Presence of Porphyromonas gingivalis in esophagus and its association with the clinicopathological characteristics and survival in patients with esophageal cancer
© Gao et al. 2016
Received: 24 November 2015
Accepted: 11 January 2016
Published: 19 January 2016
Mounting evidence suggests a causal relationship between specific bacterial infections and the development of certain malignancies. However, the possible role of the keystone periodontal pathogen, Porphyromonas gingivalis, in esophageal squamous cell carcinoma (ESCC) remains unknown. Therefore, we examined the presence of P. gingivalis in esophageal mucosa, and the relationship between P. gingivalis infection and the diagnosis and prognosis of ESCC.
The presence of P. gingivalis in the esophageal tissues from ESCC patients and normal controls was examined by immunohistochemistry using antibodies targeting whole bacteria and its unique secreted protease, the gingipain Kgp. qRT-PCR was used as a confirmatory approach to detect P. gingivalis 16S rDNA. Clinicopathologic characteristics were collected to analyze the relationship between P. gingivalis infection and development of ESCC.
P. gingivalis was detected immunohistochemically in 61 % of cancerous tissues, 12 % of adjacent tissues and was undetected in normal esophageal mucosa. A similar distribution of lysine-specific gingipain, a catalytic endoprotease uniquely secreted by P. gingivalis, and P. gingivalis 16S rDNA was also observed. Moreover, statistic correlations showed P. gingivalis infection was positively associated with multiple clinicopathologic characteristics, including differentiation status, metastasis, and overall survival rate.
These findings demonstrate for the first time that P. gingivalis infects the epithelium of the esophagus of ESCC patients, establish an association between infection with P. gingivalis and the progression of ESCC, and suggest P. gingivalis infection could be a biomarker for this disease. More importantly, these data, if confirmed, indicate that eradication of a common oral pathogen could potentially contribute to a reduction in the overall ESCC burden.
KeywordsPorphyromonas gingivalis ESCC Lys-gingipain 16S rDNA Oral pathogen Differentiation Metastasis Overall survival rate Prognoses
Since the discovery that Helicobacter pylori plays a causative role in gastric adenocarcinoma, multiple other associations between specific bacteria and cancer have been reported [1, 2], including Salmonella typhi with gall bladder cancer , Streptococcus bovis with colon cancer , Chlamydophila penumoniae with lung cancer , Bartonella species with vascular tumor formation , Propionibacterium acnes with prostate cancer , and Escherichia coli with colon cancer . Esophageal cancer is the eighth most frequent tumor and sixth leading cause of cancer death worldwide. Whereas the majority of cases occur in Asia, particularly in central China, recent data suggest that the frequency of new cases is rising in Western Europe and the USA [9, 10]. Two major histological subtypes of esophageal cancer have been identified including squamous cell carcinoma (ESCC), which is more common in developing countries, and adenocarcinoma, which is more common in developed nations . Esophageal cancer is characterized by difficulty of early diagnosis, rapid development and high mortality. Therefore, there is a considerable need to better understand causative agents in order to reduce the incidence and mortality of this disease. Like most cancers, a plethora of risk factors including age, gender, heredity, gene mutation, chemical exposure, and diet have been reported for esophageal cancer [12, 13].
A potential contribution of microbes to the development of esophageal cancer is beginning to emerge. Pei et al. reported that Streptococcus, Prevotella and Veillonella are the most prevalent genera detected in esophageal biopsies [14, 15]. Yang et al. have classified the esophageal microbiota into two subtypes: the Streptococcus-dominated type I microbiome, which is mainly associated with a normal esophagus, and the type II microbiome, in which Gram-negative anaerobes predominate, which is associated with Barrett’s esophagus (BE) and esophagitis . A significant association between the inhabitants of the upper digestive tract microbiota and esophageal squamous dysplasia, a precursor lesion of esophageal squamous cell carcinoma, has also been reported . While there are several phylum-wide studies on the esophageal microbiota and the possible associations with reflux esophagitis, Barrett’s esophagus, and esophageal squamous dysplasia, there has been no research on the esophageal microbiota in patients suffering from ESCC, especially at species level, let alone the possible association of these bacteria with the development of ESCC.
The microbiome in chronic and severe manifestations of periodontal disease is enriched for Gram-negative anaerobic bacteria. Among these, Porphyromonas gingivalis is a keystone oral pathogen which can invade epithelial cells, and interfere with host immune responses and the cell cycle machinery [18–20]. Epidemiological studies have demonstrated that periodontal diseases and tooth loss are significantly associated several cancers such as oral cancer, gastric cancer, and pancreatic cancer and may even relate to survival [20–24]. P. gingivalis-mediated immune evasion, apoptosis inhibition, carcinogen conversion, induction of MMP-9 and dysbiosis of the oral microbiota have all been posited as pro-tumorigenic mechanisms in the context of oral squamous cell carcinoma [20, 25]. Since esophageal squamous cells are histologically similar to oral squamous cells and esophageal infection arising from the oral niche is highly plausible, we hypothesized that P. gingivalis may be associated with ESCC. We set out to test this hypothesis using 100 ESCC subjects and 30 normal matched controls.
