Molecular Diagnostics

Treponema denticola chymotrypsin-like proteinase may contribute to orodigestive carcinogenesis through immunomodulation

  • British Journal of Cancer volume 118, pages 428434 (06 February 2018)
  • doi:10.1038/bjc.2017.409
  • Download Citation
Received:
Revised:
Accepted:
Published:

Abstract

Background:

Periodontal pathogens have been linked to oral and gastrointestinal (orodigestive) carcinogenesis. However, the exact mechanisms remain unknown. Treponema denticola (Td) is associated with severe periodontitis, a chronic inflammatory disease leading to tooth loss. The anaerobic spirochete Td is an invasive bacteria due to its major virulence factor chymotrypsin-like proteinase. Here we aimed to investigate the presence of Td chymotrypsin-like proteinase (Td-CTLP) in major orodigestive tumours and to elucidate potential mechanisms for Td to contribute to carcinogenesis.

Methods:

The presence of Td-CTLP within orodigestive tumour tissues was examined using immunohistochemistry. Oral, tonsillar, and oesophageal squamous cell carcinomas, alongside gastric, pancreatic, and colon adenocarcinomas were stained with a Td-CTLP-specific antibody. Gingival tissue from periodontitis patients served as positive controls. SDS–PAGE and immunoblot were used to analyse the immumodulatory activity of Td-CTLP in vitro.

Results:

Td-CTLP was present in majority of orodigestive tumour samples. Td-CTLP was found to convert pro MMP-8 and -9 into their active forms. In addition, Td-CTLP was able to degrade the proteinase inhibitors TIMP-1, TIMP-2, and α-1-antichymotrypsin, as well as complement C1q.

Conclusions:

Because of its presence within tumours and regulatory activity on proteins critical for the regulation of tumour microenvironment and inflammation, the Td-CTLP may contribute to orodigestive carcinogenesis.

  • Subscribe to British Journal of Cancer for full access:

    $659

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

Change history

  • Corrected online 06 February 2018

References

  1. , , (2012a) Oral microbiome and oral and gastrointestinal cancer risk. Cancer Causes Control 23: 399–404.

  2. , , (2012b) Periodontal disease, Porphyromonas gingivalis serum antibody levels and orodigestive cancer mortality. Carcinogenesis 33: 1055–1058.

  3. , , , , , , (1998) Tumor-associated proteases and inhibitors in gastric cancer: analysis of prognostic impact and individual risk protease patterns. Clin Exp Metastasis 16: 62–73.

  4. , , , (2015) The role of MMP-2 and MMP-9 as prognostic markers in the early stages of tongue squamous cell carcinoma. J Oral Pathol Med 44: 345–352.

  5. , (2010) The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 1803: 55–71.

  6. , , , , , , , , , (2016) C1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation. Nat Commun 7: 10346.

  7. , , , , , , , , , (2005) Case report molecular detection of Treponema denticola and Porphyromonas gingivalis in carotid and aortic atheromatous plaques by FISH: report of two cases. J Med Microbiol 54: 93–96.

  8. , , , , , (2003) Induction of osteoclastogenesis and matrix metalloproteinase expression by the lipooligosaccharide of Treponema denticola. Infect Immun 71: 226–233.

  9. , , , , (2012) Treponema denticola chymotrypsin-like proteinase (CTLP) integrates spirochaetes within oral microbial communities. Microbiology 158: 759–770.

  10. , , , (2011) Virulence factors of the oral spirochete Treponema denticola. J Dent Res 90: 691–703.

  11. , , , , , , , (1996) Membrane components of Treponema denticola trigger proteinase release from human polymorphonuclear leukocytes. J Dent Res 75: 1986–1993.

  12. (2012) Treponema denticola interactions with host proteins. J Oral Microbiol 4: 9929.

  13. , (2010) The association between periodontal disease and cancer: a review of the literature. J Dent 38: 83–95.

  14. , , , , , , (2015) Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model. Oncotarget 6: 22613–22623.

  15. , , , , , (2016) Role of oral microbiome on oral cancers, a review. Biomed Pharmacother 84: 552–558.

