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Changes of T Cells and Cytokines TGF-β1 and IL-10 in Mice During Liver Metastasis of Colon Carcinoma: Implications for Liver Anti-tumor Immunity

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Journal of Gastrointestinal Surgery Aims and scope

Abstract

Background

The local and systemic regulation of the immune system may play important roles in the process of liver metastasis of colorectal carcinoma. The aim of this study was to establish a reproducible experimental liver metastasis model, to identify changes in T cells and cytokines TGF-β1 and IL-10, and to explore a possible mechanism of liver metastasis of colon carcinoma.

Methods

We used a colon carcinoma liver metastasis model, in which different numbers of CT-26 murine colon carcinoma cells (1 × 103, 5 × 103, 1 × 104, 5 × 104, and 1 × 105) were injected into the spleen. The liver and spleen tissues were examined for T cell markers using flow cytometry. Liver tissues were analyzed for IL-10 and transforming growth factor beta 1 (TGF-β1) expression using immunohistochemistry.

Results

Spleen injection of colon carcinoma cells is a reproducible animal model for liver metastases, which resulted in quantity-dependent metastatic growth. We provided a snapshot of the hepatic immune microenvironment in the mouse liver metastasis model. Injection of A large number of tumor cells (5 × 104 and 1 × 105) decreased anti-tumor cell counts, such as CD4+ and CD8+ T cells, and increased immune-suppressive cell counts (CD4+CD25+ Treg cells). In addition, the expression levels of immunosuppressive cytokines IL-10 and TGF-β1 were also increased with the number of tumor cells.

Conclusions

Changes in the systemic and local immunological environment contribute to immunological escape mechanisms during liver metastasis of colon carcinoma, and therapies aiming at immune microenvironment may prove a useful strategy in the treatment of metastatic disease in the future.

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References

  1. Watanabe T, Kobunai T, Yamamoto Y, et al. Prediction of liver metastasis after colorectal cancer using reverse transcription-polymerase chain reaction analysis of 10 genes. Eur J Cancer, 2010; 46: 2119–26.

    Article  PubMed  CAS  Google Scholar 

  2. Kim J C, Roh S A, Kim H C, Coexpression of carcinoembryonic antigen and E-cadherin in colorectal adenocarcinoma with liver metastasis. J Gastrointest Surgs, 2003; 7:931–380.

    Article  Google Scholar 

  3. Anaya DA, Becker NS, Abraham NS. Global graying, colorectal cancer and liver metastasis: new implications for surgical management. Crit Rev Oncol Hematol, 2011; 77: 100–8.

    Article  PubMed  Google Scholar 

  4. de Jong GM, Aarts F, Hendriks T, et al. Animal models for liver metastases of colorectal cancer: research review of preclinical studies in rodents. J Surg Res, 2009; 154: 167–76.

    Article  PubMed  Google Scholar 

  5. Nathan H, de Jong MC, Pulitano C, et al. Conditional survival after surgical resection of colorectal liver metastasis: an international multi-institutional analysis of 949 patients. J Am Coll Surg, 2010; 210:755–66.

    Article  PubMed  Google Scholar 

  6. Sasaki A, Iwashita Y, Shibata K, et al. Analysis of preoperative prognostic factors for long-term survival after hepatic resection of liver metastasis of colorectal carcinoma. J Gastrointest Surg, 2005; 9:374–380.

    Article  PubMed  Google Scholar 

  7. Grimm M, Gasser M, Bueter M, et al. Evaluation of immunological escape mechanisms in a mouse model of colorectal liver metastases. BMC Cancer, 2010; 10: 82.

    Article  PubMed  Google Scholar 

  8. Kelly AM, Golden-Mason L, Traynor O, et al. Changes in hepatic immunoregulatory cytokines in patients with metastatic colorectal carcinoma: implications for hepatic anti-tumor immunity. Cytokine, 2006; 35:171–9.

    Article  PubMed  CAS  Google Scholar 

  9. Dunne J, Lynch S, O'Farrelly C, et al. Selective expansion and partial activation of human NK cells and NK receptor-positive T cells by IL-2 and IL-15. J Immunol, 2001; 167: 3129–38.

    PubMed  CAS  Google Scholar 

  10. Lutsiak ME, Semnani RT, De Pascalis R, et al. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood, 2005; 105: 2862–8.

    Article  PubMed  CAS  Google Scholar 

  11. Bierie B, Moses HL. Transforming growth factor beta (TGF-beta) and inflammation in cancer. Cytokine & Growth Factor Reviews, 2010; 21: 49–59.

    Article  CAS  Google Scholar 

  12. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature, 2003; 425: 577–84.

