Skip to main content

Advertisement

SpringerLink
Log in

Dynamic changes of peritoneal macrophages and subpopulations during ulcerative colitis to metastasis of colorectal carcinoma in a mouse model

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective and design

Patients with ulcerative colitis have increased risk of colorectal carcinoma, but little is known about how peritoneal macrophages are involved in ulcerative colitis-associated carcinogenesis. We investigated the alteration of peritoneal macrophages and M1/M2 subpopulations during ulcerative colitis-associated carcinogenesis.

Materials and methods

Expression and functional changes in peritoneal macrophages and M1/M2 subpopulations were investigated by histopathology, flow cytometry, immunofluorescence, cytokines expression by ELISA and QRT-PCR in an azoxymethane (AOM)- and dextran sodium sulfate (DSS)-induced chemical colitis-associated carcinoma mouse model using male Crj:CD-1 (ICR) mice.

Results

Striking evidence observed in histopathology, flow cytometry, cytokine detection, and gene expression analysis all revealed that inflammation-associated cytokines (IL-1β, IL-10, IL-12, IL-6, TNF-α) and migration/invasion-associated factors (G-CSF, GM-CSF, CXCR4, VEGF, TGF-β, ICAM-1) induced by peritoneal M2 macrophages increased significantly during the progression from inflammatory hyperplasia to carcinoma and metastasis. Similar functional changes occurred during peritoneal metastasis in M1 macrophages without changed polarization.

Conclusions

These results suggested that peritoneal M2 macrophages played a critical role in ulcerative colitis-associated carcinogenesis, including unbalanced pro-inflammatory and anti-inflammatory axis and enhanced expression of migration/invasion-associated factors. Furthermore, functional changes of M1 macrophages occurred without changed polarization during carcinogenesis and metastasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Nathan C, Ding A. Nonresolving inflammation. Cell. 2010;140:871–82.

    Article  PubMed  CAS  Google Scholar 

  2. Rod R. Crohn’s disease and ulcerative colitis: morbidity and mortality. Health Rep. 1990;2:343–59.

    Google Scholar 

  3. Loftus EV. J Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504–17.

    Article  PubMed  Google Scholar 

  4. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46–54.

    Article  PubMed  Google Scholar 

  5. Hanauer S. Inflammatory bowel disease: epidemiology, pathogenesis and therapeutic opportunities. Inflamm Bowel Dis. 2006;12:S3–9.

    Article  PubMed  Google Scholar 

  6. Lakatos L, Mester G, Erdelyi Z, et al. Risk factors for ulcerative colitis-associated colorectal cancer in a Hungarian cohort of patients with ulcerative colitis: results of a population-based study. Inflamm Bowel Dis. 2006;12:205–11.

    Article  PubMed  Google Scholar 

  7. Lakatos PL, Lakatos L. Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. World J Gastroenterol. 2008;14:3937–47.

    Article  PubMed  Google Scholar 

  8. Jemal A, Bray F, Center MM, et al. Global Cancer Statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  9. Gong W, Lv N, Wang B, et al. Risk of ulcerative colitis-associated colorectal cancer in China: a multi-center retrospective study. Dig Dis Sci. 2012;57:503–7.

    Article  PubMed  Google Scholar 

  10. Zisman TL, Rubin DT. Colorectal cancer and dysplasia in inflammatory bowel disease. World J Gastroenterol. 2008;14:2662–9.

    Article  PubMed  Google Scholar 

  11. Karin M. Nuclear factor-kappa B in cancer development and progression. Nature. 2006;441:431–6.

    Article  PubMed  CAS  Google Scholar 

  12. Pikarsky E, Porat RM, Stein I, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431:461–6.

    Article  PubMed  CAS  Google Scholar 

  13. Bollrath J, Phesse TJ, von Burstin VA, et al. gp130-Mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumor genesis. Cancer Cell. 2009;15:91–102.

    Article  PubMed  CAS  Google Scholar 

  14. Grivennikov S, Karin E, Terzic J, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009;15:103–13.

    Article  PubMed  CAS  Google Scholar 

  15. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007;369:1641–57.

    Article  PubMed  CAS  Google Scholar 

  16. Siveen KS, Kuttan G. Role of macrophages in tumour progression. Immunol Lett. 2009;123:97–102.

    Article  PubMed  CAS  Google Scholar 

  17. Xie J, Itzkowitz SH. Cancer in inflammatory bowel disease. World J Gastroenterol. 2008;14:378–89.

    Article  PubMed  CAS  Google Scholar 

  18. Bar-On L, Zigmond E, Jung S. Management of gut inflammation through the manipulation of intestinal dendritic cells and macrophages? Semin Immunol. 2011;23:58–64.

    Article  PubMed  CAS  Google Scholar 

  19. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.

    Article  PubMed  CAS  Google Scholar 

  20. Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011;11:750–61.

    Article  PubMed  CAS  Google Scholar 

  21. Martinez FO, Sica A, Mantovani A, et al. Macrophage activation and polarization. Front Biosci. 2008;1:453–61.

    Article  Google Scholar 

  22. Sica A, Schioppa T, Mantovani A, et al. Tumor associated macrophages are a distinct M2 polarised population promoting tumor progression: potential targets of anti-cancer therapy. Eur J Cancer. 2006;42:717–27.

    Article  PubMed  CAS  Google Scholar 

  23. Bailey C, Negus R, Morris A, et al. Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer. Clin Exp Metast. 2007;24:121–30.

    Article  CAS  Google Scholar 

  24. Solinas G, Germano G, Mantovani A, et al. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 2009;86:1065–73.

    Article  PubMed  CAS  Google Scholar 

  25. Green CE, Liu T, Montel V, et al. Chemoattractant signaling between tumor cells and macrophages regulated cancer cell migration, metastasis and neovascularization. PLoS ONE. 2009;4:e6713.

