You are on page 1of 3

Oral Oncology 53 (2016) 1719

Contents lists available at ScienceDirect

Oral Oncology
journal homepage:


Oral microbiome, periodontitis and risk of head and neck cancer

Leonardo Victor Galvo-Moreira a, Maria Carmen Fontoura Nogueira da Cruz b,

School of Medicine, Federal University of Maranho, So Lus, Brazil

Department of Dentistry II, Federal University of Maranho, So Lus, Brazil

a r t i c l e

i n f o

Article history:
Received 8 November 2015
Accepted 17 November 2015
Available online 10 December 2015
Head and neck neoplasms
Tooth loss
Dental care

s u m m a r y
A wide range of studies has been successfully exploring the association between the human
microenvironment, sustained inflammation, and cancer. Growing evidence has then emerged in this field
over the past few years. Nevertheless, reliable data addressing the impact of the oral microbiome and
periodontitis on the pathogenesis and risk of head and neck malignancies remain scarce. Hence, this
communication focuses on briefly discuss the relationship between the oral microbiome, periodontitis
and head and neck cancer based on the current understanding of such a disease-associated scenario.
2015 Elsevier Ltd. All rights reserved.

In the field of oncology, there is currently much attention given
to the possible causality between instabilities in the microbiome
dynamics, sustained inflammation and cancer [1,2]. In addition,
head and neck cancer (HNC) continues to be a major public health
issue, affecting over half a million new patients each year
worldwide [3]. Nonetheless, data regarding the significance of oral
bacteria and periodontitis in the development and rates of HNC
remain limited [4].
Most head and neck malignancies involve either the oral or
oropharyngeal sites, rates of which have not experienced significant decreases over the past few years [3]. Therefore, here we summarize important and recent findings that biological, clinical and
epidemiologic research have yielded, which started shedding light
on the impact of this pathogen-associated scenario on head and
neck carcinogenesis.

Oral microbiome and cancer

Oral epithelial surfaces can harbor either symbiotic or hostile
microbes, the roles of which in chronic and inflammatory diseases
have been increasingly clarified since a broad range of studies has
Corresponding author at: Federal University of Maranho, Department of
Dentistry II, Av. dos Portugueses, 1966, Bacanga, 65085-580 So Lus, Maranho,
Brazil. Tel.: +55 98 32728575.
E-mail address: (M.C.F.N. da Cruz).
1368-8375/ 2015 Elsevier Ltd. All rights reserved.

emerged [4]. However, much is unknown with regard to the

connection between oral microbial biofilms and the formation of
potential tumor-associated metabolites, as well as whether such
interactions can up- or down-regulate pro-oncogenic pathways
Interestingly, saliva samples of patients with esophageal cancer
have been highly correlated with the infection of several oral
pathogens, including Treponema denticola, Streptococcus mitis, and
Streptococcus anginosus [5]. Moreover, Fusobacterium nucleatum,
another component of the oral microbiome, has been associated
with colorectal cancer by amplifying intestinal tumorigenesis
through the indirect activation of b-catenin signaling [1].
Oral microbiome and HNC
The oral microbiome has been related to the establishment and
progression of precancerous lesions and neoplasms in the oral cavity [4]. Notably, it contributes to the metabolism of alcohol by
mediating the formation of acetaldehyde, which leads to countless
toxic effects and has a significant impact on the risk of HNC,
particularly oral cavity cancer (OCC) [2]. Still, germ-free rats
presented with lower acetaldehyde concentration, indicating that
might exist an epidemiologic link between poor oral hygiene,
alcohol consumption and increased risk of OCC [2,6].
In terms of the microbiome composition, the levels of
Streptococcus and Rothia were reported to be, respectively,
increased and decreased in OCC samples when compared to contralateral healthy tissues from the same patient [7]. Furthermore,


