Targeting Toll-Like Receptors for Cancer Therapy

Braunstein, Marc; Kucharczyk, John; Adams, Sylvia

doi:10.1007/s11523-018-0589-7

Cited by 96 publications

(98 citation statements)

References 170 publications

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“…Interestingly, treatment with Pam 3 CSK 4 decreases the cell survival of AMU‐AM1 cells, while the TLR1/2 antagonist CPT‐Cu‐22 increases cell survival. Indeed, stimulation and/or inhibition of TLR2 would be challenging as a novel therapeutic approach for cancer therapy . Hence, these results suggest that modulation of TLR2 signaling may affect the tumor environment and survival of ameloblastoma cells.…”

Section: Discussionmentioning

confidence: 99%

Discovery of novel molecular characteristics and cellular biological properties in ameloblastoma

et al. 2020

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Ameloblastoma is a rare odontogenic benign tumor accounting for less than 1% of head and neck tumors. Advanced next generation sequencing (NGS) analyses identified high frequency of BRAF V600E and SMO L412F mutations in ameloblastoma.Despite the existence of whole genomic sequence information from patients with ameloblastoma, entire molecular signature of and the characteristics of ameloblastoma cells are still obscure. In this study, we sought to uncover the molecular basis of ameloblastoma and to determine the cellular phenotype of ameloblastoma cells with BRAF mutations. Our comparative cDNA microarray analysis and gene set enrichment analysis (GSEA) showed that ameloblastoma exhibited a distinct gene expression pattern from the normal tissues: KRAS-responsive gene set is significantly activated in ameloblastoma. Importantly, insulin like growth factor 2 (IGF2), a member of KRAS-responsive genes, enhances the proliferation of an ameloblastoma cell line AMU-AM1 with BRAF mutation. In addition, Toll-like receptor 2 (TLR2) knockdown readily inactivated KRAS-responsive gene sets as well as increases caspase activities, suggesting that TLR2 signaling may mediate cell survival signaling in ameloblastoma cells. Collectively, the findings may help to further clarify the pathophysiology of ameloblastoma and lead to the development of precision medicine for patients with ameloblastoma.

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Section: Discussionmentioning

confidence: 99%

Discovery of novel molecular characteristics and cellular biological properties in ameloblastoma

et al. 2020

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“…Our study shows the downregulation of several TLRs in CRC patients compared to normal controls. Integral to immune cell response, TLRs provide the first point of recognition of foreign bodies or pathogen-associated molecular patterns (PAMPs) once they have evaded physical barriers such as the skin or gut [29,30]. The Toll/IL-1 receptor (TIR) domain of TLRs, found in the majority of TLRs including the ones downregulated in our CRC cohort, in association with myeloid differentiation primary-response protein 88 (MyD88), is responsible for downstream signaling including NF-kB activation and inflammatory cytokine induction to illicit an adaptive immune response [31].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Analyses Revealed Systemic Alterations in Gene Expression in Circulation and Tumor Microenvironment of Colorectal Cancer Patients

Shaath

Toor

Nair

et al. 2019

Cancers

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Colorectal cancer (CRC) is among the leading causes of cancer-related deaths worldwide, underscoring a need for better understanding of the disease and development of novel diagnostic biomarkers and therapeutic interventions. Herein, we performed transcriptome analyses on peripheral blood mononuclear cells (PBMCs), CRC tumor tissue and adjacent normal tissue from 10 CRC patients and PBMCs from 15 healthy controls. Up regulated transcripts from CRC PBMCs were associated with functions related to immune cell trafficking and cellular movement, while downregulated transcripts were enriched in cellular processes related to cell death. Most affected signaling networks were those involved in tumor necrosis factor (TNF) and interleukin signaling. The expression of selected immune-related genes from the RNA-Seq data were further validated using qRT-PCR. Transcriptome analysis of CRC tumors and ingenuity pathway analysis revealed enrichment in several functional categories related to cellular movement, cell growth and proliferation, DNA replication, recombination and repair, while functional categories related to cell death were suppressed. Upstream regulator analysis revealed activation of ERBB2 and FOXM1 networks. Interestingly, there were 18 common upregulated and 36 common downregulated genes when comparing PBMCs and tumor tissue, suggesting transcriptomic changes in the tumor microenvironment could be reflected, in part, in the periphery with potential utilization as disease biomarkers.

