• Adipose tissue
• IL-1β
• Inflammasome
• NF-κB
• Obesity
• Prostate cancer

• Male
• Humans
• Aged
• Inflammasomes/metabolism
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• Signal Transduction
• Inflammation/metabolism
• Prostatic Neoplasms
• Obesity/metabolism

• PID2019-105564RB-I00 Ministerio de Ciencia, Innovación y Universidades

• Bladder cancer
• Immunotherapy
• OncoTherad
• PRP
• Toll-Like receptors

• Humans
• Mice
• Animals
• BCG Vaccine
• Non-Muscle Invasive Bladder Neoplasms
• Neoplasm Recurrence, Local/drug therapy
• Urinary Bladder Neoplasms/drug therapy
• Phosphates/therapeutic use
• Immunotherapy
• Platelet-Rich Plasma
• Adjuvants, Immunologic/therapeutic use
• Tumor Microenvironment

• Toll-like receptor 5
• cancer immunity
• flagellin
• innate immunity
• prognosis
• prostate cancer

• Male
• Humans
• Toll-Like Receptor 5/genetics
• Toll-Like Receptor 5/metabolism
• Flagellin/genetics
• Flagellin/metabolism
• Up-Regulation
• Toll-Like Receptors/genetics
• Cytokines/metabolism
• Prostatic Neoplasms/genetics
• Prognosis

• R21 CA176698 NCI NIH HHS
• NIH HHS

• Cancer immunotherapy
• dendritic cells
• formyl peptide receptor 1
• immmunogenic cell death

• Animals
• Mice
• Toll-Like Receptor 3
• Adjuvants, Immunologic
• Melanoma/drug therapy
• Poly I-C/pharmacology

• bladder cancer
• genitourinary cancer
• long non-coding RNA
• molecular biomarkers
• prostate cancer
• renal cell carcinoma

• cancer immunotherapy
• cancer therapeutic resistance
• breast cancer
• chemokines
• immunoediting

• Animals
• Mice
• Adaptive Immunity
• Cytokines
• Flagellin/pharmacology
• Melanoma, Experimental/drug therapy
• Toll-Like Receptor 5/agonists

• P30 CA016672 NCI NIH HHS
• (P30 CA016672 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)

One of the most malignant tumors in men is prostate cancer that is still incurable due to its heterogenous and progressive natures. Genetic and epigenetic changes play significant roles in its development. The RNA molecules with more than 200 nucleotides in length are known as lncRNAs and these epigenetic factors do not encode protein. They regulate gene expression at transcriptional, post-transcriptional and epigenetic levels. LncRNAs play vital biological functions in cells and in pathological events, hence their expression undergoes dysregulation.

The role of epigenetic alterations in prostate cancer development are emphasized here. Therefore, lncRNAs were chosen for this purpose and their expression level and interaction with other signaling networks in prostate cancer progression were examined.

The aberrant expression of lncRNAs in prostate cancer has been well-documented and progression rate of tumor cells are regulated via affecting STAT3, NF-κB, Wnt, PI3K/Akt and PTEN, among other molecular pathways. Furthermore, lncRNAs regulate radio-resistance and chemo-resistance features of prostate tumor cells. Overexpression of tumor-promoting lncRNAs such as HOXD-AS1 and CCAT1 can result in drug resistance. Besides, lncRNAs can induce immune evasion of prostate cancer via upregulating PD-1. Pharmacological compounds such as quercetin and curcumin have been applied for targeting lncRNAs. Furthermore, siRNA tool can reduce expression of lncRNAs thereby suppressing prostate cancer progression. Prognosis and diagnosis of prostate tumor at clinical course can be evaluated by lncRNAs. The expression level of exosomal lncRNAs such as lncRNA-p21 can be investigated in serum of prostate cancer patients as a reliable biomarker.