L.V. Galvo-Moreira, Maria Carmen Fontoura Nogueira da Cruz / Oral Oncology 53 (2016) 1719

higher salivary counts of Capnocytophaga gingivalis, Prevotella

melaninogenica and S. mitis were reported in individuals with oral
squamous cell carcinoma when compared to controls [8].
The exact significance of such findings is not totally clear; however, one might hypothesize that the presence of neoplasms drives
alterations in the oral microenvironment architecture. On the other
hand, it may also indicate that the oral microbiome is suitable to
shifts towards facilitating carcinogenesis [7,8]. A recent report
found that the composition of microbial community in the throat
diverged significantly between patients with laryngeal squamous
cell carcinoma and healthy controls [9]. Thus, although it is not
yet possible to determine whether such a disruption promotes an
augmented risk for laryngeal carcinoma, it definitely deserves
complementary investigation.
Periodontitis, Porphyromonas gingivalis and cancer
Periodontitis is a biofilm-induced inflammatory disease that
leads to irreversible loss of attachment tissues and alveolar bone,
also increasing the risk of developing chronic systemic diseases
[10]. A dysbiotic microenvironment has been observed in
periodontal inflammation, which is triggered mainly, but not
exclusively, by Porphyromonas gingivalis. P. gingivalis is though to
exert a keystone effect via host modulation to breakdown
homeostasis by remodeling the regular microbiome into a
disease-provoking one [11].
Periodontal diseases have been also implicated in the elevated
risk of the occurrence and/or advancement of pancreatic, lung,
and hematopoietic cancers. However, the exact mechanisms
underlying these associations are far from being fully understood
[12,13]. Still, high expression of the human telomerase reverse
transcription (hTERT) enzyme was demonstrated in patients with
periodontitis [14]. This might suggest that both periodontitis and
cancer share an important disease-oriented pathway linked to cellular differentiation and immortality.
P. gingivalis interacts with HNC cells
Greater serum P. gingivalis IgG were linked to augmented mortality in patients with orodigestive cancer (relative risk [RR] = 2.25;
95% confidence interval [CI]: 1.234.14) [15]. P. gingivalis infection
was also shown to activate the ERK1/2-Ets1, p38/HSP27, and PAR2/
NFjB pathways to induce the expression of the proenzyme matrix
metalloproteinase 9 (proMMP9). This higher expression of
proMMP9 and its subsequently active form (MMP9) was then
reported to promote the invasion and metastasis of highly invasive
OCC cells [16].
Additionally, virulent P. gingivalis strains were found to induce
the expression of the B7-H1 and B7-DC receptors in squamous carcinoma cells and human gingival keratinocytes. B7-H1 expression
has been detected in the majority of human cancers, leading to
anergy and apoptosis of activated T cells and allowing tumor cells
to overcome host response, which might facilitate immune evasion
by OCC [17]. Yet, a histological analysis exhibited a greater staining
specific for P. gingivalis in malignant epithelial cells of gingival carcinoma specimens when compared to normal gingival tissues.
Hence, P. gingivalis apparently may have the ability to invade oral
cancer cells in vivo [18].
Periodontitis and HNC risk
Periodontitis was demonstrated to increase the probability of
having oral leukoplakia, a premalignant lesion, in a dosedependent manner (odds ratio [OR] = 5.3; 95% CI: 1.222.7, for
the highest severity of periodontitis). An association with gingival

