Toll-like receptor stimulation in cancer: A pro- and anti-tumor double-edged sword

Dajon, Marion; Iribarren, Kristina; Cremer, Isabelle

doi:10.1016/j.imbio.2016.06.009

Cited by 172 publications

(196 citation statements)

References 142 publications

(177 reference statements)

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“…Through downstream signaling, TLRs mediate the induction of innate and adaptive immune responses, which are critical for host antimicrobial and antitumor immunities (4, 7). Besides normal tissues, TLRs are often expressed in tumor cells, and control hyper-proliferation by inducing apoptosis and/or interferon response.…”

Section: Discussionmentioning

confidence: 99%

“…Besides their protective effect, new evidences have now shown that activation of TLRs could promote certain diseases (7). Upregulation of TLR4 in tumors and infiltrating immune cells could activate NF-κB, PI3K-AKT and STAT3 pathways, and induce proinflammatory cytokines such as IL-6, IL-1β, IL-18 or TNF-α (5, 7).…”

Section: Introductionmentioning

confidence: 99%

“…Upregulation of TLR4 in tumors and infiltrating immune cells could activate NF-κB, PI3K-AKT and STAT3 pathways, and induce proinflammatory cytokines such as IL-6, IL-1β, IL-18 or TNF-α (5, 7). In colorectal cancer, activation of the TLR4-MyD88 pathway is correlated with a high level of IL-6, which is associated with poor prognosis (8).…”

Section: Introductionmentioning

confidence: 99%

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TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway

et al. 2017

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Toll-like receptors (TLR) are conserved immune sensors mediating antimicrobial and antitumoral responses, but recent evidence implicates them in promoting carcinogenesis in certain cancers. Kaposi’s sarcoma (KS) is caused by infection of Kaposi’s sarcoma-associated herpesvirus (KSHV) and is characterized by uncontrolled neoangiogenesis and inflammation. Here we show that TLR4 is upregulated in KSHV-infected spindle tumor cells in human KS lesions. In a model of KSHV-induced cellular transformation, KSHV upregulated expression of TLR4, its adaptor MyD88, and coreceptors CD14 and MD2. KSHV induction of TLR4 was mediated by multiple viral microRNAs. Importantly, the TLR4 pathway was activated constitutively in KSHV-transformed cells resulting in chronic induction of IL-6, IL-1β and IL-18. Accordingly, IL-6 mediated constitutive activation of the STAT3 pathway, an essential event for uncontrolled cellular proliferation and transformation. TLR4 stimulation with lipopolysaccharides or live bacteria enhanced tumorigenesis while TLR4 antagonist CLI095 inhibited it. These results highlight an essential role of the TLR4 pathway and chronic inflammation in KSHV-induced tumorigenesis, which helps explain why HIV-infected patients, who frequently suffer from opportunistic bacterial infections and metabolic complications, frequently develop KS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway

et al. 2017

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“…TLRs that are activated by their individual ligands could recruit MyD88 and subsequently activate the downstream targets, including nuclear factor of kappa B, mitogen-associated protein kinase, and interferon regulatory factors 2. Furthermore, recently, numerous studies have demonstrated that TLRs could be involved in antitumor or protumor responses 45,46. For example, TLR4-deficient mice have showed enhanced tumorigenesis in inducible model of lung cancer, skin cancer, and BC.…”

Section: Discussionmentioning

confidence: 99%

Prognostic role of Toll-like receptors in cancer: a meta-analysis

Wang¹,

Zhang²,

Xiao³

et al. 2018

TCRM

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BackgroundRecent studies have shown that Toll-like receptors (TLRs) may be associated with cancers. The aim of this meta-analysis is to summarize the predicting role of TLRs for survival in patients with a variety of carcinomas.Materials and methodsEligible studies were identified and assessed for quality through multiple search strategies. We collected data from studies investigating the relationship between the expression level of TLRs and survival in cancer patients. Studies were pooled and combined hazard ratios (HRs) of TLRs for survival were analyzed.ResultsA total of 24 studies, including 2,812 patients with various cancers, were identified for the meta-analysis. Importantly, this meta-analysis showed that higher expression levels of TLR4 or TLR7 in tumor tissues could predict poorer survival, with the pooled HR being 1.29 (95% CI: 1.17, 1.42) and 1.71 (95% CI: 1.38, 2.12), respectively. However, higher expression of TLR9 had no significant association with outcome as HR was 0.84 (95% CI: 0.62, 1.115). Heterogeneity existed in TLR4 and TLR9 studies (P-value <0.001) but not in TLR7 studies (P-value >0.05).ConclusionThe expression level of TLR4 or TLR7 in cancerous tissue may have a prognosis value in patients with various cancers.

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“…These receptors are largely expressed by immune cells and epithelial cells but also by several types of tumors cells 5 . The role of TLRs in tumor microenvironment is complex.…”

Section: Introductionmentioning

confidence: 99%

Toll like receptor 7 expressed by malignant cells promotes tumor progression and metastasis through the recruitment of myeloid derived suppressor cells

et al. 2018

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In non-small cell lung carcinoma (NSCLC), stimulation of toll-like receptor 7 (TLR7), a receptor for single stranded RNA, is linked to tumor progression and resistance to anticancer chemotherapy. However, the mechanism of this effect has been elusive. Here, using a murine model of lung adenocarcinoma, we demonstrate a key role for TLR7 expressed by malignant (rather than by stromal and immune) cells, in the recruitment of myeloid derived suppressor cells (MDSCs), induced after TLR7 stimulation, resulting in accelerated tumor growth and metastasis. In adenocarcinoma patients, high TLR7 expression on malignant cells was associated with poor clinical outcome, as well as with a gene expression signature linked to aggressiveness and metastastic dissemination with high abundance of mRNA encoding intercellular adhesion molecule 1 (ICAM-1), cytokeratins 7 and 19 (KRT-7 and 19), syndecan 4 (SDC4), and p53. In addition, lung tumors expressing high levels of TLR7 have a phenotype of epithelial mesenchymal transition with high expression of vimentin and low abundance of E-cadherin. These data reveal a crucial role for cancer cell-intrinsic TLR7 expression in lung adenocarcinoma progression.

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Toll-like receptor stimulation in cancer: A pro- and anti-tumor double-edged sword

Cited by 172 publications

References 142 publications

TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway

TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway

Prognostic role of Toll-like receptors in cancer: a meta-analysis

Toll like receptor 7 expressed by malignant cells promotes tumor progression and metastasis through the recruitment of myeloid derived suppressor cells

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