• Drug resistance
• Exosome
• Immune evasion
• Long non-coding RNA (lncRNA)
• MicroRNA
• Prostate cancer

• Animals
• Apoptosis
• Cell Line, Tumor
• Humans
• Male
• Poly I-C/pharmacology
• Prostate/pathology
• Prostatic Neoplasms/pathology
• Toll-Like Receptor 3/genetics
• Toll-Like Receptor 3/metabolism

Toll like receptors (TLRs) are a group of transmembrane receptors belonging to the class of pattern recognition receptors (PRR), which are involved in recognition of pathogen associated molecular patterns (PAMPs), inducing immune response. During the past decade, a number of preclinical and clinical breakthroughs in the field of TLR agonists has immerged in cancer research and some of these agents have performed exceptionally well in clinical trials. Based on evidence from scientific studies, we draw attention to several microbial based TLR agonists and discuss their relevance in various cancer and explore various microbial based TLR agonists for developing effective immunotherapeutic strategies against cancer.

Toll-like receptors (TLRs) are typical transmembrane proteins, which are essential pattern recognition receptors in mediating the effects of innate immunity. TLRs recognize structurally conserved molecules derived from microbes and damage-associated molecular pattern molecules that play an important role in inflammation. Since the first discovery of the Toll receptor by the team of J. Hoffmann in 1996, in Drosophila melanogaster, numerous TLRs have been identified across a wide range of invertebrate and vertebrate species. TLR stimulation leads to NF-κB activation and the subsequent production of pro-inflammatory cytokines and chemokines, growth factors and anti-apoptotic proteins. The expression of TLRs has also been observed in many tumors, and their stimulation results in tumor progression or regression, depending on the TLR and tumor type. The anti-tumoral effects can result from the activation of anti-tumoral immune responses and/or the direct induction of tumor cell death. The pro-tumoral effects may be due to inducing tumor cell survival and proliferation or by acting on suppressive or inflammatory immune cells in the tumor microenvironment. The aim of this review is to draw attention to the effects of TLR stimulation in cancer, the activation of various TLRs by microbes in different types of tumors, and, finally, the role of TLRs in anti-cancer immunity and tumor rejection.

• cancer
• immunotherapy
• innate receptors
• microbial based therapy
• toll like receptors

• Immunity, Innate
• Interferons
• RNA, Double-Stranded
• RNA, Long Noncoding
• Signal Transduction/genetics

• State Key Laboratory of Veterinary Etiological Biology

• Arsenic
• PIC
• Poly (I:C)
• Prostate cancer
• RARβ
• Retinoic acid
• TLR3

• Adult
• Aged
• Aged, 80 and over
• Apoptosis/drug effects
• Cell Transformation, Neoplastic/drug effects
• Cell Transformation, Neoplastic/metabolism
• Cells, Cultured/drug effects
• Cells, Cultured/metabolism
• Epithelial Cells/drug effects
• Epithelial Cells/metabolism
• Genetic Variation
• Genotype
• Humans
• Male
• Middle Aged
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Prostate/drug effects
• Prostate/metabolism
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/physiopathology
• Sodium Compounds/metabolism
• Sodium Compounds/toxicity
• Toll-Like Receptors/drug effects
• Toll-Like Receptors/metabolism

• Z99 ES999999 Intramural NIH HHS
• ZIA ES102925 Intramural NIH HHS

Toll-like receptor 3 (TLR3) is an important member of the TLR family, which is an important group of pathogen-associated molecular patterns. TLR3 can recognize double-stranded RNA and induce activation of NF-κB and the production of type I interferons. In addition to its immune-associated role, TLR3 has also been detected in some tumors. However TLR3 can play protumor or antitumor roles in different tumors or cell lines. Here, we review the basic signaling associated with TLR3 and the pro- or antitumor roles of TLR3 in different types of tumors and discuss the possible reasons for the opposing roles of TLR3 in tumors.

