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The oral bacterium Streptococcus mutans promotes tumor metastasis by inducing vascular inflammation.

ABSTRACT: Recent studies have demonstrated a relationship between oral bacteria and systemic inflammation. Endothelial cells (ECs), which line blood vessels, control the opening and closing of the vascular barrier and contribute to hematogenous metastasis; however, the role of oral bacteria-induced vascular inflammation in tumor metastasis remains unclear. In this study, we examined the phenotypic changes in vascular ECs following Streptococcus mutans (S. mutans) stimulation in vitro and in vivo. The expression of molecules associated with vascular inflammation and barrier-associated adhesion was analyzed. Tumor metastasis was evaluated after intravenous injection of S. mutans in murine breast cancer hematogenous metastasis model. The results indicated that S. mutans invaded the ECs accompanied by inflammation and NF-κB activation. S. mutans exposure potentially disrupts endothelial integrity by decreasing vascular endothelial (VE)-cadherin expression. The migration and adhesion of tumor cells were enhanced in S. mutans-stimulated ECs. Furthermore, S. mutans-induced lung vascular inflammation promoted breast cancer cell metastasis to the lungs in vivo. The results indicate that oral bacteria promote tumor metastasis through vascular inflammation and the disruption of vascular barrier function. Improving oral hygiene in patients with cancer is of great significance in preventing postoperative pneumonia and tumor metastasis.

SUBMITTER: Yu L

PROVIDER: S-EPMC9633306 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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The oral bacterium Streptococcus mutans promotes tumor metastasis by inducing vascular inflammation.

Yu Li L Maishi Nako N Akahori Erika E Hasebe Akira A Takeda Ryo R Matsuda Aya Yanagawa AY Hida Yasuhiro Y Nam Jin-Min JM Onodera Yasuhito Y Kitagawa Yoshimasa Y Hida Kyoko K

Cancer science 20220912 11

Recent studies have demonstrated a relationship between oral bacteria and systemic inflammation. Endothelial cells (ECs), which line blood vessels, control the opening and closing of the vascular barrier and contribute to hematogenous metastasis; however, the role of oral bacteria-induced vascular inflammation in tumor metastasis remains unclear. In this study, we examined the phenotypic changes in vascular ECs following Streptococcus mutans (S. mutans) stimulation in vitro and in vivo. The expr ...[more]

PMID: 35997541

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Project description:Gram-positive bacteria utilize exported peptides to coordinate genetic and physiological processes required for biofilm formation, stress responses, and ecological competitiveness. One example is activation of natural genetic competence by ComR and the comX -inducing peptide (XIP) in Streptococcus mutans Although the competence pathway can be activated by the addition of synthetic XIP in defined medium, the hypothesis that XIP is able to function as an intercellular signaling molecule has not been rigorously tested. Coculture model systems were developed that included a "sender" strain that overexpressed the XIP precursor (ComS) and a "responder" strain harboring a green fluorescent protein (GFP) reporter fused to a ComR-activated gene (comX) promoter. The ability of the sender strain to provide a signal to activate GFP expression was monitored at the individual cell and population levels using (i) planktonic culture systems, (ii) cells suspended in an agarose matrix, or (iii) cells growing in biofilms. XIP was shown to be freely diffusible, and XIP signaling between the S. mutans sender and responder strains did not require cell-to-cell contact. The presence of a sucrose-derived exopolysaccharide matrix diminished the efficiency of XIP signaling in biofilms, possibly by affecting the spatial distribution of XIP senders and potential responders. Intercellular signaling was greatly impaired in a strain lacking the primary autolysin, AtlA, and was substantially greater when the sender strain underwent lysis. Collectively, these data provide evidence that S. mutans XIP can indeed function as a peptide signal between cells and highlight the importance of studying signaling with an endogenously produced peptide(s) in populations in various environments and physiologic states.IMPORTANCE The comX-inducing peptide (XIP) of Streptococcus mutans is a key regulatory element in the activation of genetic competence, which allows cells to take up extracellular DNA. XIP has been found in cell culture fluids, and the addition of synthetic XIP to physiologically receptive cells can robustly induce competence gene expression. However, there is a lack of consensus as to whether XIP can function as an intercellular communication signal. Here, we show that XIP indeed signals between cells in S. mutans, but that cell lysis may be a critical factor, as opposed to a dedicated secretion/processing system, in allowing for release of XIP into the environment. The results have important implications in the context of the ecology, virulence, and evolution of a ubiquitous human pathogen and related organisms.

Project description:Streptococcus mutans is the most significant pathogenic bacterium implicated in the formation of dental caries and, both directly and indirectly, has been associated with severe conditions such as multiple sclerosis, cerebrovascular and peripheral artery disease. Polymers able to selectively bind S. mutans and/or inhibit its adhesion to oral tissue in a non-lethal manner would offer possibilities for addressing pathogenicity without selecting for populations resistant against bactericidal agents. In the present work two libraries of 2-(dimethylamino)ethyl methacrylate (pDMAEMA)-based polymers were synthesized with various proportions of either N,N,N-trimethylethanaminium cationic- or sulfobetaine zwitterionic groups. These copolymers where initially tested as potential macromolecular ligands for S. mutans NCTC 10449, whilst Escherichia coli MG1655 was used as Gram-negative control bacteria. pDMAEMA-derived materials with high proportions of zwitterionic repeating units were found to be selective for S. mutans, in both isolated and S. mutans-E. coli mixed bacterial cultures. Fully sulfobetainized pDMAEMA was subsequently found to bind/cluster preferentially Gram-positive S. mutans and S. aureus compared to Gram negative E. coli and V. harveyi. A key initial stage of S. mutans pathogenesis involves a lectin-mediated adhesion to the tooth surface, thus the range of potential macromolecular ligands was further expanded by investigating two glycopolymers bearing α-mannopyranoside and β-galactopyranoside pendant units. Results with these polymers indicated that preferential binding to either S. mutans or E. coli can be obtained by modulating the glycosylation pattern of the chosen multivalent ligands without incurring unacceptable cytotoxicity in a model gastrointestinal cell line. Overall, our results allowed to identify a structure-property relationship for the potential antimicrobial polymers investigated, and suggest that preferential binding to Gram-positive S. mutans could be achieved by fine-tuning of the recognition elements in the polymer ligands.

Dataset Information

The oral bacterium Streptococcus mutans promotes tumor metastasis by inducing vascular inflammation.

Publications

The oral bacterium Streptococcus mutans promotes tumor metastasis by inducing vascular inflammation.

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