Immunohistochemical detection of P. gingivalis presence is more common in ESCC
Presence of P. gingivalis and Lys-gingipain (Kgp) detected by specific antibodies in normal esophagus mucosa, cancerous and adjacent tissues of ESCC
Pg positive cases (%)
KGP positive cases (%)
ESCC samples (n = 100)
Adjacent normal tissues (n = 100)
Normal esophageal mucosa (n = 30)
Expression of P. gingivalis lysine-gingipain (Kgp) is more common in ESCC
P. gingivalis 16S rDNA is more frequent in ESCC
PCR-detected expression of P. gingivalis in normal esophagus mucosa, cancerous and adjacent tissues of ESCC
ESCC samples (n = 100)
Adjacent normal tissue (n = 100)
Normal esophageal mucosa (n = 30)
Comparison of different methods for the detection of P. gingivalis presence
Pearson’s contingency coefficient analysis of the correlation between the levels of immunohistochemical staining of P. gingivalis and KGP in cancerous tissue of ESCC patients
Concordance between the immunohistochemistry with P. gingivalis whole cell antibodies and qPCR of P. gingivalis 16S rDNA in the cancerous tissue from patients with ESCC
P. gingivalis infection is positively correlated to clinicopathologic characteristics of ESCC
Association between the presence of P. gingivalis or Lys-gingipain and the clinicopathologic features of ESCC patients
Pg positive cases (%)
KGP positive cases (%)
ESCC samples (n = 100)
Adjacent normal tissues (n = 100)
Normal esophageal mucosa (n = 30)
Male (n = 70)
Female (n = 30)
≤60 (n = 39)
>60 (n = 61)
Smoking (n = 45)
Non-smoking (n = 55)
Well (n = 22)
Moderate (n = 58)
Poor (n = 20)
Lymph node metastasis
Positive (n = 38)
Negative (n = 62)
I+ II (n = 68)
III (n = 32)
P. gingivalis infection is negatively correlated with overall ESCC survive rate
Means and medians for the survival time (months) of ESCC patients with positive or negative expression of P. gingivalis and Lys-gingipain
95 % Confidence interval
To the best of our knowledge, the composition and potential role of the esophageal microbiota in the patients suffering from ESCC have not been investigated. Using three complementary approaches, we have established that antigens and DNA from P. gingivalis, a periodontal pathogen, can be detected in the epithelium of the esophagus of ESCC patients. The intensity of expression of whole P. gingivalis antigen, its unique protease Lys-gingipain, and detection of P. gingivalis-specific16S rDNA were all significantly higher in the cancerous tissue of ESCC patients than in the surrounding tissue or normal control sites. Moreover, our analysis indicates that the presence of P. gingivalis correlates with multiple clinicopathologic factors, including cancer cell differentiation, metastasis, and overall survival ESCC rate. These findings provide the first direct evidence that P. gingivalis infection could be a novel risk factor for ESCC, and may also serve as a prognostic biomarker for this prevalent cancer.
A number of aspects of the interaction of P. gingivalis with host epithelial cells provide a plausible molecular basis for potential P. gingivalis-mediated carcinogenesis [20, 25, 26]. First, chronic inflammation per se is associated with the development of cancer , and, for example, prolonged IL-6 signaling and STAT3 activity is known to be pro-tumorogenic [28, 29]. In this regard, both our group and others have demonstrated that P. gingivalis activates JAK2 and GSK3β pathways, thus increasing the production of IL-6 in epithelial cells [28, 30]. Secondly, P. gingivalis can promote tumorigenesis by secreting a nucleoside diphosphate kinase (NDK). NDK from P. gingivalis antagonizes ATP activation of P2X7 receptors, and thus reduces IL-1β production from epithelial cells . Since IL-1β is critical for priming IFNγ-producing, tumor–antigen-specific CD8+ T cells, NDK from P. gingivalis could promote the immune evasion of tumor cells . Moreover, NDK-mediated degradation of ATP also suppresses apoptosis dependent on ATP activation of P2X7 receptors . Thirdly, P. gingivalis inhibits epithelial cell apoptosis by a number of mechanisms, including activation of Jak1/Akt/Stat3 [33, 34], enhancing the Bcl2 (antiapoptotic): Bax (proapoptotic) ratio, blocking the release of the apoptosis effector cytochrome c, and the activation of downstream caspases . Moreover, P. gingivalis can upregulate microRNAs, such as miR-203, which suppress apoptosis in primary gingival epithelial cells . In concert with suppression of apoptosis, P. gingivalis can accelerate progression through the cell cycle by manipulation of cyclin/CDK (cyclin-dependent kinase) activity and reducing the level of the p53 tumor suppressor . Lastly, in oral squamous cell carcinoma (OSCC) cells, P. gingivalis promotes cellular migration through activation of the ERK1/2-Ets1, p38/HSP27, and PAR2/NF-κB pathways to induce pro-matrix metalloproteinase (MMP)-9 expression . Apart from all the above, another possible mechanism for P. gingivalis induced carcinogenesis is the metabolism of potentially carcinogenic substances. For example, P. gingivalis converts ethanol into its carcinogenic derivative, acetaldehyde, to levels capable of inducing DNA damage, mutagenesis and hyperproliferation of the epithelium [38, 39], which could help explain the epidemiological evidence associating heavy drinking and development of some cancers .
