Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cytokines secreted by inflamed oral mucosa: implications for oral cancer progression

Oncogene volume 42, pages 1159–1165 (2023)Cite this article

Subjects

Abstract

The oral mucosa has an essential role in protecting against physical, microbial, and chemical harm. Compromise of this barrier triggers a wound healing response. Key events in this response such as immune infiltration, re-epithelialization, and stroma remodeling are coordinated by cytokines that promote cellular migration, invasion, and proliferation. Cytokine-mediated cellular invasion and migration are also essential features in cancer dissemination. Therefore, exploration of cytokines that regulate each stage of oral wound healing will provide insights about cytokines that are exploited by oral squamous cell carcinoma (SCC) to promote tumor development and progression. This will aid in identifying potential therapeutic targets to constrain SCC recurrence and increase patient survival. In this review, we discuss cytokines that overlap in oral wounds and SCC, emphasizing how these cytokines promote cancer progression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Tumor progression and wound healing in the oral mucosa are regulated by overlapping cytokines.

Similar content being viewed by others

Data availability

This is a review manuscript; supporting references are cited within the article.

References

  1. Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Prim. 2020;6:92.

    Article  PubMed  Google Scholar 

  2. Rivera C. Essentials of oral cancer. Int J Clin Exp Pathol. 2015;8:11884–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Leemans CR, Snijders PJF, Brakenhoff RH. The molecular landscape of head and neck cancer. Nature Reviews Cancer, vol. 18. Nature Publishing Group, 2018, pp 269–82.

  4. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA: A Cancer J Clin. 2022;72:7–33.

    Google Scholar 

  5. Scanlon CS, Van Tubergen EA, Inglehart RC, D’Silva NJ. Biomarkers of epithelial-mesenchymal transition in squamous cell carcinoma. J Dent Res. 2013;92:114–21.

    Article  CAS  PubMed  Google Scholar 

  6. Lambert AW, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell. 2017;168:670–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Deyell M, Garris CS, Laughney AM. Cancer metastasis as a non-healing wound. Br J Cancer. 2021;124:1491–502.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Roh JS, Sohn DH. Damage-associated molecular patterns in inflammatory diseases. Immune Netw. 2018;18:e27.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Gonzalez ACDO, Costa TF, Andrade ZDA, Medrado ARAP. Wound healing - a literature review. An Bras Dermatol. 2016;91:614–20.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Groeger SE, Meyle J. Epithelial barrier and oral bacterial infection. Periodontology 2000. 2015;69:46–67.

    Article  PubMed  Google Scholar 

  11. Kany S, Vollrath JT, Relja B. Cytokines in inflammatory disease. Int J Mol Sci. 2019;20:6008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Feliciani C, Gupta AK, Saucier DN. Keratinocytes and cytokine/growth factors. Crit Rev Oral Biol Med. 1996;7:300–18.

    Article  CAS  PubMed  Google Scholar 

  13. Adekoya TO, Richardson RM. Cytokines and chemokines as mediators of prostate cancer metastasis. Int J Mol Sci. 2020;21:4449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Waasdorp M, Krom BP, Bikker FJ, Van Zuijlen PPM, Niessen FB, Gibbs S. The bigger picture: why oral mucosa heals better than skin. Biomolecules. 2021;11:1165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Morand D, Davideau JL, Clauss F, Jessel N, Tenenbaum H, Huck O. Cytokines during periodontal wound healing: potential application for new therapeutic approach. Oral Dis. 2017;23:300–11.

    Article  CAS  PubMed  Google Scholar 

  16. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Perspective article: growth factors and cytokines in wound healing. Wound Repair Regen. 2008;16:585–601.

    Article  PubMed  Google Scholar 

  17. Kaltalioglu K, Coskun-Cevher S. A bioactive molecule in a complex wound healing process: platelet-derived growth factor. Int J Dermatol. 2015;54:972–7.

    Article  CAS  PubMed  Google Scholar 

  18. Lazaro JL, Izzo V, Meaume S, Davies AH, Lobmann R, Uccioli L. Elevated levels of matrix metalloproteinases and chronic wound healing: an updated review of clinical evidence. J Wound Care. 2016;25:277–87.

    Article  CAS  PubMed  Google Scholar 

  19. Danella EB, Costa De Medeiros M, D’Silva NJ. Cancer-associated keratinocytes: new members of the microenvironment in head and neck cancer. Mol Cell Oncol. 2021;8:1933329.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Peltanova B, Raudenska M, Masarik M. Effect of tumor microenvironment on pathogenesis of the head and neck squamous cell carcinoma: a systematic review. Mol Cancer. 2019;18:63.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Singh P, Banerjee R, Piao S, Costa De Medeiros M, Bellile E, Liu M, et al. Squamous cell carcinoma subverts adjacent histologically normal epithelium to promote lateral invasion. J Exp Med. 2021;218:e20200944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31–46.

