Am J Clin Exp Urol 2019;7(1):1-10 www.ajceu.us /ISSN:2330-1910/AJCEU0090007

Review Article Association between oral pathogens and prostate cancer: building the relationship

Andre Paes B da Silva1, Leela Subhashini C Alluri1, Nabil F Bissada1, Sanjay Gupta2

Departments of 1Periodontics, 2Urology, Case Western Reserve University, School of Dental Medicine, Cleveland 44106, Ohio Received December 17, 2018; Accepted January 16, 2019; Epub February 18, 2019; Published February 28, 2019

Abstract: Background: Chronic inflammation and infections are associated with increased risk of prostate cancer development. There is considerable evidence that proves the interrelationship between bacterial/viral infections and carcinogenesis. Periodontitis is a chronic inflammatory disease triggered by gram-negative anaerobic bacteria. In this narrative review, we investigate the relationship between and prostate cancer by review- ing previous studies of the association and possible mechanisms that may explain this link. Methods: A comprehen- sive search for articles published was performed using the key words, “periodontal disease”, “prostate disease”, “prostate cancer”, “prostatic inflammation”. Thorough reviews of each study were conducted and assessed for eligibility, and data was summarized. Results: The role of inflammatory responses in the prostate as drivers of malignancy appears to be predisposed by periodontal pathogens and/or periodontitis inflammatory mediators. Conclusion: Periodontal diseases might be associated with prostate cancer. However, the mechanism(s) explaining this relationship remains unclear and requires further elucidation.

Keywords: Prostate cancer, periodontal diseases, prostatic inflammation, benign prostate hypertrophy

Introduction Recent studies report an association between prostate cancer, periodontal diseases, and too- Prostate cancer is the most frequent cancer to th loss [8, 9]. occur in males and second foremost cause of cancer-related death in the Western world [1]. Periodontal diseases are inflammatory condi- According to an estimate by GLOBOCAN data- tions that have a local effect on the supporting base, approximately 1.1 million men worldwide structure of the teeth, which may lead to tooth were diagnosed with prostate cancer in 2012, loss and contribute to systemic inflammation accounting for 15% of the cancers diagnosed in [10]. predominantly aff- men [1, 2]. In the United States, prostate can- ects the tissues surrounding the teeth in re- cer is the second leading cause of cancer-relat- sponse to accumulation of a subgingival bio- ed death in men, behind lung cancer [3]. Ac- film, which consists of over 700 bacterial spe- cording to an estimate by the American Cancer cies [11, 12], many protozoa species [13] and Society, in 2019 approximately 164,690 new viruses [14]. Of these, the most often recog- cases of prostate cancer will be diagnosed, and nized periodontal microbes include Actinobaci- 29,430 deaths will occur from the disease [4]. llus actinomycetemcomitans, Prevotella inter- In recent years, prostate cancer is of significant media, , Bacteroides concern due to the gradual increase in the forsythus, Campylobacter rectus, Treponema number of aging men and the existence of more denticola, , Eubacte- than 3 million men with the disease. Re- rium, and Spirochetes (sp) [14, 15]. Additionally, cent observations suggest that prostate cancer various human herpes viruses, such as Epste- is associated with chronic inflammation [5, 6]. in-Barr virus (EBV-1), and cytomegalovirus (HC- Several factors might be responsible for pros- MV) have also been detected [16]. The subgin- tate inflammation, especially the presence of gival biofilm may induce a host release of pro- pathoogens in the urine, and sexual activity [7]. inflammatory mediators that elicit a chronic Periodontal pathogens contributing to prostate cancer