While it is possible that P. gingivalis infection initiates or is a co-factor in the transformation of esophageal epithelial cells, the possibility that cancer tissues represent a preferred microenvironment for P. gingivalis cannot be excluded. Thus, while our results reveal a positive association between infection with P. gingivalis and the progression of ESCC, P. gingivalis is not yet established as a novel etiological agent or co-factor of ESCC. Should P. gingivalis prove to cause ESCC, the implications are enormous. It would suggest (i) that improved oral hygiene might reduce ESCC risk, (ii) that screening for P. gingivalis in dental plaque may identify susceptible subjects, and that (iii) antibiotic use, or other anti-bacterial strategies, may prevent ESCC progression. Should the clear association between P. gingivalis infection and ESCC turn out to be better explained by physiological conditions inside ESCC cells being more amenable to P. gingivalis survival and growth, this would imply that attenuated P. gingivalis or non-pathogenic bacteroidetes strains that contain eukaryotic lysins may represent a novel and effective therapeutic approach for ESCC. In this regard, several studies have attempted to take advantage of the oxygen-limited conditions present in malignant cells to develop anaerobic, non-pathogenic bacteria for the delivery of cancer cell cytolysins . These include Clostridium novyi for the treatment of melanoma and modified Bifidobacterium longum carrying 5-fluorocytosine for the treatment of breast cancer [41–43]. Hence, further studies to determine if P. gingivalis infection promotes the initiation and progression of ESCC are required.
Finally, colonization by P. gingivalis promotes the conversion of a symbiotic to a dysbiotic of oral microbiota, a process considered critical for the progression of periodontal disease . Dysbiosis of the microbiota in the esophagus could potentially cause or exacerbate the severity of esophageal disorders . Thus, a further possibility to be tested is that esophageal infection with P. gingivalis leads to shift in the microbiome involved in the development of esophageal cancer.
In summary, we have established that P. gingivalis molecules are present in the epithelium of the esophagus of ESCC patients and provide the first direct evidence of a positive correlation between P. gingivalis infection, ESCC severity and poor prognosis. These findings demonstrate for the first time that P. gingivalis infects the epithelium of the esophagus of ESCC patients, establish the association between the infection of P. gingivalis and the progression of ESCC, and suggest P. gingivalis infection could be a biomarker for this disease. More importantly, these data, if confirmed, indicate that eradication of an oral pathogen could potentially contribute to a reduction in the overall ESCC burden.
The study was approved by the Institutional Review Board of the University of Henan University of Science and Technology (HUST).
Patients and human tissue
One hundred patients with ESCC who underwent esophagectomy surgery from 2010 to 2014 at the First Affiliated Hospital of Henan University of Science and Technology and Anyang people’s hospital were investigated in this study. Adjacent tissue samples were obtained 3 cm distant to cancerous tissue. Thirty additional specimens were randomly selected during endoscopic examination from biopsy, and confirmed histologically as normal esophagus mucosa. Demographics (sex and age) and clinicopathologic features (differentiation status, lymphatic invasion, lymph node metastasis, TNM stage) were obtained from medical records. A smoker was defined as someone who had smoked one cigarette or more per day for at least 1 year. Overall survival rates were determined over 30 months.