• Toll-like receptor 3 - TLR-3
• dsRNA
• opposing role
• pathogen-associated molecular pattern
• tumors

Studies have shown that the presence of tumor infiltrating lymphocytes (TILs) in Triple Negative Breast Cancer (TNBC) is associated with better prognosis. However, the molecular mechanisms underlying these immune cell differences are not well delineated. In this study, analysis of hematoxylin and eosin images from The Cancer Genome Atlas (TCGA) breast cancer cohort failed to show a prognostic benefit of TILs in TNBC, whereas CIBERSORT analysis, which quantifies the proportion of each immune cell type, demonstrated improved overall survival in TCGA TNBC samples with increased CD8 T cells or CD8 plus CD4 memory activated T cells and in Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) TNBC samples with increased gamma delta T cells. Twenty-five genes showed mutational frequency differences between the TCGA high and low T cell groups, and many play important roles in inflammation or immune evasion (ATG2B, HIST1H2BC, PKD1, PIKFYVE, TLR3, NOTCH3, GOLGB1, CREBBP). Identification of these mutations suggests novel mechanisms by which the cancer cells attract immune cells and by which they evade or dampen the immune system during the cancer immunoediting process. This study suggests that integration of mutations with CIBERSORT analysis could provide better prediction of outcomes and novel therapeutic targets in TNBC cases.

• Animals
• Combined Modality Therapy
• Humans
• Neoplasms/drug therapy
• Neoplasms/immunology
• Neoplasms/radiotherapy
• Toll-Like Receptors/agonists

• 28280 Cancer Research UK

• CXCR4
• CXCR7
• Chemokine
• DHT
• Migration
• Prostate cancer

• apoptosis
• interferon
• interleukin 27
• poly I:C
• proliferation
• prostate cancer
• toll-like receptor 3

• lncRNA PART1
• prostate cancer
• toll-like receptor pathway

• Breast cancer
• IRF3
• Retinoic acid
• TRAIL
• Type-I IFNs
• dsRNA

The treatment of metastatic androgen-resistant prostate cancer remains a challenge. We describe a protein vector that selectively delivers synthetic dsRNA, polyinosinic/polycytidylic acid (polyIC), to prostate tumors by targeting prostate specific membrane antigen (PSMA), which is overexpressed on the surface of prostate cancer cells.

The chimeric protein is built from the double stranded RNA (dsRNA) binding domain of PKR tethered to a single chain anti-PSMA antibody. When complexed with polyIC, the chimera demonstrates selective and efficient killing of prostate cancer cells. The treatment causes the targeted cancer cells to undergo apoptosis and to secrete toxic cytokines. In a bystander effect, these cytokines kill neighboring cancer cells that do not necessarily overexpress PSMA, and activate immune cells that enhance the killing effect. The strong effects of the targeted polyIC are demonstrated on both 2D cell cultures and 3D tumor spheroids.

• PSMA
• ScFvJ591
• dsRNA binding domain
• polyIC

• Cancer immune surveillance
• Cancer immunity
• Cancer inflammation
• Cancer-associated stress
• Chromosome instability (CIN)
• DNA damage response (DDR)
• Danger-associated molecular patterns (DAMPs)
• ER stress
• Hyperploidy
• Immunogenic cell death
• Mitochondrial stress
• Oncometabolites
• Senescence-associated secretory phenotype (SASP)
• Tumor microenvironment
• Unfolded protein response

• Animals
• DNA Damage/immunology
• Endoplasmic Reticulum Stress/immunology
• Humans
• Immunologic Surveillance/immunology
• Mitosis/immunology
• Models, Immunological
• Neoplasms/genetics
• Neoplasms/immunology
• Neoplasms/metabolism
• Oxidative Stress/immunology
• Signal Transduction/immunology