  16. , , (1990) Cellular location of a Treponema denticola chymotrypsinlike protease and importance of the protease in migration through the basement membrane. Infect Immun 58: 347–351.

  17. , , , , (2011) B7-H1 and B7-DC receptors of oral squamous carcinoma cells are upregulated by Porphyromonas gingivalis. Immunobiology 216: 1302–1310.

  18. , , , , , , , , , , , , (2008) Matrix metalloproteinase-8 functions as a metastasis suppressor through modulation of tumor cell adhesion and invasion. Cancer Res 68: 2755–2763.

  19. , , , (1987) The collagen substrate specificity of human neutrophil collagenase. J Biol Chem 262: 10048–10052.

  20. , , , (2016) TIMPs: versatile extracellular regulators in cancer. Nat Rev Cancer 17: 38–53.

  21. , , , , , , , , (2016) Expressions of matrix metalloproteinases 2, 7, and 9 in carcinogenesis of pancreatic ductal adenocarcinoma. Dis Markers 2016: 1–7.

  22. , , (2002) Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene 21: 2245–2252.

  23. , , , , , , , , (2006) Matrix metalloproteinase polymorphisms and bladder cancer risk. Cancer Res 66: 11644–11648.

  24. , , , , (1990) Prognostic significance of alpha-1-antitrypsin in early stage of colorectal carcinomas. Int J Cancer 45: 244–250.

  25. , , (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141: 52–67.

  26. , , , (1982) Immunocytochemical demonstration of a1-antitrypsin and a1-antichymotrypsin in human gastrointestinal tract. Hepatogastroenterology 29: 275–277.

  27. , , , , , , , (2005) Plasma protein profiling for diagnosis of pancreatic cancer reveals the presence of host response proteins. Clin Cancer Res 11: 1110–1118.

  28. , , , , , , , , , , , , , , (2008) Collagenase-2 (matrix metalloproteinase-8) plays a protective role in tongue cancer. Br J Cancer 98: 766–775.

  29. , , , , , , , (2014) Intracellular localization of Treponema denticola chymotrypsin-like proteinase in chronic periodontitis. J Oral Microbiol 6: 1–6.

  30. (2013) Role of bacterial infections in pancreatic cancer. Carcinogenesis 34: 2193–2197.

  31. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , (2013) Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study. Gut 62: 1764–1770.

  32. , , , , (2002) Expression and regulation of collagenase-2 (MMP-8) in head and neck squamous cell carcinomas. J Pathol 197: 72–81.

  33. , , , , (1998) The microflora associated with human oral carcinomas. Oral Oncol 34: 304–308.

  34. , , , , , , , , , (2004) Frequent and preferential infection of Treponema denticola, Streptococcus mitis, and Streptococcus anginosus in esophageal cancers. Cancer Sci 95: 569–574.

  35. (2006) The global health burden of infection-associated cancers in the year 2002. Int J Cancer 3044: 3030–3044.

  36. , (2015) How bacterial pathogens colonize their hosts and invade deeper tissues. Microbes Infect 17: 173–183.

  37. , , , , , (2013) Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe 14: 195–206.

  38. , , , , , , , (2015) Matrix metalloproteinase 8 degrades apolipoprotein A-I and reduces its cholesterol efflux capacity. FASEB J 29: 1435–1445.

  39. , , , , (1988) Comparison of interstitial collagenases from human gingiva, sulcular fluid and polymorphonuclear leukocytes. J Periodontal Res 23: 386–393.

  40. , , , , , , , (1992) Identification of proteases from periodontopathogenic bacteria as activators of latent human neutrophil and fibroblast-type interstitial collagenases. Infect Immun 60: 4491–4495.

  41. , , , , , , , , , , , , , (1997) Activation of type IV procollagenases by human tumor-associated trypsin-2. J Biol Chem 272: 21067–21074.

  42. , , , , , , , , , (2003) Cytokine-regulated expression of collagenase-2 (MMP-8) is involved in the progression of ovarian cancer. Eur J Cancer 39: 2499–2505.

  43. , (2004) Role of imbalance between neutrophil elastase and α1-antitrypsin in cancer development and progression. Lancet Oncol 5: 182–190.

