Oral Bacteria and Cancer

Sarah E. Whitmore, Richard J. Lamont

Center for Oral Health and Systemic Disease, School of Dentistry, University of Louisville, Louisville, Kentucky, United States of America

Epidemiological Associations

Over a number of years, epidemiological studies established several well-defined risk factors for cancer, including age, heredity, diet, tobacco use, chronic viral infections, and inflammation. Paradoxically, the success of these studies left little room for incorporation of any new factors or causative agents, and, consequently, the idea that a bacterial infection could contribute to cancer was generally disregarded. However, landmark studies in the early 1990s established Helicobacter pylori as a causative agent of gastric cancers, resulting in a paradigm shift regarding the relationship between microbial agents and cancers. Indeed, H. pylori became the first bacterial species to be officially recognized by the World Health Organization as a definite cause of cancer in humans. Since then, there has been a growing body of evidence supporting an association between specific microorganisms, including those in the oral cavity, and various types of cancers.

The oral cavity is inhabited by complex multispecies communities that usually exist in a balanced immunoinflammatory state with the host. Certain species, such as Porphyromonas gingivalis, can disrupt this equilibrium, resulting in a dysbiotic host–microbiota interaction. Subsequently, other community constituents, such as Fusobacterium nucleatum, can become opportunistically pathogenic, and the combined effect of a dysbiotic microbial community along with a dysregulated immune response ultimately causes periodontal disease. These well-studied periodontal organisms have now emerged as the focal point for the developing association between oral bacteria and cancer.

Perhaps the most likely carcinogenic link with oral bacteria is with oral squamous cell carcinoma (OSCC), one of the most common cancers worldwide. OSCC surfaces have been reported to harbor significantly higher levels of Porphyromonas and Fusobacterium compared with contiguous healthy mucosa. Moreover, immunohistochemistry with P. gingivalis antibodies revealed higher levels of detection and intensity of staining in gingival carcinomas compared with healthy gingival tissue, although only a small number of cases were examined.

A striking association has also been demonstrated between P. gingivalis infection and pancreatic cancer. In a prospective cohort study, an increased risk of pancreatic cancer was observed among those with high levels of antibodies to P. gingivalis, after adjusting for known risk factors. Similarly, orodigestive cancer mortality was found to be related to the levels of P. gingivalis antibodies, independent of periodontal disease. Several recent studies have shown a strong association between F. nucleatum and colorectal cancer (CRC). F. nucleatum was found to be one of the more abundant species within and around CRC neoplasms, and levels of F. nucleatum correlated with the presence of lymph node metastases.

Mechanistic Basis Supporting a Role for Oral Bacteria in Cancer

Epidemiological studies associate oral bacteria temporally and spatially with certain cancers and render involvement in the initiation or progression of the disease plausible. However, it is equally plausible that early undetected cancer, or precancerous lesions, facilitate the colonization and growth of oral bacteria. If these organisms are active participants in the disease process, then a mechanistic basis that would support an etiological role should exist.

Chronic or dysregulated inflammation has long been appreciated as contributing to tumor development, in part through modulation of the tumor microenvironment.

Both P. gingivalis and F. nucleatum establish chronic infections that involve intracellular persistence within epithelial cells, can spread systemically and cause extra-oral infections, and have well-characterized immune disruptive properties. F. nucleatum is strongly proinflammatory and can generate a microenvironment conducive for CRC progression. The inflammatory properties of P. gingivalis are more nuanced and context-dependent but also disrupt local immune responses in the periodontal area. In addition to broadly based immune-disruptive properties, both bacteria impinge upon several aspects of epithelial cell signaling relevant to cancer progression.

P. gingivalis

Cancer cells are defective in cell death pathways, and tumorigenesis is initiated when cells are freed from growth restraints. Epithelial cell responses to P. gingivalis infection include changes to apoptosis and cell division. In primary cultures of gingival epithelial cells, P. gingivalis is strongly antiapoptotic and can suppress chemically induced apoptosis. It activates Jak1/Akt/Stat3 signaling that controls intrinsic mitochondrial apoptosis pathways. At the mitochondrial membrane, proapoptotic factors are inhibited, leading to reduced cytochrome c release and blockage of caspase activation. MicroRNA expression is also altered, contributing to apoptosis suppression. Additionally, P. gingivalis can accelerate progression through the S-phase of the cell cycle, manipulate cyclin/CDK activity, and reduce p53 tumor suppressor levels. This organism also promotes cellular invasion and metastasis by activating ERK1/2-Ets1, p38/HSP27, and PAR2/NF-κB pathways, inducing MMP-9 production and activation.

F. nucleatum

Epithelial responses to F. nucleatum infection are also consistent with carcinogenesis. It targets cell cycle kinases, increasing cell proliferation and migration, and activates p38, leading to secretion of matrix metalloproteinases such as MMP-9 and MMP-13, which aid tumor invasion and metastasis. A more direct link is seen when the fusobacterial adhesin FadA binds to E-cadherin on colon cancer cells, activating β-catenin signaling and oncogene expression, stimulating CRC cell growth.

Figure 1. Interactions between P. gingivalis and epithelial cells that could produce an oncogenic phenotype. Extracellular P. gingivalis secrete gingipains, which activate Protease Activated Receptor (PAR) leading to promatrix metalloprotease (MMP)-9 production, and they also convert proMMP-9 to mature MMP-9, along with nucleoside diphosphate kinase (NDK), which cleaves ATP and prevents activation of the proapoptotic P2X7 receptor. Intracellular P. gingivalis activate antiapoptotic Jak-Stat signaling and inhibit expression of the p53 tumor suppressor. Additionally, Erk 1/2 and p38 are activated, which also elevates proMMP-9 expression.

Figure 2. Interactions between F. nucleatum and epithelial cells that could produce an oncogenic phenotype. Binding of the FadA adhesin to E-cadherin activates b-catenin signaling, resulting in activation of genes that control cell survival and proliferation. F. nucleatum also activates several cyclin dependent kinases (CDKs) and p38, which controls the production of matrix metalloproteases MMP-9 and MMP-13.

Conclusions

Both P. gingivalis and F. nucleatum have attributes consistent with a role in cancer development and progression, although widespread infection does not lead to cancer in most individuals. The multifactorial nature of cancer and the oral microbial community’s interactions likely influence this outcome. Detecting these bacteria in precancerous lesions may serve as a poor prognosis indicator. Improved oral hygiene and treatment of periodontitis may help limit cancer development or spread. Virulence factors like FimA and FadA may provide future therapeutic targets.