Bacteria Peptidoglycan Promoted Breast Cancer Cell Invasiveness and Adhesiveness by Targeting Toll-Like Receptor 2 in the Cancer Cells

Xie, Wenjie; Huang, Yu‐Chen; Xie, Wenling; Guo, Aimin; Wu, Wei

doi:10.1371/journal.pone.0010850

Cited by 49 publications

(37 citation statements)

References 48 publications

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“…Moreover, the IgG-type antibodies against PGN endured for 8 weeks after the last immunization, which indicates that MAP-P31 as a thymus-dependent antigen induces a secondary antibody response to S. aureus, as only thymus-dependent antigens can induce secondary antibody responses and persist in the body for this length of time. We also found that MAP-P31 stimulated pMØ to release IL-6 and TNF-a independently of LPS, which suggests that MAP-P31 can also mimic the biological activities of PGN, as PGN plays a vital role in inflammation by inducing excessive amounts of inflammatory factors (Lin al., 2010;MacKenzie et al, 2010;Visser et al, 2005;Xie et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Peptide mimics of peptidoglycan are vaccine candidates and protect mice from infection with Staphylococcus aureus

Chen

Liu

Yang

et al. 2011

Journal of Medical Microbiology

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Staphylococcus aureus drug resistance to antibiotics is a serious situation that has drawn greater attention to immunotherapy and prophylaxis. Peptidoglycan (PGN) is a common and conserved component of the cell wall of Gram-positive bacteria such as S. aureus. However, PGN, as a thymus-independent antigen, cannot be considered a vaccine candidate because of its very weak immunogenicity. In this study we have attempted to enhance the immunogenicity of PGN by identifying a PGN peptide mimic sequence that would act as a thymus-dependent antigen. Several peptide sequences were obtained from a phage display peptide library using a mAb against S. aureus PGN, and a 12-mer linear single peptide (Sp-31) and a four-branch multiple antigen peptide (MAP) (MAP-P31) were synthesized. Both Sp-31 and MAP-P31 were shown to bind directly to anti-PGN mAb and a polyclonal antibody against S. aureus. These peptides could also inhibit the binding of PGN to a mAb against PGN. Furthermore, MAP-P31 was able to provoke an effective secondary antibody response in mice to PGN and to cell-wall fragments isolated from S. aureus, Escherichia coli, Staphylococcus epidermidis and Pseudomonas aeruginosa by sonication. In addition, the MAP-P31 antiserum showed a potent bactericidal or bacteriostatic activity against S. aureus in the presence and absence of complement in vitro. Importantly, immunization with MAP-P31 significantly prolonged the survival and enhanced bacterial clearance in BALB/c mice challenged with live S. aureus. In addition, the serum IgG-type antibodies against PGN persisted in mice, demonstrating that MAP-P31, as a peptide mimicking epitopes on PGN, provokes an effective secondary or memory antibody response, which can only be induced by a thymus-dependent antigen and which protects against infection with S. aureus. These results suggest that MAP-31 may be a novel vaccine candidate against S. aureus.

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Section: Discussionmentioning

confidence: 99%

Peptide mimics of peptidoglycan are vaccine candidates and protect mice from infection with Staphylococcus aureus

Chen

Liu

Yang

et al. 2011

Journal of Medical Microbiology

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“…It has been found that TLR9 overexpression and stimulation with hypomethylated DNA augment the migratory capacity of cancer cells [84]. In addition, highly metastatic human breast cancer cells express high levels of TLR2 in contrast to poorly metastatic breast cancer cells and homogenous untransformed breast cells [85]. TLR8 expression is also an independent prognostic factor for CRC [86].…”

Section: Expression Of Toll-like Receptors Is Associated With the Promentioning

confidence: 99%

“…Lm activates MAPKs and NF-jB in tumor cells through TLR2 signaling, resulting in the increased production of NO and IL-6 and increased proliferation of tumor cells [94]. Activation of TLR2 in breast cancer cells by peptidoglycan (PGN) from infectious bacterium Staphylococcus aureus (PGN-SA) induces TLR2-dependent NF-jB activation and secretion of IL-6 and TGF-b and promotes the invasiveness and adhesiveness of the cancer cells in vitro, illustrating a new link between component of infectious bacteria and the cancer [85]. PGN-SAstimulated NF-jB activity results in STAT3 and Smad3 sequential activation, which contributes to invasiveness and adhesiveness [85].…”

Section: Tlr7mentioning

confidence: 99%

“…Activation of TLR2 in breast cancer cells by peptidoglycan (PGN) from infectious bacterium Staphylococcus aureus (PGN-SA) induces TLR2-dependent NF-jB activation and secretion of IL-6 and TGF-b and promotes the invasiveness and adhesiveness of the cancer cells in vitro, illustrating a new link between component of infectious bacteria and the cancer [85]. PGN-SAstimulated NF-jB activity results in STAT3 and Smad3 sequential activation, which contributes to invasiveness and adhesiveness [85]. STAT3 and Smad3 were identified as important factors responsible for malignant tumor progression [95,96].…”

Section: Tlr7mentioning

confidence: 99%

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Exogenous or endogenous Toll-like receptor ligands: which is the MVP in tumorigenesis?

