Molecular Mechanisms Leading from Periodontal Disease to Cancer

Abstract

Periodontitis is prevalent in half of the adult population and raises critical health concerns as it has been recently associated with an increased risk of cancer. While information about the topic remains somewhat scarce, a deeper understanding of the underlying mechanistic pathways promoting neoplasia in periodontitis patients is of fundamental importance. This manuscript presents the literature as well as a panel of tables and figures on the molecular mechanisms of Porphyromonas gingivalis and Fusobacterium nucleatum, two main oral pathogens in periodontitis pathology, involved in instigating tumorigenesis. We also present evidence for potential links between the RANKL-RANK signaling axis as well as circulating cytokines/leukocytes and carcinogenesis. Due to the nonconclusive data associating periodontitis and cancer reported in the case and cohort studies, we examine clinical trials relevant to the topic and summarize their outcome.

Keywords: Fusobacterium nucleatum; Porphyromonas gingivalis; RANK ligand; cancer; immune response; periodontal disease; tumorigenesis.

Figure 1

Proposed molecular mechanisms of P. gingivalis and F. nucleatum-mediated tumorigenesis in tumorous and nontumorous cells. Nontumorigenic pathways: (left). P. gingivalis promotes antiapoptosis by activating JAK1/STAT3 and PI3K/AKT prosurvival signaling pathways to inhibit caspase3 (casp3) and activate survivin. P. gingivalis-mediated activation of PI3K/AKT leads to the phosphorylation of Bad at serine residue 136 and its activation results in its dissociation from antiapoptotic Bcl2 and Bcl-XL proteins, which enhances the antiapoptotic effect of the Bcl2 family reflected by the inhibition of apoptotic protein Bax. Furthermore, Bcl-2 and Bcl-XL are upregulated by P. gingivalis gigipain’s adhesin peptide A44, which also inhibits Casp9 activation at early stages. Inhibition of Bax impedes cytochrome c (cytc) release from the mitochondria and blocks the cleavage of casp9 and subsequent activation of effector caspase3, which obstructs the mitochondrial intrinsic apoptotic pathway. P. gingivalis inhibits P2X7 receptor (P2X7R)/NADPH oxidase-mediated ROS production and subsequent apoptosis by blocking extracellular ATP (eATP) ligation to P2X7R through its ATP-scavenging enzyme, nucleoside diphosphate kinase (NDK). Additionally, P. gingivalis induces antioxidant responses by increasing glutathione (GSH) levels intracellularly possibly by upregulating the uncoupling protein 2 (UCP2). Carcinogenic pathways: (right). P. gingivalis activates protease-activated receptor 4 (PAR4), which in turn activates the ERK1/2/Ets1 and p38/Hsp27 pathways resulting in pro-MMP9 production. P. gingivalis’s activation of PAR2 can mediate pro-MMP9 production via the NF-kB pathway. The cleaved active form of pro-MMP9 is MMP9. Metalloproteinase (MMP) families are involved in ECM and basement membrane degradation and enhance invasion in neoplastic cells. P. gingivalis through its virulent factor, a cysteine protease termed gingipain, can cleave pro-MMP9 into its active form MMP9. Gingipains consist of arginine-specific protease A (RgpA) and B (RgpB) and a lysine-specific protease (Kgp), which are responsible for the cleavage of pro-MMP9 into MMP9. Apple polyphenol (AP), hop bract polyphenol (HBP) and high-molecular weight HBP (HMW-HBP) are polyphenols that can inhibit the proteolytic activity of gingipains and can inhibit the PAR2/NF-kB release of pro-MMP9. Thus, P. gingivalis promotes invasion through gingipain-mediated activation of MMP9. F. nucleatum’s virulent factor FadA binds to the extracellular domain 5 (EC5) of E-cadherin receptor and activates β-catenin that stimulate cyclin D1 and Myc upregulation and binds to T-cell factor/lymphoid enhancer factor (TCF/LEF) to stimulate the secretion of Wnt7a, Wnt7b and Wnt9a, all of which promote cellular growth and proliferation. β-catenin enhances the production of cytokines IL-6, IL-8 and IL-18 and NF-kB1/2 and promotes inflammation, an optimal microenvironment for the prosperity of cancerous cells. F. nucleatum and P. gingivalis can activate toll-like receptor 2 (TLR2) and mediate TNF-α and IL-6 cytokine production via the TLR2-NF-kB pathway. IL-6 stimulates the activation of the IL-6 receptor (IL-6R), which in turn activates STAT3, known to ultimately upregulate the production of cyclin D1 and promote cellular proliferation.

Figure 2

Bone metastasis and RANKL expression in human cancers. The upper panel shows the percentage of patients with bone metastasis at the cancer diagnosis time. Studies utilized Surveillance, Epidemiology and End Results (SEER) and Oncology Services Comprehensive Electronic Records (OSCER) databases [139,140,141]. The percentage of patients is presented as a heatmap with the color intensity corresponding to higher percentage of cases. Missing data for selected cancer types are in gray. The lower panel shows the expression of RANKL (TNFSF11) in selected primary tumors. Violin plots show log2-transformed expression of RANKL gene in selected cancer types. Cancers with the confirmed role of RANKL–RANK signaling in metastases are marked in red. The horizontal red line shows the median expression for all cancers in the dataset. Abbreviations: PAAD—pancreatic adenocarcinoma, CHOL—cholangiocarcinoma, READ—rectum adenocarcinoma, COAD—colorectal adenocarcinoma, STAD—stomach adenocarcinoma, LIHC—liver hepatocellular carcinoma, ESCA—esophageal carcinoma, LUSC—lung squamous cell carcinoma, LUAD—lung adenocarcinoma, BRCA—breast invasive carcinoma, BLCA—bladder carcinoma, THCA—thyroid carcinoma, SKCM—skin cutaneous melanoma, KIRC—kidney renal clear cell carcinoma, KIRP—kidney renal papillary cell carcinoma, PRAD—prostate adenocarcinoma. Data for GDC Pan-Cancer (PANCAN) dataset were downloaded from the UCSC Xena portal (https://xena.ucsc.edu/, accessed on 20 November 2021).

Figure 3

The inflammatory response in periodontal disease and its systemic consequences. The figure illustrates changes in chemokines, proteins, interleukins levels and CD markers present on lymphocytes in the periodontal disease. Inflammatory molecules enter the bloodstream and increases the susceptibility of the organism to systemic diseases like cardiovascular, respiratory, metabolic diseases and pregnancy problems.