Table 1. Studies on the relationship between periodontal disease and prostate cancer Author (Year) Study Design Purpose/Criteria Results/Conclusions Lee et al. (2017) [34] Cohort To investigate the association between PD The incidence of PC with PD and PC using records from the National Health in men with 40 and above Insurance Service-Health Examinee Cohort age group was 0.28%. PD (NHIS-HEC). was linked with a 14% greater hazard of PC. Ing-ming Hwang et al. (2014) [32] Cohort To assess the effect of treatment of PD and the Treatment of PD reduces the risks for cancers in Taiwan. Therapy included risk of overall cancer and , subgingival curettage individual cancers. and periodontal flap surgery. Risk of PC was higher in the treatment cohort group. Arora et al. (2009) [8] Prospective co-twin study Investigation of hereditary risk factors between PD and PC (Hazard ratio 1.47) periodontal disease and cancers. PD measured by questionnaire-recorded . Hiraki et al. (2008) [33] Case-control To determine the significance of tooth loss An inverse association between on the risk of 14 cancers. The teeth loss was the number of teeth loss and categorized into four groups depending on the risk of PC number of remaining dentition Michaud et al. (2008) [31] Cohort To determine if PD or teeth loss is associ- PD was associated with risk of ated with cancer risk. Individuals surveyed on overall cancer and individual the history of PD with bone loss, number of cancers. An inverse association remaining teeth; status and history of smoking; between the number of teeth frequency of food intake; any new diagnose of loss and risk of prostate cancer cancer. Survey obtained at baseline and in all subsequent follow-up. Hujoel et al. (2003) [9] Cohort To investigate PD and cancer relationship. Indi- Demonstrated a correlation viduals with PD or , a healthy periodon- between PC and PD measured tium or edentulous were identified at the com- by Russell’s periodontal index mencement of the follow-up. These groups are (odds ratio 1.81). identified by the teams of dentists and trained Increased risk of PC in individu- recorders evaluated the periodontal status of als with the PD. individual participants. The diagnosis of cancer was determined from death certificates. Acronyms: PD - periodontal disease. PC - prostate cancer. inflammatory response, leading to alveolar bo- advance the hypothesis that periodontal dis- ne loss [10]. Furthermore, studies have indicat- eases may be significant in its contribution to ed that oral health may influence systemic he- prostate inflammation and cancer. alth [10]. Several reports showed an associa- tion between periodontal disease and systemic Materials and methods conditions such as cardiovascular disease [10], type 2 diabetes mellitus [10], preterm low birth An electronic search was carried out in PubMed weight infants [17-20], osteoporosis [10], rheu- database until August 2018 for all relevant matoid arthritis [21, 22], Parkinson’s disease publications that explored the association be- [23], Alzheimer’s disease [24], psoriasis [25], tween periodontal diseases and/or periodontal respiratory functions [26] and several types of microbes in prostate inflammation and malig- human cancers [27]. In particular, individuals nancy. The following MeSH terms were used, with periodontal disease have a greater risk of “Periodontal Disease [All Field]”, “Prostate dis- cancer overall and site-precise malignancies ease [MeSH terms]”, “Prostate cancer [MeSH terms]”, “Prostatic Inflammation [MeSH terms]”. including oral [28], gastrointestinal [29], lung Literature published in the English language [9], pancreatic [30], hematologic [31] and pros- was included. tate [8, 9]. It has been reported that chronic inflammatory response to periodontal infection Results and discussion impacts beyond the oral cavity [22] and might increase the risk of various malignancies [23- Association between periodontal disease and 25]. This association is supported by the effec- prostate cancer tiveness of anti-inflammatory drugs in reducing the risk of oesophageal, gastric, colorectal, bil- A growing number of reports suggest that peri- iary, breast, pancreatic [21], and genitourinary odontal disease is significantly associated with cancers [26, 27]. The aim of this review is to an increased risk of prostate cancer [8, 9].

