Periodontal disease affects oral cancer progression in a surrogate animal model for tobacco exposure

Spuldaro,Tobias R.; Wagner,Vivian P.; Nör,Felipe; Gaio,Eduardo J.; Squarize,Cristiane H.; Carrard,Vinicius C.; Rösing,Cassiano K.; Castilho,Rogerio M.

doi:10.3892/ijo.2022.5367

Periodontal disease affects oral cancer progression in a surrogate animal model for tobacco exposure

Authors:
- Tobias R. Spuldaro
- Vivian P. Wagner
- Felipe Nör
- Eduardo J. Gaio
- Cristiane H. Squarize
- Vinicius C. Carrard
- Cassiano K. Rösing
- Rogerio M. Castilho
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Affiliations: Department of Periodontology, Federal University of Rio Grande do Sul, Porto Alegre, RS 90010‑150, Brazil, Department of Oral Pathology, Federal University of Rio Grande do Sul, Porto Alegre, RS 90010‑150, Brazil, Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI 48109‑1078, USA
Published online on: May 5, 2022 https://doi.org/10.3892/ijo.2022.5367
Article Number: 77
Copyright: © Spuldaro et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

For decades, the link between poor oral hygiene and the increased prevalence of oral cancer has been suggested. Most recently, emerging evidence has suggested that chronic inflammatory diseases from the oral cavity (e.g., periodontal disease), to some extent, play a role in the development of oral squamous cell carcinoma (OSCC). The present study aimed to explore the direct impact of biofilm‑induced periodontitis in the carcinogenesis process using a tobacco surrogate animal model for oral cancer. A total of 42 Wistar rats were distributed into four experimental groups: Control group, periodontitis (Perio) group, 4‑nitroquinoline 1‑oxide (4‑NQO) group and 4NQO/Perio group. Periodontitis was stimulated by placing a ligature subgingivally, while oral carcinogenesis was induced by systemic administration of 4NQO in the drinking water for 20 weeks. It was observed that the Perio, 4NQO and 4NQO/Perio groups presented with significantly higher alveolar bone loss compared with that in the control group. Furthermore, all groups receiving 4NQO developed lesions on the dorsal surface of the tongue; however, the 4NQO/Perio group presented larger lesions compared with the 4NQO group. There was also a modest overall increase in the number of epithelial dysplasia and OSCC lesions in the 4NQO/Perio group. Notably, abnormal focal activation of cellular differentiation (cytokeratin 10‑positive cells) that extended near the basal cell layer of the mucosa was observed in rats receiving 4NQO alone, but was absent in rats receiving 4NQO and presenting with periodontal disease. Altogether, the presence of periodontitis combined with 4NQO administration augmented tumor size in the current rat model and tampered with the protective mechanisms of the cellular differentiation of epithelial cells.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Sahingur SE and Yeudall WA: Chemokine function in periodontal disease and oral cavity cancer. Front Immunol. 6:2142015. View Article : Google Scholar : PubMed/NCBI
3	Leemans CR, Braakhuis BJ and Brakenhoff RH: The molecular biology of head and neck cancer. Nat Rev Cancer. 11:9–22. 2011. View Article : Google Scholar
4	Warnakulasuriya S: Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 45:309–316. 2009. View Article : Google Scholar
5	Perera M, Al-Hebshi NN, Speicher DJ, Perera I and Johnson NW: Emerging role of bacteria in oral carcinogenesis: A review with special reference to perio-pathogenic bacteria. J Oral Microbiol. 8:327622016. View Article : Google Scholar : PubMed/NCBI