inflammation, measured by bleeding on probing scores (BOP), was

also identified (OR = 3.8; 95% CI: 1.59.8, for the highest BOP score)
[19]. Leukoplakia is the most frequent precancerous lesion in the
oral cavity, the prevalence of which has been reported to range
from 1.1% to 3.6% worldwide [20].
Moreover, orodigestive cancer mortality was shown to be elevated according to the severity of periodontitis (RR = 2.28; 95%
CI: 1.174.45) [14]. Data obtained from NHANES III indicate that
the severity of periodontitis was found to be markedly associated
with both precancerous lesions (OR = 1.55; 95% CI: 1.062.27)
and oral cancer (OR = 4.57; 95% CI: 2.259.30) [21]. Likewise, periodontitis increased the risk of developing head and neck squamous
cell carcinoma (OR = 4.36; 95% CI: 3.166.01), particularly in the
oral cavity, in a large clinical sample [22].
This is agreement with a recent meta-analysis, which showed
periodontitis to be a risk factor for HNC (OR = 2.63; 95% CI:
1.1684.14) [23]. Although in some small studies, tobacco or alcohol use and socioeconomic confounders attenuated the association
between periodontitis and OCC, overall findings of a recent systematic review concluded that periodontitis is likely to be associated
with increased HNC risk [24].
A history of alveolar bone loss due to chronic periodontitis was
also associated with the presence of the human papilloma virus
(HPV) infection in tumors of HNC patients, in particular those with
oropharyngeal cancer [25]. Although there is a body of evidence to
support the involvement of HPV, especially the genotypes HPV16
and HPV18, in the pathogenesis of HNC, the association between
periodontitis, HNC and HPV infection should be further explored
towards clarifying its clinical relevance [26].
Tooth loss, dental care and HNC
Unlike periodontal disease, dental caries has not been directly
linked to carcinogenesis and HNC rates. Nevertheless, poor levels
of oral hygiene in individuals with cancer may suggest an indirect
relation as poor oral hygiene has been largely reported in HNC
patients before anticancer therapy [27]. Tooth loss is the worst
direct outcome of periodontitis [10], and was observed to significantly elevate the risk of developing HNC according to a recent
meta-analysis (OR = 2.00; 95% CI: 1.283.14) [28]. Another metaanalysis found tooth loss to have a doseresponse effect on cancer
risk as it showed individuals with more than six missed teeth to be
at higher risk of developing HNC (OR = 1.58; 95% CI: 1.082.32)
Furthermore, individuals who had been using dental care in the
past twelve months were 62% less likely to be diagnosed with OCC
(OR = 0.38; 95% CI: 0.131.10) among a population-based sample,
after the adjustment for confounding variables [30]. This is in
agreement with a recent study, which found poor oral health
(OR = 2.36; CI: 1.513.67) and lack of access to dental care
(OR = 2.22; CI: 1.453.41) to be independent risk factors for
upper-aerodigestive tract cancer [31].
Considering that several lines of evidence have implicated P.
gingivalis and periodontitis in HNC rates, it is reasonable to assume
a plausible association from the clinical and epidemiologic standpoints. Conversely, the molecular pathways underlying the roles
of oral bacteria and periodontitis in HNC pathogenesis require
greater exploration, since their current comprehension would preclude us from drawing conclusions about a causal relationship.
Accordingly, further research is required in order to clarify biological mechanisms and their clinical significance. Finally, these findings should be taken into account when developing approaches for
the prevention and management of HNC.

L.V. Galvo-Moreira, Maria Carmen Fontoura Nogueira da Cruz / Oral Oncology 53 (2016) 1719

Conflict of interest
None declared.
[1] Garrett WS. Cancer and the microbiota. Science 2015;348:806.
[2] Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer
[3] Chi AC, Day TA, Neville BW. Oral cavity and oropharyngeal squamous cell
carcinoma an update. CA Cancer J Clin 2015;65:40121.
[4] Atanasova KR, Yilmaz O. Looking in the Porphyromonas gingivalis cabinet of
curiosities: the microbium, the host and cancer association. Mol Oral Microbiol
[5] Khan AA, Shrivastava A, Khurshid M. Normal to cancer microbiome
transformation and its implication in cancer diagnosis. Biochim Biophys Acta
[6] Takahashi N. Oral microbiome metabolism: from who are they? to what are
they doing?. J Dent Res 2015;94:162837.
[7] Schmidt BL, Kuczynski J, Bhattacharya A, Huey B, Corby PM, Queiroz ELS, et al.
Changes in abundance of oral microbiota associated with oral cancer. PLoS One
[8] Mager DL, Haffajee AD, Devlin PM, Norris CM, Posner MR, Goodson JM.
The salivary microbiota as a diagnostic indicator of oral cancer: a descriptive,
non-randomized study of cancer-free and oral squamous cell carcinoma
subjects. J Transl Med 2005;3:27.
[9] Gong H-L, Shi Y, Zhou L, Wu C-P, Cao P-Y, Tao L, et al. The composition of
microbiome in larynx and the throat biodiversity between laryngeal squamous
cell carcinoma patients and control population. PLoS One 2013;8:e66476.
[10] Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet
[11] Hajishengallis G, Darveau RP, Curtis MA. The keystone-pathogen hypothesis.
Nat Rev Microbiol 2012;10:71725.
[12] Michaud DS, Joshipura K, Giovannucci E, Fuchs CS. A prospective study of
periodontal disease and pancreatic cancer in US male health professionals. J
Natl Cancer Inst 2007;99:1715.
[13] Michaud DS, Liu Y, Meyer M, Giovannucci E, Joshipura K. Periodontal disease,
tooth loss and cancer risk in a prospective study of male health professionals.
Lancet Oncol 2008;9:5508.
[14] Katarkar A, Saha A, Mukherjee S, Kundu D, Bandyopadhyay P, Chaudhuri K.
Telomerase expression in individuals with chronic and aggressive
periodontitis. J Periodontol 2015;86:65665.
[15] Ahn J, Segers S, Hayes RB. Periodontal disease, Porphyromonas gingivalis serum
antibody levels and orodigestive cancer mortality. Carcinogenesis


