Toll-Like Receptor 4 Activation in Cancer Progression and Therapy

Oblak, Alja; Jerala, Roman

doi:10.1155/2011/609579

Cited by 130 publications

(134 citation statements)

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“…TLR4 was the first discovered human TLR activated by LPS of gram-negative bacteria (34). TLR4 is expressed not only in immune cells but also in many tumors, including breast cancer (35) and colon and ovarian cancer (36) where TLR4-related signaling can promote tumor growth and immune escape (33,37,38). Here, we revealed strong association of TLR4 with gastric cancer by demonstrating higher TLR4 expression in gastric cancer cell lines and gastric tumors compared with normal gastric cells and noncancerous tissues (Fig.…”

Section: Discussionmentioning

confidence: 52%

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Uncontrolled Inflammation Induced by AEG-1 Promotes Gastric Cancer and Poor Prognosis

Zhao

et al. 2014

Cancer Research

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Gastric cancer is one of the most common causes of cancer-related death worldwide. Helicobacter pylori infection plays an important role in the development and progression of gastric cancer. The expression of astrocyte-elevated gene-1 (AEG-1) is increased in gastric cancer tissues, thereby contributing to the inflammatory response. We investigated whether and how AEG-1 regulated proinflammatory signaling in gastric cancer cells. We used human gastric cancer cell lines and athymic nude mice to investigate the role of AEG-1 in the regulation of the TLR4/nuclear factor-kB (NF-kB) signaling pathway and cancer invasion and compared the expression of AEG-1 and related proteins in 93 patients with gastric cancer by immunohistochemistry. In human gastric cancer cells, both AEG-1 and TLR4 could be induced by lipopolysaccharide (LPS) stimulation. AEG-1 was upregulated via LPS-TLR4 signaling and in turn promoted nuclear translocation of the NF-kB p65 subunit. At the same time, AEG-1 overexpression decreased the levels of suppressor of cytokine signaling (SOCS) protein SOCS-1, a negative regulator of the TLR4 pathway. Furthermore, nude mice engrafted with AEG-1/TLR4-expressing cells demonstrated larger tumor volumes than control animals. In patients with gastric cancer, the expression of AEG-1 correlated with that of TLR4, SOCS-1, and NF-kB and was higher in tumors compared with noncancerous adjacent tissues. Overall survival in patients with gastric cancer with simultaneous expression of AEG-1 and TLR4 was poor. Our results demonstrate that AEG-1 can promote gastric cancer progression by a positive feedback TLR4/NF-kB signaling-related mechanism, thus providing new mechanistic explanation for the role of inflammation in cancer progression. Cancer Res; 74(19);

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Section: Discussionmentioning

confidence: 52%

“…Toll-like receptors (TLR) play a key role in the innate immune system (33). TLR4 was the first discovered human TLR activated by LPS of gram-negative bacteria (34).…”

Section: Discussionmentioning

confidence: 99%

Uncontrolled Inflammation Induced by AEG-1 Promotes Gastric Cancer and Poor Prognosis

Zhao

et al. 2014

Cancer Research

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“…Similar to most TLR agonists, TLR4 ligands may be considered as double-edged swords, as they not only bind to DC TLR4 to activate the immune system but also interact with TLR4 (or RAGE) on tumor cells to favor the manifestation of cell-intrinsic tumorigenic hallmarks and chemoresistance. 52,53 In our model system, we ruled out the possibility that DEN would directly act on CT26, MCA205 or EL4 to enhance (or reduce) tumor cell proliferation (not shown). Moreover, a single injection at day 2 post chemotherapy was sufficient to amplify the immune effects of chemotherapy, bypassing the requirement for a prolonged exposure to TLR4 agonists (Supplementary Figure 2).…”