Tissues were fixed in formalin and then embedded in paraffin. Serial sections of 4 mm thickness were prepared and deparaffinized by submersion in three separate concentrations of ethanol (100, 95, and 70 %), and rinsing continuously in distilled water for 5 min. Antigen retrieval was performed by incubating slides in antigen retrieval Citra plus solution (BioGenex, San Ramon, USA), according to the manufacturer’s instructions. Slides were blocked 1.5 % normal goat serum (Vector Laboratories, Burlingame, USA) for 30 min. Polyclonal rabbit anti-P. gingivalis 33277  and monoclonal mice anti-Lys-gingipain (Kgp) (15C8G5E6C2) antibodies  were utilized for the detection of P. gingivalis. Pre-immune rabbit IgG and normal mouse IgG was used as a negative control. Primary antibodies were incubated with tissue sections (anti-whole cells 1:1000 dilution; anti-Lys-gingipain 1:500 dilution) for 12 h, 4 °C, followed by biotin-conjugated secondary antibody for 1 h at room temperature, streptavidin-peroxidase for 30 min at room temperature, and enzyme substrate (3,3′-Diaminobenzidine, Dako, Denmark). As an additional control, sections were also incubated with phosphate buffered saline (PBS) only, followed by incubation with biotin-conjugated secondary antibody, streptavidin-peroxidase, and enzyme substrate. PBS washes (3 times, 5 min each) were performed during each incubation step. Sections were counterstained with methyl green and visualized by light microscopy (Eclipse 80i, Nikon, Japan). Every tissue section was evaluated by two senior pathologists (Dr. Mi and Dr. Zhang). The kappa statistic was used to assess inter-observer variability with a score of >0.75 indicating excellent agreement. Staining intensity was classified using a numerical scale; grade 0 (none, 0–10 % staining); grade 1 (weak, 10–30 %); grade 2 (moderate, 30–60 %), and grade 3 (strong, over 60 %), with a score of > =2 considered positive of staining with P. gingivalis or Lys-gingipain.
Determination of16S rDNA in fresh ESSC tissue
For each patient, tissues from cancer and adjacent to cancer sites (minimum 3 cm distant) were harvested and used as experimental and internal controls, respectively. Endoscopy biopsy specimens from healthy age- and gender-matched individuals were obtained from normal controls (n = 30). Tissues were suspended in 500 μl of sterile phosphate-buffered saline, vortexed for 30 s and sonicated for 10 s. Proteinase K (2.5 mg/ml final concentration) was added and the samples were incubated overnight at 55 °C, homogenized with sterile disposable pestle and vortexed. DNA was extracted as described previously  and purified by phenol-chloroform extraction. All samples were stored at −20 °C until further analysis. For amplification, DNA concentrations were adjusted to 20 ng/ml. 16S rDNA samples were amplified as described previously  using P. gingivalis specific and universal 16S rDNA primers (P. gingivalis 16S rDNA primer sequences were: 5′ AGGCAGCTTGCCATACTGCG 3′ (forward) and 5′ ACTGTTAGCAACTACCGATGT 3′ (reverse), and the PCR product size was 404 bp; The universal 16S rDNA primer sequences were 5′ GATTAGATACCCTGGTAGTCCAC 3′ (forward) and 5′ CCCGGGAACGTATTCACCG 3′ (reverse), and the PCR product size was 688 bp). PCR reactions were performed at 95 °C for 5 min, followed by 30 cycles of denaturation at 95 °C for 1 min, annealing at 52 °C for 1 min, and elongation at 72 °C for 1 min with final elongation at 72 °C for 5 min.
All statistical analyses were performed by SPSS statistical package, version 17.0 (SPSS Inc., Chicago, IL, USA). Pearson’s contingency coefficient was used to test for the association between the immunohistochemical staining levels of P. gingivalis and Kgp. Correlations between the presence of P. gingivalis and clinicopathologic factors were analyzed by ANOVA or Chi-square test, as appropriate. Overall survival was estimated using the Kaplan-Meier method and the log-rank test for comparison. Multivariate analysis was performed to examine if P. gingivalis presence was an independent prognostic factor using the Cox proportional-hazards regression model. P values of ≤ 0.05 were considered to be statistically significant.
Esophageal squamous cell carcinoma
Signal transducer and activator of transcription
Janus kinase 2
Glycogen synthesis kinase 3 beta
Nucleoside diphosphate kinase
Oral squamous cell carcinoma
We acknowledge the financial supports by Natural Science Foundation of China (NSFC, GS 81472234; NSFC, YX U1404817), and partially by National Institute of Dental and Craniofacial Research at National Institutes of Health, USA, DE023633 (HW), DE017921, DE011111 (RJL), and JP acknowledges support by NIDCR/NIH DE 022597, European Commission (FP7-PEOPLE-2011-ITN-290246 “RAPID” and FP7-HEALTH-F3-2012-306029 “TRIGGER”) and Polish Ministry of Science and Higher Education (project 2975/7.PR/13/2014/2).
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