    Article  CAS  PubMed  Google Scholar 

  23. Chiamulera MMA, Zancan CB, Remor AP, Cordeiro MF, Gleber-Netto FO, Baptistella AR. Salivary cytokines as biomarkers of oral cancer: a systematic review and meta-analysis. BMC Cancer. 2021;21:205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ferrari E, Pezzi ME, Cassi D, Pertinhez TA, Spisni A, Meleti M. Salivary cytokines as biomarkers for oral squamous cell carcinoma: a systematic review. Int J Mol Sci. 2021;22:6795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rébé C, Ghiringhelli F. Interleukin-1β and cancer. Cancers. 2020;12:1791.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lee CH, Chang JSM, Syu SH, Wong TS, Chan JYW, Tang YC, et al. IL‐1β promotes malignant transformation and tumor aggressiveness in oral cancer. J Cell Physiol. 2015;230:875–84.

    Article  CAS  PubMed  Google Scholar 

  27. Lee MK, Park JH, Gi SH, Hwang YS. IL-1β induces fascin expression and increases cancer invasion. Anticancer Res. 2018;38:6127–32.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang X, Hwang Y.Cancer‑associated fibroblast stimulates cancer cell invasion in an interleukin‑1 receptor (IL‑1R)‑dependent manner. Oncol Lett. 2019;18:4645–4650.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Culig Z. Interleukin-6 as a therapy target in oral squamous carcinoma. Expert Opin Ther Targets. 2013;17:53–9.

    Article  CAS  PubMed  Google Scholar 

  30. Van Tubergen E, Vander Broek R, Lee J, Wolf G, Carey T, Bradford C, et al. Tristetraprolin regulates interleukin-6, which is correlated with tumor progression in patients with head and neck squamous cell carcinoma. Cancer. 2011;117:2677–89.

    Article  PubMed  Google Scholar 

  31. Mirkeshavarz M, Ganjibakhsh M, Aminishakib P, Farzaneh P, Mahdavi N, Vakhshiteh F, et al. Interleukin-6 secreted by oral cancer- associated fibroblast accelerated VEGF expression in tumor and stroma cells. Cell Mol Biol. 2017;63:131–6.

    Article  CAS  PubMed  Google Scholar 

  32. Qin X, Yan M, Wang X, Xu Q, Wang X, Zhu X, et al. Cancer-associated fibroblast-derived il-6 promotes head and neck cancer progression via the osteopontin-NF-kappa B signaling pathway. Theranostics (Res Pap). 2018;8:921–40.

    Article  CAS  Google Scholar 

  33. Lafuente Ibáñez De Mendoza I, Maritxalar Mendia X, García De La Fuente AM, Quindós Andrés G, Aguirre Urizar JM. Role of porphyromonas gingivalis in oral squamous cell carcinoma development: a systematic review. J Periodontal Res. 2020;55:13–22.

    Article  PubMed  Google Scholar 

  34. Wen L, Mu W, Lu H, Wang X, Fang J, Jia Y, et al. Porphyromonas gingivalis promotes oral squamous cell carcinoma progression in an immune microenvironment. J Dent Res. 2020;99:666–75.

    Article  CAS  PubMed  Google Scholar 

  35. Gallimidi AB, Fischman S, Revach B, Bulvik R, Maliutina A, Rubinstein AM, et al. Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model. Oncotarget. 2015;6:22613–23.

    Article  PubMed Central  Google Scholar 

  36. Bickel M. The role of interleukin-8 in inflammation and mechanisms of regulation. J Periodontol. 1993;64:456–60.

    CAS  PubMed  Google Scholar 

  37. Alfaro C, Sanmamed MF, Rodríguez-Ruiz ME, Teijeira Á, Oñate C, González Á, et al. Interleukin-8 in cancer pathogenesis, treatment and follow-up. Cancer Treat Rev. 2017;60:24–31.

    Article  CAS  PubMed  Google Scholar 

  38. Chan L-P, Wang L-F, Chiang F-Y, Lee K-W, Kuo P-L, Liang C-H. IL-8 promotes HNSCC progression on CXCR1/2-meidated NOD1/RIP2 signaling pathway. Oncotarget. 2016;7:61820–31.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Ha NH, Park DG, Woo BH, Kim DJ, Choi JI, Park BS, et al. Porphyromonas gingivalis increases the invasiveness of oral cancer cells by upregulating IL-8 and MMPs. Cytokine. 2016;86:64–72.