• Hartwell Foundation (US)
• National Cancer Institute

The present study investigated the mechanism underlying Toll-like receptor 4 (TLR4)-mediated stimulation of hypoxia-inducible factor-1α (HIF-1α) activity and its association with reactive oxygen species (ROS) in cervical cancer cells. SiHa cells were cultured and randomized to control, lipopolysaccharide (LPS), methyl-β-cyclodextrin (MβCD)+LPS, ammonium pyrrolidinedithiocarbamate (PDTC)+LPS, ST2825+LPS and small interfering (si) RNA TLR4+LPS treatment groups. Cell proliferation was quantified using an MTT assay, cell cloning was performed using soft agar colony formation and HIF-1α expression was detected by immunocytochemical staining and western blot analyses. Dichloro-dihydro-fluorescein diacetate and lucigenin luminescence assays were used to detect alterations in ROS and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase content, respectively. Co-localization of TLR4 and HIF-1α was detected by immunofluorescence staining and observed using fluorescence microscopy. Compared with the control group, cell proliferation was enhanced in the LPS-treated group and was not altered in the PDTC+LPS treatment group. Cell proliferation was reduced in all other treatment groups (P<0.05). Compared with the LPS group, cell proliferation decreased in all other groups. Compared with the PDTC+LPS treatment group, cell proliferation significantly decreased when LPS was co-administered with ST2825, siTLR4 and MβCD (P<0.01). Treatment with MβCD+LPS exhibited an increased inhibitory effect on cell activity and proliferation. Compared with the control group, HIF-1α expression was enhanced following treatment with LPS, although it decreased when LPS was co-administered with ST2825, siTLR4 and MβCD (P<0.05). HIF-1α expression decreased following treatment with ST2825, siTLR4, MβCD and PDTC+LPS, compared with treatment with LPS alone. Compared with the PDTC+LPS group, HIF-1α activity decreased when LPS was co-administered with ST2825, siTLR4 and MβCD. NADPH oxidase and ROS levels increased in cells treated with LPS, compared with the control group, at 24 and 12 h following treatment, respectively, and decreased at 12 h when LPS was co-administered with ST2825, siTLR4 and MβCD. There was no difference between the LPS and PDTC+LPS groups with respect to NADPH and ROS levels. Compared with the PDTC+LPS group, NADPH oxidase activity and ROS content decreased when LPS was co-administered with ST2825, siTLR4 and MβCD. NADPH oxidase activity and ROS content were lowest in the MβCD+LPS treatment group, and immunofluorescent staining demonstrated that TLR4 was localized to the cell surface and HIF-1α was primarily localized to the cytoplasm. TLR4 was co-expressed with HIF-1α in cervical cancer cells. The results of the present study suggested that TLR4 signaling primarily promoted HIF-1α activity via activation of lipid rafts/NADPH oxidase redox signaling and may be associated with the initiation and progression of cervical cancer. This promoting effect was stronger in TLR4/lipid rafts/NADPH oxidase pathway than that in TLR4-NF-κB signaling pathway. Therefore, the TLR4/lipid raft-associated redox signal may be a target for therapeutic intervention to prevent the growth of cervical cancer.

• Angiogenesis
• Cytokines
• DAMPs
• T cell trafficking
• Toll-like receptors
• Tumor microenvironment

Toll-like receptor 5 (TLR5) is considered an attractive target for anticancer immunotherapy. TLR5 agonists, bacterial flagellin and engineered flagellin derivatives, have been shown to have potent antitumor and metastasis-suppressive effects in multiple animal models and to be safe in both animals and humans. Anticancer efficacy of TLR5 agonists stems from TLR5-dependent activation of nuclear factor-κB (NF-κB) that mediates innate and adaptive antitumor immune responses. To extend application of TLR5-targeted anticancer immunotherapy to tumors that do not naturally express TLR5, we created an adenovirus-based vector for intratumor delivery, named Mobilan that drives expression of self-activating TLR5 signaling cassette comprising of human TLR5 and a secreted derivative of Salmonella flagellin structurally analogous to a clinical stage TLR5 agonist, entolimod. Co-expression of TLR5 receptor and agonist in Mobilan-infected cells established an autocrine/paracrine TLR5 signaling loop resulting in constitutive activation of NF-κB both in vitro and in vivo. Injection of Mobilan into primary tumors of the prostate cancer-prone transgenic adenocarcinoma of the mouse prostate (TRAMP) mice resulted in a strong induction of multiple genes involved in inflammatory responses and mobilization of innate immune cells into the tumors including neutrophils and NK cells and suppressed tumor progression. Intratumoral injection of Mobilan into subcutaneously growing syngeneic prostate tumors in immunocompetent hosts improved animal survival after surgical resection of the tumors, by suppression of tumor metastasis. In addition, vaccination of mice with irradiated Mobilan-transduced prostate tumor cells protected mice against subsequent tumor challenge. These results provide proof-of-concept for Mobilan as a tool for antitumor vaccination that directs TLR5-mediated immune response toward cancer cells and does not require identification of tumor antigens.

