol. 2010;7(3):164–174.
Reynolds JM, Angkasekwinai P, Dong C. IL-17 family member cytokines: regulation and function in innate immunity. Cytokine Growth Factor Rev. 2010;21(6):413–423.
Camporeale A, Poli V. IL-6, IL-17 and STAT3: a holy trinity in auto-immunity? Front Biosci (Landmark Ed). 2012;17:2306–2326.
Maniati E, Soper R, Hagemann T. Up for mischief? IL-17/Th17 in the tumour microenvironment. Oncogene. 2010;29(42):5653–5662.
Murugaiyan G, Saha B. Protumor vs antitumor functions of IL-17. J Immunol. 2009;183(7):4169–4175.
Dong C. Regulation and pro-inflammatory function of interleukin-17 family cytokines. Immunol Rev. 2008;226:80–86.
Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer. 2014;14(11):736–746.
Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9(11):798–809.
Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med. 2009;206(7):1457–1464.
O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 2013;368(2):161–170.
Talmadge JE, Gabrilovich DI. History of myeloid-derived suppressor cells. Nat Rev Cancer. 2013;13(10):739–752.
Diaz-Montero CM, Finke J, Montero AJ. Myeloid-derived suppressor cells in cancer: therapeutic, predictive, and prognostic implications. Semin Oncol. 2014;41(2):174–184.
Kryczek I, Wei S, Szeliga W, Vatan L, Zou W. Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood. 2009;114(2):357–359.
Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 2014;15(11):e493–e503.
Atsumi T, Singh R, Sabharwal L, et al. Inflammation amplifier, a new paradigm in cancer biology. Cancer Res. 2014;74(1):8–14.
Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13(11):759–771.
Candido J, Hagemann T. Cancer-related inflammation. J Clin Immunol. 2013;33 Suppl 1:S79–S84.
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–899.
Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–444.
Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–867.
Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539–545.
Silva J, Cerqueira F, Medeiros R. Chlamydia trachomatis infection: implications for HPV status and cervical cancer. Arch Gynecol Obstet. 2014;289(4):715–723.
Sears CL, Geis AL, Housseau F. Bacteroides fragilis subverts mucosal biology: from symbiont to colon carcinogenesis. J Clin Invest. 2014;124(10):4166–4172.
Woodman CB, Collins SI, Young LS. The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer. 2007;7(1):11–22.
Polk DB, Peek RM Jr. Helicobacter pylori: gastric cancer and beyond. Nat Rev Cancer. 2010;10(6):403–414.
Arzumanyan A, Reis HM, Feitelson MA. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer. 2013;13(2):123–135.
Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer. 2004;4(10):757–768.
Mesri EA, Cesarman E, Boshoff C. Kaposi’s sarcoma and its associated herpesvirus. Nat Rev Cancer. 2010;10(10):707–719.
Boshoff C, Weiss R. AIDS-related malignancies. Nat Rev Cancer. 2002;2(5):373–382.
Qayyum S, Choi JK. Adult T-cell leukemia/lymphoma. Arch Pathol Lab Med. 2014;138(2):282–286.
Moens U, Rasheed K, Abdulsalam I, Sveinbjørnsson B. The role of Merkel cell polyomavirus and other human polyomaviruses in emerging hallmarks of cancer. Viruses. 2015;7(4):1871–1901.
Rosin MP, Anwar WA, Ward AJ. Inflammation, chromosomal instability, and cancer: the schistosomiasis model. Cancer Res. 1994;54(7 Suppl):1929s–1933s.
Sithithaworn P, Yongvanit P, Duenngai K, Kiatsopit N, Pairojkul C. Roles of liver fluke infection as risk factor for cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2014;21(5):301–308.
Decramer M, Janssens W. Chronic obstructive pulmonary disease and comorbidities. Lancet Respir Med. 2013;1(1):73–83.
Houghton AM. Mechanistic links between COPD and lung cancer. Nat Rev Cancer. 2013;13(4):233–245.
Park J, Morley TS, Kim M, Clegg DJ, Scherer PE. Obesity and cancer – mechanisms underlying tumour progression and recurrence. Nat Rev Endocrinol. 2014;10(8):455–465.
Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185.
Gorbachev AV, Fairchild RL. Regulation of chemokine expression in the tumor microenvironment. Crit Rev Immunol. 2014;34(2):103–120.
Blonska M, Agarwal NK, Vega F. Shaping of the tumor microenvironment: stromal cells and vessels. Semin Cancer Biol. Epub 2015 Mar 18.
Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49–61.
Ostuni R, Kratochvill F, Murray PJ, Natoli G. Macrophages and cancer: from mechanisms to therapeutic implications. Trends Immunol. 2015;36(4):229–239.
Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27(4):462–472.
Whiteside TL. Regulatory T cell subsets in human cancer: are they regulating for or against tumor progression? Cancer Immunol Immunother. 2014;63(1):67–72.
Fisher DT, Appenheimer MM, Evans SS. The two faces of IL-6 in the tumor microenvironment. Semin Immunol. 2014;26(1):38–47.
Chang Q, Daly L, Bromberg J. The IL-6 feed-forward loop: a driver of tumorigenesis. Semin Immunol. 2014;26(1):48–53.
Ngiow SF, Teng MW, Smyth MJ. A balance of interleukin-12 and -23 in cancer. Trends Immunol. 2013;34(11):548–555.
Bierie B, Moses HL. Transforming growth factor beta (TGF-beta) and inflammation in cancer. Cytokine Growth Factor Rev. 2010;21(1):49–59.
Drabsch Y, ten Dijke P. TGF-β signalling and its role in cancer progression and metastasis. Cancer Metastasis Rev. 2012;31(3–4):553–568.
Chandrakumar SF, Yeung J. Interleukin-17 antagonists in the treatment of psoriasis. J Cutan Med Surg. 2015;19(2):109–114.
Huynh D, Kavanaugh A. Psoriatic arthritis: current therapy and future approaches. Rheumatology (Oxford). 2015;54(1):20–28.
Jacobs A, Rosumeck S. Systematic review and meta-analysis of ustekinumab for moderate to severe psoriasis: comment. Clin Exp Dermatol. 2015.
Zarogoulidis P, Katsikogianni F, Tsiouda T, Sakkas A, Katsikogiannis N, Zarogoulidis K. Interleukin-8 and interleukin-17 for cancer. Cancer Invest. 2014;32(5):197–205.
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