  44. , , , (1988) Isolation of a chymotrypsinlike enzyme from Treponema denticola. Infect Immun 56: 2717–2722.

  45. , , , , , , (1995) Cytopathic effects of Treponema denticola chymotrypsin-like proteinase on migrating and stratified epithelial cells. Infect Immun 63: 3401–3410.

  46. , , , , (2014) Matrix metalloproteinases and gastrointestinal cancers: impacts of dietary antioxidants. World J Biol Chem 5: 355.

  47. , , , (2013) Treponema denticola associates with increased levels of MMP-8 and MMP-9 in gingival crevicular fluid. Oral Dis 19: 694–701.

  48. , , , , , , (2013) Clinicopathological and prognostic role of MMP-9 in esophageal squamous cell carcinoma: a meta-analysis. Chin J Cancer Res 25: 637–645.

Download references

Acknowledgements

This study was supported by Directorate General of Human Resource for Science, Technology and Higher Education of Indonesia, Center for International Mobility (CIMO TM-15-9588), Selma and Maja-Lisa Selanders fund, Otto A Malm Foundation, FINDOS travel grant, Sigrid Jusélius Foundation, Finska Läkaresällskapet, FONDECYT 1160741 grant, Helsinki University Hospital Research Foundation (TYH 2016251, TYH 2017251, and Y 1149SUL32), Helsinki, Finland, and the Karolinska Institutet, Stockholm, Sweden. Dr Anne Järvensivu, DDS is acknowledged for providing the periodontitis-affected human tissue specimen.

Author information

Author notes

    • Mikko T Nieminen
    •  & Dyah Listyarifah

    These authors contributed equally to this work.

Affiliations

  1. Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, Helsinki 00029, Finland

    • Mikko T Nieminen
    • , Veli-Jukka Uitto
    • , Taina Tervahartiala
    •  & Timo Sorsa
  2. Department of Dental Biomedical Sciences, Faculty of Dentistry, Universitas Gadjah Mada, Jl. Denta Sekip Utara no 1, Yogyakarta 55281, Indonesia

    • Dyah Listyarifah
  3. Department of Medicine, Clinicum, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, Helsinki 00029, Finland

    • Dyah Listyarifah
    •  & Mari Ainola
  4. Department of Pathology, Haartman Institute and HUSLab, University of Helsinki and Helsinki University Hospital, PO Box 21, Haartmaninkatu 3, 00014 Helsinki, Finland

    • Jaana Hagström
  5. Research Program Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland

    • Jaana Hagström
    •  & Caj Haglund
  6. Department of Surgery, University of Helsinki and Helsinki University Central Hospital, PO Box 340, Helsinki 00029, Finland

    • Caj Haglund
  7. Faculté de Médecine Dentaire, Université Laval, Quebec City, Quebec G1V 0A6, Canada

    • Daniel Grenier
  8. Department of Internal Medicine and Rehabilitation, University of Helsinki and Helsinki University Central Hospital, Helsinki 00029, Finland

    • Dan Nordström
  9. Laboratory of Periodontal Biology and Department of Oral Pathology and Medicine, Faculty of Dentistry, University of Chile, Santiago, Chile

    • Marcela Hernandez
  10. Dentistry Unit, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago, Chile

    • Marcela Hernandez
  11. Division of Periodontology, Department of Oral Diseases, Karolinska Institutet, Box 4064, Huddinge SE-141 04, Sweden

    • Tülay Yucel-Lindberg
    •  & Timo Sorsa

Authors

  1. Search for Mikko T Nieminen in:

  2. Search for Dyah Listyarifah in:

  3. Search for Jaana Hagström in:

  4. Search for Caj Haglund in:

  5. Search for Daniel Grenier in:

  6. Search for Dan Nordström in:

  7. Search for Veli-Jukka Uitto in:

  8. Search for Marcela Hernandez in:

  9. Search for Tülay Yucel-Lindberg in:

  10. Search for Taina Tervahartiala in:

  11. Search for Mari Ainola in:

  12. Search for Timo Sorsa in:

Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Mikko T Nieminen.

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License.

Creative Commons BY-NC-SAFrom twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/