6	Chocolatewala N, Chaturvedi P and Desale R: The role of bacteria in oral cancer. Indian J Med Paediatr Oncol. 31:126–131. 2010. View Article : Google Scholar
7	Bravi F, Lee YA, Hashibe M, Boffetta P, Conway DI, Ferraroni M, La Vecchia C and Edefonti V; INHANCE Consortium investigators: Lessons learned from the INHANCE consortium: An overview of recent results on head and neck cancer. Oral Dis. 27:73–93. 2021. View Article : Google Scholar
8	Tezal M, Grossi SG and Genco RJ: Is periodontitis associated with oral neoplasms? J Periodontol. 76:406–410. 2005. View Article : Google Scholar : PubMed/NCBI
9	Gondivkar SM, Gondivkar RS, Gadbail AR, Chole R, Mankar M and Yuwanati M: Chronic periodontitis and the risk of head and neck squamous cell carcinoma: Facts and figures. Exp Oncol. 35:163–167. 2013.PubMed/NCBI
10	Michaud DS, Lu J, Peacock-Villada AY, Barber JR, Joshu CE, Prizment AE, Beck JD, Offenbacher S and Platz EA: Periodontal disease assessed using clinical dental measurements and cancer risk in the ARIC study. J Natl Cancer Inst. 110:843–854. 2018. View Article : Google Scholar : PubMed/NCBI
11	Tonetti MS, Jepsen S, Jin L and Otomo-Corgel J: Impact of the global burden of periodontal diseases on health, nutrition and wellbeing of mankind: A call for global action. J Clin Periodontol. 44:456–462. 2017. View Article : Google Scholar : PubMed/NCBI
12	Nagy KN, Sonkodi I, Szöke I, Nagy E and Newman HN: The microflora associated with human oral carcinomas. Oral Oncol. 34:304–308. 1998. View Article : Google Scholar : PubMed/NCBI
13	Binder Gallimidi A, Fischman S, Revach B, Bulvik R, Maliutina A, Rubinstein AM, Nussbaum G and Elkin M: Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model. Oncotarget. 6:22613–22623. 2015. View Article : Google Scholar : PubMed/NCBI
14	Wu JS, Zheng M, Zhang M, Pang X, Li L, Wang SS, Yang X, Wu JB, Tang YJ, Tang YL and Liang XH: Porphyromonas gingivalis Promotes 4-nitroquinoline-1-oxide-induced oral carcinogenesis with an alteration of fatty acid metabolism. Front Microbiol. 9:20812018. View Article : Google Scholar :
15	Ribeiro DA and Salvadori DM: Gingival changes in wistar rats after oral treatment with 4-nitroquinoline 1-oxide. Eur J Dent. 1:152–157. 2007. View Article : Google Scholar : PubMed/NCBI
16	Ribeiro DA, Fracalossi AC, Uatari SA, Oshima CT and Salvadori DM: Imbalance of tumor suppression genes expression following rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide. In Vivo. 23:937–942. 2009.PubMed/NCBI
17	Dayan D, Hirshberg A, Kaplan I, Rotem N and Bodner L: Experimental tongue cancer in desalivated rats. Oral Oncol. 33:105–109. 1997. View Article : Google Scholar : PubMed/NCBI
18	Cavagni J, de Macedo IC, Gaio EJ, Souza A, de Molon RS, Cirelli JA, Hoefel AL, Kucharski LC, Torres IL and Rösing CK: Obesity and hyperlipidemia modulate alveolar bone loss in Wistar rats. J Periodontol. 87:e9–e17. 2016. View Article : Google Scholar
19	Verzeletti GN, Gaio EJ, Linhares DS and Rösing CK: Effect of obesity on alveolar bone loss in experimental periodontitis in Wistar rats. J Appl Oral Sci. 20:218–221. 2012. View Article : Google Scholar : PubMed/NCBI
20	Squarize CH, Castilho RM, Abrahao AC, Molinolo A, Lingen MW and Gutkind JS: PTEN deficiency contributes to the development and progression of head and neck cancer. Neoplasia. 15:461–471. 2013. View Article : Google Scholar : PubMed/NCBI