    Article  PubMed  CAS  Google Scholar 

  13. Yang L, Pang Y, Moses HL. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol, 2010; 31: 220–7.

    Article  PubMed  CAS  Google Scholar 

  14. Herbeuval JP, Lelievre E, Lambert C, et al. (2004) Recruitment of STAT3 for production of IL-10 by colon carcinoma cells induced by macrophage-derived IL-6. J Immunol, 172: 4630–6.

    PubMed  CAS  Google Scholar 

  15. Liu HY, Huang ZL, Yang GH, et al. Inhibitory effect of modified citrus pectin on liver metastases in a mouse colon cancer model. World J Gastroenterol, 2008. 14(48): p. 7386–91.

    Article  PubMed  CAS  Google Scholar 

  16. Kollmar O, Schilling MK, Menger MD. Experimental liver metastasis. Standards for local cell implantation to study isolated tumor growth in mice. Clin Exp Metastasis 2004; 5 :453–460.

    Article  Google Scholar 

  17. Disis ML, Bernhard H, Jaffee EM. Use of tumor-responsive T cells as cancer treatment. Lancet, 2009; 373: 673–83.

    Article  PubMed  CAS  Google Scholar 

  18. Ostrand-Rosenberg S. Immune surveillance: a balance between protumor and antitumor immunity. Current Opinion in Genetics & Development, 2008; 18:11–8.

    Article  CAS  Google Scholar 

  19. de la Cruz-Merino, L, et al. Immune microenvironment in colorectal cancer: a new hallmark to change old paradigms. Clin Dev Immunol, 2011. 2011: p. 174149.

    PubMed  Google Scholar 

  20. Folprecht G, Gruenberger T, Bechstein WO. Tumor response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol, 2010; 11: 38–47.

    Article  PubMed  CAS  Google Scholar 

  21. Midgley R, Kerr D. Immunotherapy for colorectal cancer: a challenge to clinical trial design. Lancet Oncol, 2000; 1: 159–68.

    Article  PubMed  CAS  Google Scholar 

  22. Almeida AR, et al. CD4(+)CD25(+) Treg regulate the contribution of CD8(+) T-cell subsets in repopulation of the lymphopenic environment. Eur J Immunol, 2010; 40:3478–88.

    Article  PubMed  CAS  Google Scholar 

  23. Zanin-Zhorov A, Ding Y, Kumari S, et al. Protein kinase C-theta mediates negative feedback on regulatory T cell function. Science, 2010; 328:372–6.

    Article  PubMed  CAS  Google Scholar 

  24. Bierie B, Moses HL. Tumor microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer, 2006; 6: 506–20.

    Article  PubMed  CAS  Google Scholar 

  25. Nagaraj NS, Datta PK. Targeting the transforming growth factor-beta signaling pathway in human cancer. Expert Opin Investig Drugs, 2010; 19: 77–91.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by the National Natural Scientific Foundation of China grant 81072046 and the Research Fund for the Doctoral Program of Higher Education of China 20100171110075 to Dr. P. Lan and Medical Scientific Research Foundation of Guangdong Province (#B2012149).

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Authors and Affiliations

  1. Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancunerheng Road, Guangzhou, 510655, People’s Republic of China

    Xiaoming Huang, Yifeng Zou, Lei Lian, Xiaojian Wu, Xiaosheng He, Xiaowen He, Xianrui Wu & Ping Lan

  2. Gastrointestinal Institute of Sun Yat-Sen University, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancunerheng Road, Guangzhou, 510655, People’s Republic of China

    Xiaoming Huang, Lei Lian, Xianrui Wu & Ping Lan

  3. Department of Pathology, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancunerheng Road, Guangzhou, 510655, People’s Republic of China

    Yan Huang

  4. Department of Colorectal Surgery, Gastrointestinal institute of Sun Yat-sen University, The Sixth Affiliated Hospital (Gastrointestinal and Anal Hospital) of Sun Yat-Sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, People’s Republic of China

    Ping Lan

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  1. Xiaoming Huang
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  2. Yifeng Zou
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  3. Lei Lian
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  5. Xiaosheng He
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  6. Xiaowen He
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  8. Yan Huang
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  9. Ping Lan
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Corresponding author

Correspondence to Ping Lan.

Additional information

Xiaoming Huang and Yifeng Zou contributed equally to this paper.

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Huang, X., Zou, Y., Lian, L. et al. Changes of T Cells and Cytokines TGF-β1 and IL-10 in Mice During Liver Metastasis of Colon Carcinoma: Implications for Liver Anti-tumor Immunity. J Gastrointest Surg 17, 1283–1291 (2013). https://doi.org/10.1007/s11605-013-2194-5

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  • DOI: https://doi.org/10.1007/s11605-013-2194-5

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