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“…TLR3 synthetic ligands were used with conventional chemotherapies or radiotherapy in clinical trials for the treatment of cancer patients (Braunstein et al, 2018; Aranda et al, 2014; Smith et al, 2018). This reported tumor suppressive and apoptotic effect of TLR3 is achieved predominantly by induction of type I IFN and activation of effector cells, when TLR3 is located within the endosomal compartment (Bugge et al, 2017; Gambar et al, 2014; Braunstein et al, 2018). TLR3 synthetic ligand poly-ICLC with Sorafenib significantly reduces tumor growth, both in-vitro and in-vivo in hepatocellular carcinoma (Ho et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…However, there are several contradictory reports on the working mechanism and failure in clinical trials. It has also been reported to promote cellular proliferation in head and neck and multiple myeloma cell lines via c-Myc- and NF-κB, respectively following TLR3 ligand poly(I:C) stimulation (Braunstein et al, 2018). In squamous cell carcinomas of the head and neck (HNSCC), triggering the TLR3 signaling pathway along with cisplatin that induces production of the pro-inflammatory cytokine IFN-β, IL-6 and CCL5 to promote cellular survival (Chuang et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…TLR3 agonists have been used in immunotherapy for various clinical and preclinical studies. The majority of clinical studies establish TLR3 as a tumor suppressor using synthetic ligand poly(I:C) or poly-ICLC for adjuvant therapy or targeted therapy (Jia and Wang 2015; Braunstein et al, 2018; Ho et al, 2015, Schau et al, 2019). Ligand binding has been reported to induce endosomal TLR3 mediated recruitment of TIR domain-containing adapter-inducing interferon β (TRIF) (O’Neill and Bowie 2007) to trigger type-I IFN and to induce cellular apoptosis (Conforti et al, 2010; Salaun et al, 2006; Gambara et al, 2014; Oshiumi et al, 2003; Yamamoto 2003).…”

Section: Introductionmentioning

confidence: 99%

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Alternative MyD88 -Cyclin D1 signaling in breast cancer cells regulates TLR3 mediated cell proliferation

Singh

Devkar

Basu

2020

Preprint

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TLR3 mediated apoptotic changes in cancer cells are well documented and hence several synthetic ligands of TLR3 are being used for adjuvant therapy. But there are reports showing contradictory effect of TLR3 signaling which includes our previous report that had shown cell proliferation following surface localization of TLR 3. However, the underlying mechanism of cell surface localization of TLR3 and subsequent cell proliferation lacks clarity. This study addresses TLR3 ligand mediated signaling cascade that regulates a proliferative effect in breast cancer cells (MDA MB 231 and T47D) challenged with TLR3 ligand in the presence of MyD88 inhibitor. Evidences were obtained using immunoblotting, co-immunoprecipitation, confocal microscopy, Immunocytochemistry, ELISA, and flowcytometry. Results had revealed that TLR3 ligand treatment significantly enhanced breast cancer cell proliferation marked by an upregulated expression of cyclinD1 but the same were suppressed by addition of MyD88 inhibitor. Also, expression of IRAK1-TRAF6-TAK1 were altered in the given TLR3-signaling pathway. Inhibition of MyD88 disrupted the downstream adaptor complex and mediated signaling through TLR3-MyD88-NF-κB (p65)-IL6-Cyclin D1 pathway. TLR3 mediated alternative signaling of the TLR3-MyD88-IRAK1-TRAF6-TAK1-TAB1-NF-κB axis leads to upregulation of IL6 and cyclinD1. This response is hypothesized to be via the MyD88 gateway that culminates in proliferation of breast cancer cells. Overall, this study provides first comprehensive evidence on involvement of canonical signaling of TLR3 using MyD88 - Cyclin D1 mediated breast cancer cell proliferation. The findings elucidated herein will provide valuable insights into understand the TLR3 mediated adjuvant therapy in cancer.

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Targeting Toll-Like Receptors for Cancer Therapy

Cited by 96 publications

References 170 publications

Discovery of novel molecular characteristics and cellular biological properties in ameloblastoma

Discovery of novel molecular characteristics and cellular biological properties in ameloblastoma

Transcriptomic Analyses Revealed Systemic Alterations in Gene Expression in Circulation and Tumor Microenvironment of Colorectal Cancer Patients

Alternative MyD88 -Cyclin D1 signaling in breast cancer cells regulates TLR3 mediated cell proliferation

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