    Article  PubMed  Google Scholar 

  26. Wirtz S, Neufert C, Weigmann B, et al. Chemically induced mouse models of intestinal inflammation. Nat Protoc. 2007;2:541–6.

    Article  PubMed  CAS  Google Scholar 

  27. Cooper HS, Murthy SN, Shah RS, et al. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest. 1993;69:238–49.

    PubMed  CAS  Google Scholar 

  28. Clapper ML, Cooper HS, Chang WC. Dextran sulfate sodium-induced colitis-associated neoplasia: a promising model for the development of chemopreventive interventions. Acta Pharmacol Sin. 2007;28:1450–9.

    Article  PubMed  CAS  Google Scholar 

  29. Lai CS, Tsai ML, Cheng AC, et al. Chemoprevention of colonic tumorigenesis by dietary hydroxylated polymethoxyflavones in azoxymethane-treated mice. Mol Nutr Food Res. 2011;55:278–90.

    Article  PubMed  CAS  Google Scholar 

  30. Tang A, Li N, Li X, et al. Dynamic activation of the key pathways: linking colitis to colorectal cancer in a mouse mode. Carcinogenesis. 2012;33:1375–83.

    Article  PubMed  CAS  Google Scholar 

  31. Hanahan D, Weinberg RA. Hallmarks of Cancer: the next generation. Cell. 2011;144:646–74.

    Article  PubMed  CAS  Google Scholar 

  32. Lutgens MW, Vleggaar FP, Schipper ME, et al. High frequency of early colorectal cancer in inflammatory bowel disease. Gut. 2008;57:1246–51.

    Article  PubMed  CAS  Google Scholar 

  33. Forssell J, Oberg A, Henriksson ML, et al. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res. 2007;13:1472–9.

    Article  PubMed  CAS  Google Scholar 

  34. Mantovani A, Sica A, Locati M. Macrophage polarization comes of age. Immunity. 2005;23:344–6.

    Article  PubMed  CAS  Google Scholar 

  35. Mantovani A. Inflammation and cancer: the macrophage connection. Medicina. 2007;67:32–4.

    CAS  Google Scholar 

  36. Erreni M, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) and inflammation in colorectal cancer. Cancer Microenviron. 2011;4:141–54.

    Article  PubMed  CAS  Google Scholar 

  37. Moriya M, Harada T, Shirasu Y. Inhibition of carcinogenicities of 1,2-dimethylhydrazine and azoxymethane by pyrazole. Cancer Lett. 1982;17:147–52.

    Article  PubMed  CAS  Google Scholar 

  38. Sugie S, Mori Y, Okumura A, et al. Promoting and synergistic effects of chrysazin on 1,2-dimethylhydrazine-induced carcinogenesis in male ICR/CD-1 mice. Carcinogenesis. 1994;15:1175–9.

    Article  PubMed  CAS  Google Scholar 

  39. Nardin A, Abastado JP. Macrophages and cancer. Front Biosci. 2008;13:3494–505.

    Article  PubMed  CAS  Google Scholar 

  40. Sica A, Allavena P, Mantovani A. Cancer related inflammation: the macrophage connection. Cancer Lett. 2008;267:204–15.

    Article  PubMed  CAS  Google Scholar 

  41. Imtiyaz HZ, Williams EP, Hickey MM, et al. Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest. 2010;120:2699–714.

    Article  PubMed  CAS  Google Scholar 

  42. Low-Marchelli JM, Ardi VC, Vizcarra EA, et al. Twist1 induces CCL2 and recruits macrophages to promote angiogenesis. Cancer Res. 2013;73:662–71.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by National Natural Science Foundation of China (81172300, 81272975, 81272736), Key Project of Hunan Provincial Natural Science Foundation (12JJ2044), Project of Hunan Provincial Development and Reform Commission, Hunan Provincial Innovation Foundation for Postgraduate (CX2011B073), and Mittal Student Innovation Project (11MX25). We are grateful to the members of our laboratory, Professor Songqing Fan and Lei Shi (The Second Xiangya Hospital), and technical support of Beckman Coulter and Medjaden Bioscience Limited.

Conflict of interest

The authors have no financial or other potential conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China

    Wei Wang, Xiayu Li, Decai Zhang, Shuo Huang, Xuemei Zhang, Feiyan Ai, Xiaoyan Wang & Shourong Shen

  2. Key Laboratory of Carcinogenesis, Ministry of Health, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Institute of Cancer Research, Central South University, No. 110 of Xiangya Road, Changsha, 410078, Hunan, China

    Danwei Zheng, Jian Ma, Wei Xiong, Yanhong Zhou & Guiyuan Li

  3. Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China

    Wei Wang, Xiayu Li, Decai Zhang, Shuo Huang, Xuemei Zhang, Feiyan Ai, Xiaoyan Wang, Jian Ma, Wei Xiong, Yanhong Zhou, Guiyuan Li & Shourong Shen

Authors
  1. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiayu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Danwei Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Decai Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shuo Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xuemei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Feiyan Ai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaoyan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jian Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wei Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yanhong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Guiyuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shourong Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yanhong Zhou or Shourong Shen.

Additional information

Responsible Editor: Michael J. Parnham.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 46 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, W., Li, X., Zheng, D. et al. Dynamic changes of peritoneal macrophages and subpopulations during ulcerative colitis to metastasis of colorectal carcinoma in a mouse model. Inflamm. Res. 62, 669–680 (2013). https://doi.org/10.1007/s00011-013-0619-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-013-0619-y

Keywords

Search

Navigation