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Arora et al. (2010), in a prospective co-twin stu- sis that periodontal pathogens may be migrat- dy, reported an association of prostate cancer ing through the systemic circulation to initiate and periodontal disease measured by ques- an infection and inflammatory response in the tionnaire-recorded tooth mobility and prostate prostate. The prostate inflammatory responses cancer (hazard ratio 1.47) [8]. In another inves- may in turn induce neoplastic transformations. tigation, Hujoel et al. (2003), in a prospective cohort study, evaluated data from 11,328 indi- Chronic inflammation and prostate cancer viduals and verified a correlation between pros- tate cancer and periodontal disease (odds ratio Grading and types of prostate inflammation 1.81) [9]. Despite the small sample size of (20 cases) of prostate cancer, this study was the Several studies have suggested that inflam- only one to include a direct evaluation of the mation is common within the prostate [5]. The periodontal condition and establish a positive National Institutes of Health (NIH) consensus association between both diseases [9]. A study classification refers chronic intraprostatic in- in Taiwan, by Hwang et al. (2014) showed that flammation as chronic prostatitis (CP)/chronic periodontal treatment consisting of scaling and pelvic pain syndrome (CPSS) [38]. According root planing, subgingival curettage and perio- to NIH, prostatitis is classified into four catego- dontal flap surgery decreased the risk of cancer ries: (1) acute bacterial prostatitis (category I); of the gastrointestinal tract, lungs, brain, and (2) chronic bacterial prostatitis (category II); (3) female reproductive organs [32]. However, the CP/CPPS (category III); and (4) asymptomatic risk of prostate and thyroid cancers was signifi- inflammatory prostatitis (category IV) [38]. CP/ cantly greater even after periodontal treatment CPPS (category III) is the most common prosta- [32]. Michaud and Hiraki (2008) reported an titis syndrome, covering approximately 95% of inverse association between the number of prostatitis cases [38]. This condition is extre- teeth lost and the risk of prostate cancer mely common in adults: 2-10% of adults suffer [31, 33]. However, the tooth loss is not neces- from symptoms compatible with chronic pros- sarily representative of periodontal disease; tatitis, and approximately 15% of men suffer for instance, an individual may lose teeth due from symptoms of prostatitis [39]. Subgroup to caries or fracture. Furthermore, in a more IIIA of this category consists of individuals with recent study it was found that periodontal dis- white blood cells in their prostatic fluid, post- ease was associated with a 14% higher risk of prostate massage urine/or seminal fluid [39], prostate cancer [34]. Overall, these studies in- and subgroup IIIB consist of individuals without dicate that, an association probably exists be- leukocytes in any fluid [38]. It has been report- tween periodontal diseases and prostate can- ed that genitourinary tract pathogens such as cer, see Table 1. Joshi et al. (2010) from Case Chlamydia trachomatis, Ureaplasma urealyti- Western Reserve University evaluated serum cum, protozoan pathogen Trichomonas vagina- prostate-specific antigen (PSA) levels as a mar- lis, Neisseria gonorrhea, herpes simplex types I ker of inflammation in patients with prostatitis and II, and cytomegalovirus may be playing a and periodontitis and showed that subjects role in CP/CPPS [40-44]. Category IV, asymp- with both diseases have greater levels of PSA tomatic inflammatory prostatitis, is present in compared with either disease alone [35]. Fur- patients undertaking examination for other uro- thermore, Alwithanani et al. (2015) reported genital conditions, such as increased PSA [38]. the impact of treatment of periodontal disease The estimated prevalence of category IV pros- on clinical symptoms of prostatitis showing that tatitis is 11.2-32.3% in patients with elevated periodontal treatment improves prostate symp- PSA [45]. It has been reported by Roberts et al. toms and lowered serum PSA levels in patients (2004) that prostatitis category III was associ- having both periodontitis and prostatitis [36]. ated with prostate malignancy whereas catego- Estemalik et al. (2017) further substantiated ry I, II, IV was not [46, 47]. the association between periodontitis and pro- statitis, as evidenced by the presence of simi- Chronic inflammation-mediated histological lar oral bacteria such as P. gingivalis and T. den- changes in the prostate ticola DNA in both the expressed prostatic secretion (EPS) and of the same Epidemiological, histopathological, and in vivo patient [37]. This finding support the hypothe- investigations have determined an association