    Article  CAS  PubMed  Google Scholar 

  40. Salvo E, Tu NH, Scheff NN, Dubeykovskaya ZA, Chavan SA, Aouizerat BE, et al. TNFα promotes oral cancer growth, pain, and Schwann cell activation. Sci Rep. 2021;11:1840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Scheff NN, Ye Y, Bhattacharya A, Macrae J, Hickman DN, Sharma AK, et al. Tumor necrosis factor alpha secreted from oral squamous cell carcinoma contributes to cancer pain and associated inflammation. Pain. 2017;158:2396–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wu Y, Zhou BP. TNF-α/NF-κB/Snail pathway in cancer cell migration and invasion. Br J Cancer. 2010;102:639–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tang D, Tao D, Fang Y, Deng C, Xu Q, Zhou J. TNF-alpha promotes invasion and metastasis via NF-Kappa B pathway in oral squamous cell carcinoma. Med Sci Monit Basic Res. 2017;23:141–9.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Xu Q, Zhang Q, Ishida Y, Hajjar S, Tang X, Shi H, et al. EGF induces epithelial-mesenchymal transition and cancer stem-like cell properties in human oral cancer cells via promoting Warburg effect. Oncotarget. 2017;8:9557–71.

    Article  PubMed  Google Scholar 

  45. Zhang Z, Dong Z, Lauxen IS, Filho MSA, Nör JE. Endothelial cell-secreted EGF induces epithelial to mesenchymal transition and endows head and neck cancer cells with stem-like phenotype. Cancer Res. 2014;74:2869–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Banerjee R, Liu M, Bellile E, Schmitd LB, Goto M, Hutchinson MND, et al. Phosphorylation of TRIP13 at Y56 induces radiation resistance but sensitizes head and neck cancer to cetuximab. Mol Ther. 2022;30:468–84.

    Article  CAS  PubMed  Google Scholar 

  47. Frederick BA, Gupta R, Atilano-Roque A, Su TT, Raben D. Combined EGFR1 and PARP1 inhibition enhances the effect of radiation in head and neck squamous cell carcinoma models. Radiat Res. 2020;194:519–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yanase M, Kato K, Yoshizawa K, Noguchi N, Kitahara H, Nakamura H. Prognostic value of vascular endothelial growth factors A and C in oral squamous cell carcinoma. J Oral Pathol Med. 2014;43:514–20.

    Article  CAS  PubMed  Google Scholar 

  49. Davies M, Robinson M, Smith E, Huntley S, Prime S, Paterson I. Induction of an epithelial to mesenchymal transition in human immortal and malignant keratinocytes by TGF-beta1 involves MAPK, Smad and AP-1 signalling pathways. J Cell Biochem. 2005;95:918–31.

    Article  CAS  PubMed  Google Scholar 

  50. Liarte S, Bernabé-García Á, Nicolás FJ. Human skin keratinocytes on sustained TGF-β stimulation reveal partial EMT features and weaken growth arrest responses. Cells. 2020;9:255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pisani LP, Estadella D, Ribeiro DA. The role of toll like receptors (TLRs) in oral carcinogenesis. Anticancer Res. 2017;37:5389–94.

    CAS  PubMed  Google Scholar 

  52. Duan T, Du Y, Xing C, Wang HY, Wang R-F. Toll-like receptor signaling and its role in cell-mediated immunity. Front Immunol. 2022;13:812774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct Target Ther. 2021;6:263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sharma Y, Bala K. Role of Toll like receptor in progression and suppression of oral squamous cell carcinoma. Oncol Rev. 2020;14:456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bakhoum SF, Cantley LC. The multifaceted role of chromosomal instability in cancer and its microenvironment. Cell. 2018;174:1347–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ramnath D, Powell EE, Scholz GM, Sweet MJ. The toll-like receptor 3 pathway in homeostasis, responses to injury and wound repair. Semin Cell Develop Biol. 2017;61:22–30.

    Article  CAS  Google Scholar 

  57. Hasnat S, Hujanen R, Nwaru BI, Salo T, Salem A. The prognostic value of toll-like receptors in head and neck squamous cell carcinoma: a systematic review and meta-analysis. Int J Mol Sci. 2020;21:7255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ruan M, Zhang Z, Li S, Yan M, Liu S, Yang W, et al. Activation of toll-like receptor-9 promotes cellular migration via up-regulating MMP-2 expression in oral squamous cell carcinoma. PLoS ONE. 2014;9:e92748.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Şenel S. An overview of physical, microbiological and immune barriers of oral mucosa. Int J Mol Sci. 2021;22:7821.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Wang SS, Tang YL, Pang X, Zheng M, Tang YJ, Liang XH. The maintenance of an oral epithelial barrier. Life Sci. 2019;227:129–36.