Wang

Chen

2011

Cell. Mol. Life Sci.

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Toll-like receptors (TLRs) are a class of pattern recognition receptors sensing microbial components and triggering an immune response against pathogens. In addition to their role in anti-infection immunity, increasing evidence indicates that engagement of TLRs can promote cancer cell survival and proliferation, induce tumor immune evasion, and enhance tumor metastasis and chemoresistance. Recent studies have demonstrated that endogenous molecules or damage-associated molecular patterns released from damaged/necrotic tissues are capable of activating TLRs and that the endogenous ligands-mediated TLR signaling is implicated in the tumor development and affects the therapeutic efficacy of tumors. Since both exogenous and endogenous TLR ligands can initiate TLR signaling, which is the most valuable player in tumor development becomes an interesting question. Here, we summarize the effect of TLR signaling on the development and progression of tumors, and discuss the role of exogenous and endogenous TLR ligands in the tumorigenesis.

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“…This heterogeneity is evident from the contradictory findings from studies that investigated TLR2 signaling in various tumor models [3,11,53,56]. TLR2 ligation has been reported to induce either promising anti-cancer activity [39,[57][58][59][60] or confounding pro-tumorigenic effects [61][62][63][64][65]. Clearly, characterization of the precise function of each TLR in any given tumor type is critical [3], and the contrasting roles of TLR2 are thought to have significantly impaired the development of TLR2 agonists as adjuvants in anti-cancer immunotherapy [2,66].…”

mentioning

confidence: 99%

Heterodimer‐specific TLR2 stimulation results in divergent functional outcomes in B‐cell precursor acute lymphoblastic leukemia

et al. 2015

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Reports of spontaneous acute lymphoblastic leukemia (ALL) remissions following severe bacterial infections suggest that bacterial components may trigger elimination of ALL. To date, TLR2, which recognizes a broad range of bacterial pathogens through TLR1 or TLR6 heterodimerization, has not been fully evaluated for direct effects on ALL. Studies investigating TLR2 signaling in other tumor cell types utilizing single ligands have yielded contradictory results, and comparative, heterodimer-specific analyses of TLR2 stimulation are lacking. In this study, we report that two well-characterized heterodimer-specific TLR2 ligands, Pam 3 CSK 4 (TLR2/1), and Pam 2 CSK 4 (TLR2/6), induce ALL cell lines and primary ALL samples to upregulate CD40 expression. However, only Pam 3 CSK 4 triggers Caspase-8-mediated apoptosis and sensitizes cells to vincristine-mediated cytotoxicity. Consistent with this result, stimulation of ALL cells through TLR2/1 or TLR2/6 activates Mal, p38 and the NF-κB and PI3K signaling pathways with divergent kinetics that may underlie their distinct downstream effects. Our results reveal a novel branching in downstream responses to heterodimer-specific TLR2 stimulation in ALL cells and emphasize the need for comparative studies to determine differential biological effects observed in specific tumor cells. Based on our results, TLR2/1 ligand Pam 3 CSK 4 possesses potential for generating anti-ALL activity through its direct effects on leukemic blasts.Keywords: CD40 r Caspase-8-mediated apoptotic cell death r Heterodimer-specific TLR2 stimulation r Pediatric acute lymphoblastic leukemia r Signaling kinetics Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIt is now widely accepted that tumor remissions induced by the proinflammatory activity of Coley's toxin, which contains various bacterial components, is mediated by the engagement of TollCorrespondence: Dr. Kirk R. Schultz e-mail: kschultz@mail.ubc.ca like receptors (TLRs) on immune cells [1][2][3][4][5]. TLRs are a family of germline-encoded pattern recognition receptors that induce innate and adaptive immune responses after binding pathogenand damage-associated molecular patterns [6][7][8][9][10]. In recent years, many studies have demonstrated that purified TLR ligands exert * These authors contributed equally to this work as senior authors.www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1980-1990 Immunomodulation 1981 potent anti-cancer effects against various types of established tumors in both mice and humans [2,5]. However, while some TLR ligands are currently in clinical trials [11,12], their promising preclinical efficacy as anti-cancer agents has not been consistently observed in the clinic [12]. A greater understanding of the cellular and molecular processes that mediate the beneficial and detrimental outcomes of TLR signaling is needed in order to optimize the translation of this approach. Spontaneous remissions of acute lymphoblastic leukemia (ALL) associated with se...

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Bacteria Peptidoglycan Promoted Breast Cancer Cell Invasiveness and Adhesiveness by Targeting Toll-Like Receptor 2 in the Cancer Cells

Cited by 49 publications

References 48 publications

Peptide mimics of peptidoglycan are vaccine candidates and protect mice from infection with Staphylococcus aureus

Peptide mimics of peptidoglycan are vaccine candidates and protect mice from infection with Staphylococcus aureus

Exogenous or endogenous Toll-like receptor ligands: which is the MVP in tumorigenesis?

Heterodimer‐specific TLR2 stimulation results in divergent functional outcomes in B‐cell precursor acute lymphoblastic leukemia

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