3 Am J Clin Exp Urol 2019;7(1):1-10 Periodontal pathogens contributing to prostate cancer between chronic inflammation and an increas- icity [56]. This study provides evidence that ed risk of prostate cancer [5, 48, 49]. However, prostatitis may trigger the development of pros- the significance of inflammation of the prostate tate cancer. gland, and the mechanisms that lead to the de- velopment of prostate cancer are still unclear. Role of infectious organisms in prostatic can- Numerous meta-analysis and case-control stu- cer dies have shown that men with prostatitis have a considerable increase risk of having prostate Periodontal microorganisms cancer. Daniels et al. (2005) conducted a pro- Dental biofilm is an organized mass, consist- spective cohort study of 5821 men, and sh- ing mainly of microorganisms, that adheres to owed an association between a history of pr- teeth [57, 58]. In the gingival crevice and peri- ostatitis and a history of prostate cancer (OR odontal pocket, a dysbiotic biofilm is one of the 5.4, 95% CI 4.4-6.6) [50]. Dennis et al. (2002) main factors contributing to periodontal diseas- reported in a meta-analysis of 11 case-control es [59]. Nearly 50% of the American popula- studies that there is an increased risk of pros- tions have chronic periodontitis as manifest- tate malignancy among men with a history of ed by alveolar bone resorption [61]. There is an prostatitis (odds ratio = 1.6) [48]. The presence association between periodontal diseases and of inflammatory cell infiltrates and proliferative systemic diseases [10, 62, 63]. This link may inflammatory atrophy (PIA) are often detected be due to a metastatic, spreading/diffusion of in histologic samples of benign and malignant periodontal bacteria and/or bacterial toxins prostates [51-54]. PIA consists of lesions that [63] to other parts of the body. Many authors might include epithelial atrophy [51, 52, 55, 56] have provided a comprehensible correlation low apoptotic index, and an increased prolifera- among two or more systemic diseases with tive index [51, 55], typically with inflammation periodontitis [62-66]. characterized by mononuclear infiltrates in the periglandular stroma or by macrophages and For instance, oral microbial pathogens are as- neutrophils in the glandular lumina or epitheli- sociated with undesirable pregnancy outcomes um. PIA is an inflammatory lesion emerging as [67, 68]. Periodontal pathogens P. gingivalis, F. a result of infection or cell injury subsequent nucleatum [68, 70, 71] and A. actinomycetem- from free radical toxicity, hypoxia, infection or comitans [69, 70] have the ability to cross the autoimmunity. These lesions may lead to malig- placental barrier and have been detected in the nancy through an accumulation of transmuta- amniotic fluid of women with preterm low-birth- tion in rapidly dividing cells. PIA is probably a weight infants [71-73]. Additionally, F. nuclea- precursor lesion to cancer and frequently exist tum DNA is identified in the synovial fluid of near to high-grade prostatic intraepithelial neo- individuals who have rheumatoid arthritis [75]. plasia (HGPIN) or early cancer. It has been de- Recent studies link periodontal bacteria to termined that a genetic association between prostate inflammation and cancers [76, 77]. In PIA, HGPIN, and cancer exists [51]. MacLennan a study conducted in the Department of Perio- et al. (2006), in a five years follow-up study, dontics at CWRU, Estemalik et al. (2017) de- examined prostate biopsy specimens of men tected DNA of the periodontitis pathogens P. with clinically abnormal findings and reported gingivalis, T. denticola, and E. coli in prostatic that the majority had chronic inflammation of secretions of men with both periodontal and prostate gland and that 6% of these patients prostate diseases [37]. Oral microbes migrate had adenocarcinomas [5]. These studies sug- to other parts of the body via the bloodstream, gest that the history of chronic inflammation is causing chronic inflammation that may initiate associated with an increased risk for prostate neoplastic transformation, the first step to- cancer. Elkahwaji et al. (2009), in a 25 weeks wards malignancy [71]. A series of studies sh- follow-up study, using an animal model of ch- owed the association of F. nucleatum species ronic prostatitis induced by E. coli infection, to colorectal carcinomas [78-80]. Also, Hwang detected the development of prostate hyper- mentioned that studies showed the presence plasia and dysplasia [56]. Furthermore, the of fusobacteria in normal tissue next to colon prostate epithelium exhibited positive nuclear cancer [32]. According to Jacob et al. (2016) staining for 8-hydroxy-20-deoxyguanosine, a individuals with P. gingivalis in their oral cavity biomarker of DNA injury due to free radical tox- had a 59% increased risk of pancreatic cancer