21	Oballe HJR, Muniz FWMG, Bueno CC, Klein IP, Carrard VC, Rösing CK and Gaio EJ: Spontaneous alveolar bone loss after 4NQO exposure in Wistar rats. Arch Oral Biol. 89:44–48. 2018. View Article : Google Scholar : PubMed/NCBI
22	Dale BA, Salonen J and Jones AH: New approaches and concepts in the study of differentiation of oral epithelia. Crit Rev Oral Biol Med. 1:167–190. 1990. View Article : Google Scholar : PubMed/NCBI
23	Atanasova KR and Yilmaz O: Looking in the Porphyromonas gingivalis cabinet of curiosities: The microbium, the host and cancer association. Mol Oral Microbiol. 29:55–66. 2014. View Article : Google Scholar : PubMed/NCBI
24	Ahn J, Segers S and Hayes RB: Periodontal disease, Porphyromonas gingivalis serum antibody levels and orodigestive cancer mortality. Carcinogenesis. 33:1055–1058. 2012. View Article : Google Scholar : PubMed/NCBI
25	Katz J, Onate MD, Pauley KM, Bhattacharyya I and Cha S: Presence of Porphyromonas gingivalis in gingival squamous cell carcinoma. Int J Oral Sci. 3:209–215. 2011. View Article : Google Scholar : PubMed/NCBI
26	Groeger S, Domann E, Gonzales JR, Chakraborty T and Meyle J: B7-H1 and B7-DC receptors of oral squamous carcinoma cells are upregulated by Porphyromonas gingivalis. Immunobiology. 216:1302–1310. 2011. View Article : Google Scholar : PubMed/NCBI
27	Meyer MS, Joshipura K, Giovannucci E and Michaud DS: A review of the relationship between tooth loss, periodontal disease, and cancer. Cancer Causes Control. 19:895–907. 2008. View Article : Google Scholar : PubMed/NCBI
28	Graves DT, Fine D, Teng YT, Van Dyke TE and Hajishengallis G: The use of rodent models to investigate host-bacteria interactions related to periodontal diseases. J Clin Periodontol. 35:89–105. 2008. View Article : Google Scholar : PubMed/NCBI
29	Duarte PM, Tezolin KR, Figueiredo LC, Feres M and Bastos MF: Microbial profile of ligature-induced periodontitis in rats. Arch Oral Biol. 55:142–147. 2010. View Article : Google Scholar
30	Al-Koshab M, Alabsi AM, Mohd Bakri M, Ali-Saeed R and Selvi Naicker M: Antitumor activity of ficus deltoidea extract on oral cancer: An in vivo study. J Oncol. 2020:54904682020. View Article : Google Scholar :
31	Yanaida Y, Kohno H, Yoshida K, Hirose Y, Yamada Y, Mori H and Tanaka T: Dietary silymarin suppresses 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats. Carcinogenesis. 23:787–794. 2002. View Article : Google Scholar : PubMed/NCBI
32	Al-Afifi N, Alabsi A, Kaid F, Bakri M and Ramanathan A: Prevention of oral carcinogenesis in rats by Dracaena cinnabari resin extracts. Clin Oral Investig. 23:2287–2301. 2019. View Article : Google Scholar
33	Araújo AA, Pereira ASBF, Medeiros CACX, Brito GAC, Leitão RFC, Araújo LS, Guedes PMM, Hiyari S, Pirih FQ and Araújo Júnior RF: Effects of metformin on inflammation, oxidative stress, and bone loss in a rat model of periodontitis. PLoS One. 12:e01835062017. View Article : Google Scholar : PubMed/NCBI
34	Miranda SR, Noguti J, Carvalho JG, Oshima CT and Ribeiro DA: Oxidative DNA damage is a preliminary step during rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide. J Mol Histol. 42:181–186. 2011. View Article : Google Scholar : PubMed/NCBI
35	Canakçi CF, Ciçek Y and Canakçi V: Reactive oxygen species and human inflammatory periodontal diseases. Biochemistry (Mosc). 70:619–628. 2005. View Article : Google Scholar