Section: Discussionmentioning

confidence: 99%

Defective immunogenic cell death of HMGB1-deficient tumors: compensatory therapy with TLR4 agonists

et al. 2013

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Immunogenic cell death induced by anticancer chemotherapy is characterized by a series of molecular hallmarks that include the exodus of high-mobility group box 1 protein (HMGB1) from dying cells. HMGB1 is a nuclear nonhistone chromatin-binding protein. It is secreted at the late stages of cellular demise and engages Toll-like receptor4 (TLR4) on dendritic cells (DCs) to accelerate the processing of phagocytic cargo in the DC and to facilitate antigen presentation by DC to T cells. The absence of HMGB1 expression by dying tumor cells exposed to anthracyclines or oxaliplatin compromises DC-dependent T-cell priming by tumor-associated antigens. Here, we show that transplantable tumors exhibiting weak expression of nuclear HMGB1 respond to chemotherapy more effectively if the treatment is combined with the local or systemic administration of a highly purified and physiochemically defined and standardized lipopolysaccharide solution, which acts as a high-potency and exclusive TLR4 agonist, called Dendrophilin (DEN). The synergistic antitumor effects mediated by the combination of chemotherapy and immunotherapy relied upon the presence of the MyD88 (myeloid differentiation primary response gene) adapter of TLR4 (but not that of the TIR-domain-containing adapter-inducing interferon-b adapter), in line with the well-characterized action of DEN on the MyD88 signaling pathway. DEN and anthracyclines synergized to induce intratumoral accumulation of interferon-c-producing CD4 þ and CD8 þ T lymphocytes. Moreover, DEN could restore the immunogenicity of dying tumor cells from which HMGB1 had been depleted by RNA interference. These findings underscore the potential clinical utility of combination regimens involving immunogenic chemotherapy and certain TLR4 agonists in advanced HMGB1-deficient cancers.

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“…Such studies highlight the importance of TLRs as exploited processes in tumor biology that promote tumor growth by a number of mechanisms and aid in immune evasion, while other studies describe the antitumoral effects of TLRs. This leads to the understanding that TLRs can act as double-edged swords in the progression or treatment of cancer [6,9,10,11,12]. Antitumor therapeutics dates back over 100 years when Dr. William Coley demonstrated that repeated administrations of crude microbial extracts from Streptococcus pneumoniae and Serratia marcescens (Coley's toxin) promoted antitumoral responses in a variety of human cancers - a response that was undoubtedly attributed to the activation of TLRs to promote tumoricidal activity [6,12].…”

Section: Toll-like Receptor Signaling: Role In Innate Immune Responsementioning

confidence: 99%

Epigenetic Regulation of Toll-Like Receptor Signaling: Implications for Cancer Development

Boi¹,

Elsawa²

2013

Med Epigenet

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The innate immune response acts in a myriad of ways to protect the host from pathogenic agents. This interplay requires changes in gene expression patterns that allow the host to effectively respond. Epigenetic mechanisms are important in this scenario. Understanding these mechanisms is of great interest for the development of appropriate therapies modulating the immune response. One of the important receptor families responsible for the activity of the innate immune system is the Toll-like receptor (TLR) family. This family is important for the innate immune response to infections and has been implicated to play a role in cancer. Understanding the epigenetic mechanisms regulated by TLR signaling is important for the development of novel therapies for a multitude of diseases including cancer. In this article, we present an overview of this pathway and its role in carcinogenesis, and we discuss the epigenetic mechanisms regulating its activity.

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Toll-Like Receptor 4 Activation in Cancer Progression and Therapy

Cited by 130 publications

References 133 publications

Uncontrolled Inflammation Induced by AEG-1 Promotes Gastric Cancer and Poor Prognosis

Uncontrolled Inflammation Induced by AEG-1 Promotes Gastric Cancer and Poor Prognosis

Defective immunogenic cell death of HMGB1-deficient tumors: compensatory therapy with TLR4 agonists

Epigenetic Regulation of Toll-Like Receptor Signaling: Implications for Cancer Development

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