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01-12-2017 | Original Article

Upregulation of Treg-Related Genes in Addition with IL6 Showed the Significant Role for the Distant Metastasis in Colorectal Cancer

Authors: L. D. Miteva, N. S. Stanilov, G. М. Cirovski, Spaska Angelova Stanilova

Published in: Cancer Microenvironment | Issue 1-3/2017

Abstract

T helper 17 (Th17) and T regulatory (Treg) cytokines appear to be contributing greatly to colorectal cancer (CRC) development and progression. The aim of the current study was to investigate the expression of Foxp3; IL10; TGFB1; IL17A; IL6 and NOS2 genes in tumor tissue, regional positive lymph nodes and distant metastasis obtained from 26 patients with advanced CRC. Quantitative real-time polymerase chain reaction (qPCR) was performed for mRNA detection by TaqMan gene expression assay. In distant metastasis, IL6 was strongly expressed, over 7.5 fold, followed by Treg-related genes Foxp3; IL10 and TGFB1 in contrast to IL17A and NOS2. The similar pattern of expression was observed in positive regional lymph node in addition to significant down-regulation of NOS2 (RQ = 0.287; p = 0.011) and a trend for the elevation of IL17A. In tumor tissue, Fopx3 was significantly upregulated and Foxp3 mRNA positively correlated with TGFB1 in all investigated tissue types. In tumor tissue, expression of IL17A was correlated with NOS2 (r = 0.68; p = 0.005), while in distant metastasis IL10 was in strong relation with TGFB1 and IL6. In addition, a reverse correlation between IL6 and NOS2 (r = −0.66; p = 0.009), was observed in distant metastasis. The simultaneous expression of given Treg and Th17-related genes found both in the primary tumor and in the regional lymph nodes appears to provide suitable microenvironment sufficient for promoting metastatic growth. The upregulation of Foxp3; IL10, TGFB1 and IL6 might be a transcriptional profile hallmark for colorectal metastases.

Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A (2009) Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30:1073–1081. https://doi.org/10.1093/carcin/bgp127. CrossRefPubMed

Mantovani A (2009) Cancer: inflaming metastasis. Nature 457:36–37. https://doi.org/10.1038/457036b CrossRefPubMed

Dobrzanski MJ (2013) Expanding roles for CD4 T cells and their subpopulations in tumor immunity and therapy. Front Oncol 3:63. https://doi.org/10.3389/fonc.2013.00063 CrossRefPubMedPubMedCentral

Betts G, Jones E, Junaid S, El-Shanawany T, Scurr M, Mizen P, Kumar M, Jones S, Rees B, Williams G, Gallimore A, Godkin A (2012) Suppression of tumour-specific CD4⁺ T cells by regulatory T cells is associated with progression of human colorectal cancer. Gut 61:1163–1171. https://doi.org/10.1136/gutjnl-2011-300970 CrossRefPubMed

Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899. https://doi.org/10.1016/j.cell.2010.01.025 CrossRefPubMedPubMedCentral

Omenetti S, Pizarro TT (2015) The Treg/Th17 Axis: a dynamic balance regulated by the gut microbiome. Front Immunol 6:639. https://doi.org/10.3389/fimmu.2015.00639 CrossRefPubMedPubMedCentral

Manel N, Unutmaz D, Littmanet DR (2008) The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORγt. Nat Immunol 9:641–649. https://doi.org/10.1038/ni.1610 CrossRefPubMedPubMedCentral

de Leeuw RJ, Kost SE, Kakal JA, Nelson BH (2012) The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin Cancer Res 18:3022–3029. https://doi.org/10.1158/1078-0432.CCR-11-3216 CrossRef

Frey DM, Droeser RA, Viehl CT, Zlobec I, Lugli A, Zingg U, Oertli D, Kettelhack C, Terracciano L, Tornillo L (2010) High frequency of tumor-infiltrating FOXP3 (+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer 126:2635–2643. https://doi.org/10.1002/ijc.24989 PubMed

10.

Shang B, Liu Y, Jiang SJ, Liu Y (2015) Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep 5:15179. https://doi.org/10.1038/srep15179 CrossRefPubMedPubMedCentral

11.

Amicarella F, Muraro MG, Hirt C, Cremonesi E, Padovan E, Mele V, Governa V, Han J, Huber X, Droeser RA, Zuber M, Adamina M, Bolli M, Rosso R, Lugli A, Zlobec I, Terracciano L, Tornillo L, Zajac P, Eppenberger-Castori S, Trapani F, Oertli D, Iezzi G (2017) Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer. Gut 66:692–704. https://doi.org/10.1136/gutjnl-2015-310016 CrossRefPubMed

12.

Wang J, Xu K, Wu J, Luo C, Li Y, Wu X, Gao H, Feng G, Yuan BZ (2012) The changes of Th17 cells and the related cytokines in the progression of human colorectal cancer. BMC Cancer 12:418. https://doi.org/10.1186/1471-2407-12-418 CrossRefPubMedPubMedCentral

13.

Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pagès F, Galon J (2011) Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, Th2, Treg, Th17) in patients with colorectal cancer. Cancer Res 71:1263–1271. https://doi.org/10.1158/0008-5472.CAN-10-2907 CrossRefPubMed

14.

Brucklacher-Waldert V, Carr EJ, Linterman MA, Veldhoen M (2014) Cellular plasticity of CD4+ T cells in the intestine. Front Immunol 5:488. https://doi.org/10.3389/fimmu.2014.00488 eCollection 2014CrossRefPubMedPubMedCentral

15.

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-(Delta Delta C(T)) method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262 CrossRefPubMed

16.

Ling KL, Pratap SE, Bates GJ, Singh B, Mortensen NJ, George BD, Warren BF, Piris J, Roncador G, Fox SB, Banham AH, Cerundolo V (2007) Increased frequency of regulatory T cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients. Cancer Immun 7:7PubMedPubMedCentral

17.

Colombo MP, Piconese S (2007) Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nat Rev Cancer 7:880–887. https://doi.org/10.1038/nrc2250 CrossRefPubMed

18.

Deng L, Zhang H, Luan Y, Zhang J, Xing Q, Dong S, Wu X, Liu M, Wang S (2010) Accumulation of Foxp3+ T regulatory cells in draining lymph nodes correlates with disease progression and immune suppression in colorectal cancer patients. Clin Cancer Res 16:4105–4112. https://doi.org/10.1158/1078-0432.CCR-10-1073 CrossRefPubMed

19.

Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27:186–192. https://doi.org/10.1200/JCO.2008.18.7229 CrossRefPubMed

20.

Kim M, Grimmig T, Grimm M, Lazariotou M, Meier E, Rosenwald A, Tsaur I, Blaheta R, Heemann U, Germer CT, Waaga-Gasser AM, Gasser M (2013) Expression of Foxp3 in colorectal cancer but not in Treg cells correlates with disease progression in patients with colorectal cancer. PLoS One 8:e53630. https://doi.org/10.1371/journal.pone.0053630 CrossRefPubMedPubMedCentral

21.

Miossec P, Kolls JK (2012) Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov 11:763–776. https://doi.org/10.1038/nrd3794 CrossRefPubMed

22.

Kryczek I, Wu K, Zhao E, Wei S, Vatan L, Szeliga W, Huang E, Greenson J, Chang A, Roliński J, Radwan P, Fang J, Wang G, Zou W (2011) IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. J Immunol 186:4388–4395. https://doi.org/10.4049/jimmunol.1003251 CrossRefPubMed

23.

Stanilov N, Miteva L, Mintchev N, Stanilova S (2009) High expression of Foxp3, IL-23p19 and survivin mRNA in colorectal carcinoma. Int J Color Dis 24:151–157. https://doi.org/10.1007/s00384-008-0588-8 CrossRef

24.

Miteva LD, Stanilov NS, Deliysky TS, Stanilova SA (2014) Significance of -1082A/G polymorphism of IL10 gene for progression of colorectal cancer and IL-10 expression. Tumour Biol 35:12655–12664. https://doi.org/10.1007/s13277-014-2589-2 CrossRefPubMed

25.

Kimura A, Kishimoto T (2010) IL-6: regulator of Treg/Th17 balance. Eur J Immunol 40:1830–1835. https://doi.org/10.1002/eji.201040391 CrossRefPubMed

26.

Duhen T, Duhen R, Lanzavecchia A, Sallusto F, Campbell DJ (2012) Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood 119:4430–4440. https://doi.org/10.1182/blood-2011-11-392324 CrossRefPubMedPubMedCentral

27.

Barbi J, Pardoll D, Pan F (2013) Metabolic control of the Treg/Th17 axis. Immunol Rev 252:52–77. https://doi.org/10.1111/imr.12029 CrossRefPubMedPubMedCentral

28.

Obermajer N, Wong JL, Edwards RP, Chen K, Scott M, Khader S, Kolls JK, Odunsi K, Billiar TR, Kalinski P (2013) Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling. J Exp Med 210:1433–1445. https://doi.org/10.1084/jem.20121277 CrossRefPubMedPubMedCentral

Title: Upregulation of Treg-Related Genes in Addition with IL6 Showed the Significant Role for the Distant Metastasis in Colorectal Cancer
Authors: L. D. Miteva
N. S. Stanilov
G. М. Cirovski
Spaska Angelova Stanilova
Publication date: 01-12-2017
Publisher: Springer Netherlands
Published in: Cancer Microenvironment / Issue 1-3/2017
Print ISSN: 1875-2292
Electronic ISSN: 1875-2284
DOI: https://doi.org/10.1007/s12307-017-0198-5

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