    Article  CAS  PubMed  Google Scholar 

  61. Healy CM, Moran GP. The microbiome and oral cancer: More questions than answers. Oral Oncology, vol. 89. Elsevier Ltd, 2019, pp 30–33.

  62. Teles FRF, Alawi F, Castilho RM, Wang Y. Association or causation? Exploring the oral microbiome and cancer links. J Dent Res. 2020;99:1411–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Saliem SS, Bede SY, Cooper PR, Abdulkareem AA, Milward MR, Abdullah BH. Pathogenesis of periodontitis – a potential role for epithelial-mesenchymal transition. Jpn Dent Sci Rev. 2022;58:268–78.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Gholizadeh P, Eslami H, Yousefi M, Asgharzadeh M, Aghazadeh M, Kafil HS. Role of oral microbiome on oral cancers, a review. Biomedicine and Pharmacotherapy, vol. 84. Elsevier Masson SAS, 2016, pp 552–8.

  65. Bostanci N, Bao K, Wahlander A, Grossmann J, Thurnheer T, Belibasakis GN. Secretome of gingival epithelium in response to subgingival biofilms. Mol Oral Microbiol. 2015;30:323–35.

    Article  CAS  PubMed  Google Scholar 

  66. Brown JL, Johnston W, Delaney C, Rajendran R, Butcher J, Khan S, et al. Biofilm-stimulated epithelium modulates the inflammatory responses in co-cultured immune cells. Sci Rep. 2019;9:15779.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Ebersole JL, Peyyala R, Gonzalez OA. Biofilm-induced profiles of immune response gene expression by oral epithelial cells. Mol Oral Microbiol. 2019;34:14–25.

    Article  Google Scholar 

  68. Ramage G, Lappin DF, Millhouse E, Malcolm J, Jose A, Yang J, et al. The epithelial cell response to health and disease associated oral biofilm models. J Periodontal Res. 2017;52:325–33.

    Article  CAS  PubMed  Google Scholar 

  69. Stathopoulou PG, Benakanakere MR, Galicia JC, Kinane DF. Epithelial cell pro-inflammatory cytokine response differs across dental plaque bacterial species. J Clin Periodontol. 2010;37:24–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sandros J, Karlsson C, Lappin DF, Madianos PN, Kinane DF, Papapanou PN. Cytokine responses of oral epithelial cells to Porphyromonas gingivalis infection. J Dent Res. 2000;79:1808–14.

    Article  CAS  PubMed  Google Scholar 

  71. Uchida Y, Shiba H, Komatsuzawa H, Takemoto T, Sakata M, Fujita T, et al. Expression of IL-1 beta and IL-8 by human gingival epithelial cells in response to Actinobacillus actinomycetemcomitans. Cytokine. 2001;14:152–61.

    Article  CAS  PubMed  Google Scholar 

  72. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Feller L, Altini M, Lemmer J. Inflammation in the context of oral cancer. Oral Oncol. 2013;49:887–92.

    Article  CAS  PubMed  Google Scholar 

  74. Zuazo-Gaztelu I, Casanovas O. Unraveling the role of angiogenesis in cancer ecosystems. Front Oncol. 2018;8:248.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by NIDCR R35-DE027551 (NJD), NCI R01- CA250214 (NJD), NIDCR T32-DE007057 (EBD), and NIDCR F30-DE03194001 (EBD).

Author information

Authors and Affiliations

  1. Periodontics and Oral Medicine, University of Michigan School of Dentistry, 1011 N. University Ave, Ann Arbor, MI, USA

    Erika B. Danella, Marcell Costa de Medeiros & Nisha J. D’Silva

  2. Pathology, University of Michigan Medical School, 1500 E Medical Center Dr, Ann Arbor, MI, USA

    Nisha J. D’Silva

  3. Rogel Cancer Center, 1500 E Medical Center Dr, Ann Arbor, MI, USA

    Nisha J. D’Silva

Authors
  1. Erika B. Danella
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcell Costa de Medeiros
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nisha J. D’Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

EBD, MCM, and NJD all contributed to the concept and design of the work as well as critical revision of the article. EBD drafted the article and MCM contributed to figure design. All authors gave final approval of the submission to be published.

Corresponding author

Correspondence to Nisha J. D’Silva.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Danella, E.B., Costa de Medeiros, M. & D’Silva, N.J. Cytokines secreted by inflamed oral mucosa: implications for oral cancer progression. Oncogene 42, 1159–1165 (2023). https://doi.org/10.1038/s41388-023-02649-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-023-02649-y

Search

Advanced search

Quick links