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may involve an infectious com- ponent [48]. The microbial pa- thogens in urinary tract infec- tions are similar to bacterial prostatitis in category and dis- tribution [85]. Bacterial prosta- titis may be an outcome of ascending urinary tract infec- tions, resulting from urethral inoculation during sexual inter- course [85]. In addition, sexu- ally transmitted agents have been identified in the prostate, such as the human papilloma- virus, human herpes simplex virus type 2, cytomegalovirus, Neisseria gonorrhea, Chlamy- dia trachomatis, Treponema pallidum, Trichomonas vagina- lis, and some Gram-negative pathogens, such as Escheri- chia coli [49, 86]. Epstein-Barr virus (EBV) and cytomegalovi- Figure 1. Association of periodon- tal disease and prostate cancer. rus’s (CMV) may cause mono- nucleosis, well-known as ‘kiss- ing disease’ by spreading th- rough direct mouth-to-mouth contact [87, 88]. Interestingly, than those who did not harbor this microbe these organisms are risk factors for the devel- [81]. The authors also reported that individuals opment of periodontitis [16, 89]. Patients with with A. actinomycetemcomitans in their oral periodontal conditions associated with the sub- cavity had a 50% greater chance of developing gingival viruses recover upon antiviral therapy pancreatic cancer [81]. Furthermore, Michaud (500 mg valaciclovir, Valtrex, orally twice daily et al. (2012) showed that individuals with in- over 10 days), which suggests a clinical role creased levels of antibodies to P. gingivalis are for these viruses in periodontitis [90, 91]. The- at significant incresed risk of pancreatic cancer refore, these organisms may be involved in the [82]. Fan et al. (2018) demonstrated that P. development of both diseases. gingivalis and A. actinomycetemcomitans were associated to a higher threat of pancreatic can- Role of periodontal and prostate inflamma- cer [83]. P. gingivalis and A. actinomycetem- tory mediators on prostate cancer comitans are capable of commencing the Toll- like receptor (TLR) signaling pathways, which Periodontitis inflammatory mediators and its are significant for the progression of pancreatic expression carcinogenesis [84]. Overall, the information Periodontal pathogens and/or microbes har- presented provides a strong association be- boring LPS endotoxins induce innate immune tween periodontal microorganism and the risk pathways such as toll-like receptors (TLR). Ac- of development of several human cancers. tivation of these pathways causes downstre- Sexually transmitted microorganisms am synthesis and release of pro-inflammatory mediators such as IL-1β, IL-6, TNF-α, PGE2, and Pathogens of venereal diseases may affect the matrix metalloproteinases [92-95]. These mol- prostate by eliciting an inflammatory response. ecules may enter into systemic circulation le- The prostate, like other organs, produces a nor- ading to an increase in systemic inflammatory mal immune response after exposure to an markers [94]. The presence of IL-6 in the sys- antigen. The etiology of prostatic inflammation temic circulation is associated with the severity