[16] Inaba H, Sugita H, Kuboniwa M, Iwai S, Hamada M, Noda T, et al.

Porphyromonas gingivalis promotes invasion of oral squamous cell carcinoma
through induction of proMMP9 and its activation. Cell Microbiol
[17] Groeger S, Domann E, Gonzales JR, Chakraborty T, Meyle J. B7-H1 and B7-DC
receptors of oral squamous carcinoma cells are upregulated by Porphyromonas
gingivalis. Immunobiology 2011;216:130210.
[18] Katz J, Onate MD, Pauley KM, Bhattacharyya I, Cha S. Presence of
Porphyromonas gingivalis in gingival squamous cell carcinoma. Int J Oral Sci
[19] Meisel P, Holtfreter B, Biffar R, Suemnig W, Kocher T. Association of
periodontitis with the risk of oral leukoplakia. Oral Oncol 2012;48:85963.
[20] Petersen PE, Bourgeois D, Ogawa H, Estupinan-Day S, Ndiaye C. The global
burden of oral diseases and risks to oral health. Bull World Health Organ
[21] Tezal M, Grossi SG, Genco RJ. Is periodontitis associated with oral neoplasms? J
Periodontol 2015;76:40610.
[22] Tezal M, Sullivan MA, Hyland A, Marshall JR, Stoler D, Reid ME, et al. Chronic
periodontitis and the incidence of head and neck squamous cell carcinoma.
Cancer Epidemiol Biomarkers Prev 2009;18:240612.
[23] Zeng X-T, Deng A-P, Li C, Xia L-Y, Niu Y-M, Leng W-D. Periodontal disease and
risk of head and neck cancer: a meta-analysis of observational studies. PLoS
One 2013;8:e79017.
[24] Javed F, Warnakulasuriya S. Is there a relationship between periodontal
disease and oral cancer? A systematic review of currently available evidence.
Crit Rev Oncol Hematol 2015. pii: S1040-8428(15)30033-0.
[25] Tezal M, Scannapieco FA, Wactawski-Wende J, Hyland A, Marshall JR, Rigual
NR, et al. Local inflammation and human papillomavirus status of head and
neck cancers. Arch Otolaryngol Head Neck Surg 2012;138:66975.
[26] Ndiaye C, Mena M, Alemany L, Arbyn M, Castellsagu X, Laporte L, et al. HPV
DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a
systematic review and meta-analysis. Lancet Oncol 2014;15:131931.
[27] Meurman JH, Bascones-Martinez A. Are oral and dental diseases linked to
cancer? Oral Dis 2011;17:77984.
[28] Wang R-S, Hu X-Y, Gu W-J, Hu Z, Wei B. Tooth loss and risk of head and neck
cancer: a meta-analysis. PLoS One 2013;8:e71122.
[29] Zeng X-T, Luo W, Huang W, Wang Q, Guo Y, Leng W-D. Tooth loss and head
and neck cancer: a meta-analysis of observational studies. PLoS One 2013;8:
[30] Holmes Jr L, desVignes-Kendrick M, Slomka J, Mahabir S, Beeravolu S, Emani
SR. Is dental care utilization associated with oral cavity cancer in a large
sample of community-based United States residents? Community Dent Oral
Epidemiol 2009;37:13442.
[31] Ahrens W, Pohlabeln H, Foraita R, Nelis M, Lagiou P, Lagiou A, et al. Oral health,
dental care and mouthwash associated with upper aerodigestive tract cancer
risk in Europe: the ARCAGE study. Oral Oncol 2014;50:61625.