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

Department of Pathology, The First Affiliated Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou 510080, People's Republic of China.
Cellular and Molecular Life Sciences CMLS (Impact Factor: 5.81). 11/2011; 69(6):935-49. DOI: 10.1007/s00018-011-0864-6
Source: PubMed


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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    • "Other kinds of stimuli, named endogenous damage-associated molecular patterns (DAMPs), are also capable of activating MyD88-dependent innate immune signaling by TLRs [21]. Some of the well- characterized DAMPs include: fibronectins [22], heat-shock proteins [23], pro-inflammatory cytokines from the monocyte-macrophage system [24], and free fatty acids (FFA) [25]. Among the TLRs, TLR2 constitutes a molecular link between elevated circulating FFA and inflammation [26]–[28]. "
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    PLoS ONE 04/2014; 9(4):e93741. DOI:10.1371/journal.pone.0093741 · 3.23 Impact Factor
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    • "Other types of stimuli, known as endogenous damage-associated molecular patterns (DAMPs), can also activate MyD88-dependent innate immune signaling by TLRs (Beg, 2002). A variety of molecules have been classified as DAMPs, including fibronectins (Okamura et al., 2001), chromosomal DNA (Viglianti et al., 2003), heat shock proteins (Wallin et al., 2002), free fatty acids (Lee et al., 2004) and proinflammatory cytokines from the monocyte-macrophage system (Yu et al., 2012). Activation of the MyD88-dependent pathway also promotes the development of atherosclerosis and myocardial injury following ischemia-reperfusion (Michelsen and Arditi, 2006), is involved in autoimmune responses, diabetes (Zipris, 2010) and acute colitis (O'Neill, 2003). "
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    ABSTRACT: Most snake accidents in North Brazil are attributed to Bothrops atrox, a snake species of the Viperidae family whose venom simultaneously induces local and systemic effects in the victims. The former are clinically more important than the latter, as they cause severe tissue lesions associated with strong inflammatory responses. Although several studies have shown that inflammatory mediators are produced in response to B. atrox venom (BaV), there is little information concerning the molecular pathways involved in innate immune system signaling. Myeloid differentiation factor 88 (MyD88) is an adaptor molecule responsible for transmitting intracellular signals from most toll-like receptors (TLRs) after they interact with pathogen-associated molecular patterns (PAMPs) or other stimuli such as endogenous damage-associated molecular patterns (DAMPs). The MyD88-dependent pathway leads to activation of transcription factors, which in turn induce synthesis of inflammatory mediators such as eicosanoids, cytokines and chemokines. The aim of this study was to investigate the involvement of MyD88 on the acute inflammatory response induced by BaV. Wild-type (WT) C57BL/6 mice and MyD88 knockout (MyD88-/-) mice were intraperitoneally injected with BaV. Compared to WT mice, MyD88-/- animals showed an impaired inflammatory response to BaV, with lower influx of polymorphonuclear and mononuclear cells to the peritoneal cavity. Furthermore, peritoneal leukocytes from BaV-injected MyD88-/- mice did not induce COX-2 or LTB4 protein expression and released low concentrations of PGE2. These mice also failed to produce Th1 and Th17 cytokines and CCL-2, but IL-10 levels were similar to those of BaV-injected WT mice. Our results indicate that MyD88 signaling is required for activation of the inflammatory response elicited by BaV, raising the possibility of developing new therapeutic targets to treat Bothrops sp. poisoning.
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    ABSTRACT: Toll-like receptors (TLRs) belong to a class of pattern-recognition receptors that play an important role in host defense against pathogens by recognizing a wide variety of pathogen-associated molecular patterns (PAMPs). Besides driving inflammatory responses, TLRs also regulate cell proliferation and survival by expanding useful immune cells and integrating inflammatory responses and tissue repair processes. TLR signaling, which is centrally involved in the initiation of both innate and adaptive immune responses, has been thought to be restricted to immune cells. However, recent studies have shown that functional TLRs are expressed not only on immune cells, but also on cancer cells, thus implicating a role of TLRs in tumor biology. Increasing bodies of evidence have suggested that TLRs act as a double-edged sword in cancer cells because uncontrolled TLR signaling provides a microenvironment that is necessary for tumor cells to proliferate and evade the immune response. Alternatively, TLRs can induce an antitumor immune response in order to inhibit tumor progression. In this review, we summarize the dual roles of TLRs in tumor cells and, more importantly, delve into the therapeutic potential of TLRs in the context of tumorigenesis.
    Archives of Pharmacal Research 08/2012; 35(8):1297-316. DOI:10.1007/s12272-012-0802-7 · 2.05 Impact Factor
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