Inflammation Research

, Volume 62, Issue 7, pp 669–680 | Cite as

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

  • Wei Wang
  • Xiayu Li
  • Danwei Zheng
  • Decai Zhang
  • Shuo Huang
  • Xuemei Zhang
  • Feiyan Ai
  • Xiaoyan Wang
  • Jian Ma
  • Wei Xiong
  • Yanhong Zhou
  • Guiyuan Li
  • Shourong Shen
Original Research Paper
First Online:
Received:
Accepted:

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.

Keywords

Peritoneal macrophages Hyperplasia Dynamic changes Ulcerative colitis Carcinogenesis 
This is a preview of subscription content, log in to check access.

Notes

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.

Supplementary material

11_2013_619_MOESM1_ESM.doc (46 kb)
Supplementary material 1 (DOC 46 kb)

References

  1. 1.
    Nathan C, Ding A. Nonresolving inflammation. Cell. 2010;140:871–82.PubMedCrossRefGoogle Scholar
  2. 2.
    Rod R. Crohn’s disease and ulcerative colitis: morbidity and mortality. Health Rep. 1990;2:343–59.Google Scholar
  3. 3.
    Loftus EV. J Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504–17.PubMedCrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 5.
    Hanauer S. Inflammatory bowel disease: epidemiology, pathogenesis and therapeutic opportunities. Inflamm Bowel Dis. 2006;12:S3–9.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 7.
    Lakatos PL, Lakatos L. Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. World J Gastroenterol. 2008;14:3937–47.PubMedCrossRefGoogle Scholar
  8. 8.
    Jemal A, Bray F, Center MM, et al. Global Cancer Statistics. CA Cancer J Clin. 2011;61:69–90.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 10.
    Zisman TL, Rubin DT. Colorectal cancer and dysplasia in inflammatory bowel disease. World J Gastroenterol. 2008;14:2662–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Karin M. Nuclear factor-kappa B in cancer development and progression. Nature. 2006;441:431–6.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 15.
    Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007;369:1641–57.PubMedCrossRefGoogle Scholar
  16. 16.
    Siveen KS, Kuttan G. Role of macrophages in tumour progression. Immunol Lett. 2009;123:97–102.PubMedCrossRefGoogle Scholar
  17. 17.
    Xie J, Itzkowitz SH. Cancer in inflammatory bowel disease. World J Gastroenterol. 2008;14:378–89.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 19.
    Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.PubMedCrossRefGoogle Scholar
  20. 20.
    Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011;11:750–61.PubMedCrossRefGoogle Scholar
  21. 21.
    Martinez FO, Sica A, Mantovani A, et al. Macrophage activation and polarization. Front Biosci. 2008;1:453–61.CrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 26.
    Wirtz S, Neufert C, Weigmann B, et al. Chemically induced mouse models of intestinal inflammation. Nat Protoc. 2007;2:541–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Cooper HS, Murthy SN, Shah RS, et al. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest. 1993;69:238–49.PubMedGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 31.
    Hanahan D, Weinberg RA. Hallmarks of Cancer: the next generation. Cell. 2011;144:646–74.PubMedCrossRefGoogle Scholar
  32. 32.
    Lutgens MW, Vleggaar FP, Schipper ME, et al. High frequency of early colorectal cancer in inflammatory bowel disease. Gut. 2008;57:1246–51.PubMedCrossRefGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 34.
    Mantovani A, Sica A, Locati M. Macrophage polarization comes of age. Immunity. 2005;23:344–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Mantovani A. Inflammation and cancer: the macrophage connection. Medicina. 2007;67:32–4.Google Scholar
  36. 36.
    Erreni M, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) and inflammation in colorectal cancer. Cancer Microenviron. 2011;4:141–54.PubMedCrossRefGoogle Scholar
  37. 37.
    Moriya M, Harada T, Shirasu Y. Inhibition of carcinogenicities of 1,2-dimethylhydrazine and azoxymethane by pyrazole. Cancer Lett. 1982;17:147–52.PubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 39.
    Nardin A, Abastado JP. Macrophages and cancer. Front Biosci. 2008;13:3494–505.PubMedCrossRefGoogle Scholar
  40. 40.
    Sica A, Allavena P, Mantovani A. Cancer related inflammation: the macrophage connection. Cancer Lett. 2008;267:204–15.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Wei Wang
    • 1
    • 3
  • Xiayu Li
    • 1
    • 3
  • Danwei Zheng
    • 2
  • Decai Zhang
    • 1
    • 3
  • Shuo Huang
    • 1
    • 3
  • Xuemei Zhang
    • 1
    • 3
  • Feiyan Ai
    • 1
    • 3
  • Xiaoyan Wang
    • 1
    • 3
  • Jian Ma
    • 2
    • 3
  • Wei Xiong
    • 2
    • 3
  • Yanhong Zhou
    • 2
    • 3
  • Guiyuan Li
    • 2
    • 3
  • Shourong Shen
    • 1
    • 3
  1. 1.Department of GastroenterologyThe Third Xiangya Hospital of Central South UniversityChangshaChina
  2. 2.Key Laboratory of Carcinogenesis, Ministry of Health, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Institute of Cancer ResearchCentral South UniversityChangshaChina
  3. 3.Hunan Key Laboratory of Nonresolving Inflammation and CancerChangshaChina

Personalised recommendations