5 Am J Clin Exp Urol 2019;7(1):1-10 Periodontal pathogens contributing to prostate cancer of disease [94]. IL-6 is the major procoagulant Conclusions and future directions cytokine that may stimulate cells of the liver to produce acute-phase proteins such as C-reac- Periodontal disease appears to be associated tive protein (CRP), fibrinogen and plasminogen with prostate cancer. To date, there is no defi- activator inhibitor 1 [94]. The chronic and ele- nite mechanism(s) that can explain this rela- vated levels of CRP in the systemic circulation tionship. It is hypothesized that this association may indicate risk for myocardial infarction, might be influenced by periodontal pathogens stroke, and peripheral arterial disease even in and/or periodontitis inflammatory mediators. healthy individuals [96]. In the , The host response to periodontal pathogens the control of infection/inflammation may in- and/or any infectious agents could contribute hibit markers of systemic inflammation and to an exacerbated inflammatory response and dysfunction of endothelial cells within 2-6 mon- PIA/PIN in the prostate that may progress to ths [97]. Locally chronic inflammation results in cancer. In addition, certain periodontal patho- hypoxia, which leads to the release of nitric gens are associated with prostatitis. These oxide and other reactive oxygen species (ROS) pathogens may be migrating from the periodon- [6]. This leads to the conversion of arachidonic tium to the prostate gland through the blood- acid by cyclooxygenases into prostaglandin, stream and contributing to prostatic inflamma- which acts on the regulation of cell proliferation tion and cancer development (Figure 1). Further [6]. Also, hypoxia activates the discharge of studies are warranted to better characterize vascular endothelial growth factors (VEGF), the role of periodontal pathogens in initiating triggering neoangiogenesis and fibroblast dif- malignancy in the prostate gland. ferentiation, which are developmental factors in prostatic hyperplasia or neoplasm [98]. Disclosure of conflict of interest Therefore, the pro-inflammatory cells and medi- ators in periodontal disease result in cellular None. proliferation, angiogenesis, mutagenesis, de- crease adaptation to oxidative stress, and sup- Abbreviations pression of apoptosis [99]. PD, Periodontal Disease, Prostate disease; PIA, Inflammatory cytokines induction in neoplastic Proliferative Inflammatory Atrophy; PC, Prostate tissue cancer.

Inflammatory mediators generated during pros- Address correspondence to: Dr. Andre Paes B da tatitis or in chronic inflammatory diseases in Silva, Department of Periodontics, Case Western other parts of the body such as in periodontitis Reserve University, School of Dental Medicine, may promote neoplastic tissue development Cleveland 44106, Ohio. Tel: 216.368.0879; E-mail: [5, 27, 46, 48, 50, 56, 60, 100]. These me- [email protected] diators may be involved in the communication between inflammatory cells and prostate tumor References cells [100]. For instance, interleukin-1 (IL-1) pro- [1] Gaudreau PO, Stagg J, Soulières D, Saad F. The motes proliferation [101], growth, and progres- present and future of biomarkers in prostate sion of the prostate epithelium and connective cancer: proteomics, genomics, and immunolo- tissue stroma [102, 103]. IL-6 is capable of gy advancements. Biomark Cancer 2016: 8: manipulating neoplastic developments such as 15-33. reduction of apoptosis and upturn of angio- [2] Torre LA, Bray F, Siegel RL, Ferlay J, Lortet- genesis [104]. In addition, IL-6 and TNF-alpha Tieulent J, Jemal A. Global cancer statistics, enhance proliferation and promote survival sig- 2012. CA Cancer J Clin 2015; 65: 87-108. nal for different cancer cell types, including [3] Xie T, Dong B, Yan Y, Hu G, Xu Y. Association neoplastic prostate cell lines [51]. Nelson et between MMP-2 expression and prostate can- cer: a meta-analysis. Biomed Rep 2016; 4: al. (2004) suggested that these cells may influ- 241-5. ence the development of neoplasm [105]. In [4] Siegel RL, Miller KD and Jemal A. Cancer sta- prostate cancer, both TNF-alpha and IL-6 serum tistics, 2018. CA Cancer J Clin 2018; 68: 7-30. levels are elevated and correlate to advance- [5] MacLennan GT, Eisenberg R, Fleshman RL, stage disease and decreased patient survival Taylor JM, Fu P, Resnick MI, Gupta S. The influ- [106]. ence of chronic inflammation in prostatic carci-

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