36	Takane M, Sugano N, Iwasaki H, Iwano Y, Shimizu N and Ito K: New biomarker evidence of oxidative DNA damage in whole saliva from clinically healthy and periodontally diseased individuals. J Periodontol. 73:551–554. 2002. View Article : Google Scholar : PubMed/NCBI
37	Kanojia D and Vaidya MM: 4-nitroquinoline-1-oxide induced experimental oral carcinogenesis. Oral Oncol. 42:655–667. 2006. View Article : Google Scholar : PubMed/NCBI
38	El-Rouby DH: Histological and immunohistochemical evaluation of the chemopreventive role of lycopene in tongue carcinogenesis induced by 4-nitroquinoline-1-oxide. Arch Oral Biol. 56:664–671. 2011. View Article : Google Scholar : PubMed/NCBI
39	Yao QW, Zhou DS, Peng HJ, Ji P and Liu DS: Association of periodontal disease with oral cancer: A meta-analysis. Tumour Biol. 35:7073–7077. 2014. View Article : Google Scholar : PubMed/NCBI
40	Harrandah AM, Chukkapalli SS, Bhattacharyya I, Progulske-Fox A and Chan EKL: Fusobacteria modulate oral carcinogenesis and promote cancer progression. J Oral Microbiol. 13:18494932020. View Article : Google Scholar :
41	Stashenko P, Yost S, Choi Y, Danciu T, Chen T, Yoganathan S, Kressirer C, Ruiz-Tourrella M, Das B, Kokaras A and Frias-Lopez J: The oral mouse microbiome promotes tumorigenesis in oral squamous cell carcinoma. mSystems. 4:e00323–19. 2019. View Article : Google Scholar : PubMed/NCBI
42	Royer C and Lu X: Epithelial cell polarity: A major gatekeeper against cancer? Cell Death Differ. 18:1470–1477. 2011. View Article : Google Scholar : PubMed/NCBI
43	Martin-Belmonte F and Perez-Moreno M: Epithelial cell polarity, stem cells and cancer. Nat Rev Cancer. 12:23–38. 2011. View Article : Google Scholar : PubMed/NCBI
44	Moll R, Divo M and Langbein L: The human keratins: Biology and pathology. Histochem Cell Biol. 129:705–733. 2008. View Article : Google Scholar : PubMed/NCBI
45	Paramio JM, Santos M and Jorcano JL: The ends of a conundrum? J Cell Sci. 120:1145–1148. 2007. View Article : Google Scholar : PubMed/NCBI
46	Garcia NG, Oliveira DT, Lauris JR, Domingues MA, Minicucci EM and Soares CT: Loss of cytokeratin 10 indicates malignant transformation in actinic cheilitis. Clin Oral Investig. 20:745–752. 2016. View Article : Google Scholar
47	Reichelt J, Furstenberger G and Magin TM: Loss of keratin 10 leads to mitogen-activated protein kinase (MAPK) activation, increased keratinocyte turnover, and decreased tumor formation in mice. J Invest Dermatol. 123:973–981. 2004. View Article : Google Scholar : PubMed/NCBI
48	Paramio JM, Casanova ML, Segrelles C, Mittnacht S, Lane EB and Jorcano JL: Modulation of cell proliferation by cytokeratins K10 and K16. Mol Cell Biol. 19:3086–3094. 1999. View Article : Google Scholar : PubMed/NCBI
49	Santos M, Paramio JM, Bravo A, Ramirez A and Jorcano JL: The expression of keratin k10 in the basal layer of the epidermis inhibits cell proliferation and prevents skin tumorigenesis. J Biol Chem. 277:19122–19130. 2002. View Article : Google Scholar : PubMed/NCBI
50	Santos M, Perez P, Segrelles C, Ruiz S, Jorcano JL and Paramio JM: Impaired NF-kappa B activation and increased production of tumor necrosis factor alpha in transgenic mice expressing keratin K10 in the basal layer of the epidermis. J Biol Chem. 278:13422–13430. 2003. View Article : Google Scholar : PubMed/NCBI
51	Czerninski R, Amornphimoltham P, Patel V, Molinolo AA and Gutkind JS: Targeting mammalian target of rapamycin by rapamycin prevents tumor progression in an oral-specific chemical carcinogenesis model. Cancer Prev Res (Phila). 2:27–36. 2009. View Article : Google Scholar