Although long non‐coding RNAs (lncRNAs) have been associated with a variety of cancers, the interplay between lncRNAs and androgen receptor signaling in prostate cancer is still unclear. We identified an androgen‐dependent lncRNA, POTEF‐AS1, whose expression was regulated by androgen receptor in two androgen‐dependent cells by using directional RNA sequencing analysis. POTEF‐AS1 promoted cell growth, repressed genes related to the Toll‐like receptor signaling and apoptosis pathways, and inhibited apoptosis in docetaxel‐treated LNCaP cells. These findings suggest that POTEF‐AS1 would play a key role in the progression of prostate cancer by repressing Toll‐like receptor signaling.

• AR
• TLR3
• TNFSF10
• lncRNA
• prostate cancer

Selective delivery of drugs to tumor cells can increase potency and reduce toxicity. In this study, we describe a novel recombinant chimeric protein, dsRBEC, which can bind polyIC and deliver it selectively into EGFR over-expressing tumor cells. dsRBEC, comprises the dsRNA binding domain (dsRBD) of human PKR (hPKR), which serves as the polyIC binding moiety, fused to human EGF (hEGF), the targeting moiety. dsRBEC shows high affinity towards EGFR and triggers ligand-induced endocytosis of the receptor, thus leading to the selective internalization of polyIC into EGFR over-expressing tumor cells. The targeted delivery of polyIC by dsRBEC induced cellular apoptosis and the secretion of IFN-β and other pro-inflammatory cytokines. dsRBEC-delivered polyIC is much more potent than naked polyIC and is expected to reduce the toxicity caused by systemic delivery of polyIC.

• Animals
• Apoptosis/drug effects
• Cell Line, Tumor
• Chemokine CCL5/biosynthesis
• Chemokine CCL5/metabolism
• Cloning, Molecular
• Drug Delivery Systems
• Endocytosis
• Epidermal Growth Factor/genetics
• Epidermal Growth Factor/metabolism
• ErbB Receptors/genetics
• ErbB Receptors/metabolism
• Escherichia coli/genetics
• Escherichia coli/metabolism
• Gene Expression
• Humans
• Interferon Inducers/chemistry
• Interferon Inducers/metabolism
• Interferon Inducers/pharmacology
• Interferon-beta/biosynthesis
• Interferon-beta/metabolism
• MCF-7 Cells
• Poly I-C/chemistry
• Poly I-C/metabolism
• Poly I-C/pharmacology
• Protein Binding
• Protein Domains
• Recombinant Fusion Proteins/genetics
• Recombinant Fusion Proteins/metabolism
• Tumor Necrosis Factor-alpha/biosynthesis
• Tumor Necrosis Factor-alpha/metabolism
• eIF-2 Kinase/genetics
• eIF-2 Kinase/metabolism

• European Research Council

• DNA methylation
• Inflammation and prostate cancer
• Sex steroid hormones

• Toll-like receptor
• cancer stem cells
• glioblastoma
• neural progenitor cells

Hepatocellular carcinoma (HCC) is a primary cancer of the liver that is predominant in developing countries and is responsible for nearly 600000 deaths each year worldwide. Similar to many other tumors, the development of HCC must be understood as a multistep process involving the accumulation of genetic and epigenetic alterations in regulatory genes, leading to the activation of oncogenes and the inactivation or loss of tumor suppressor genes. Extensive research over the past decade has identified a number of molecular biomarkers, including aberrant expression of HCC-related genes and microRNAs. The challenge facing HCC research and clinical care at this time is to address the heterogeneity and complexity of these genetic and epigenetic alterations and to use this information to direct rational diagnosis and treatment strategies. The multikinase inhibitor sorafenib was the first molecularly targeted drug for HCC to show some extent of survival benefits in patients with advanced tumors. Although the results obtained using sorafenib support the importance of molecular therapies in the treatment of HCC, there is still room for improvement. In addition, no molecular markers for drug sensitivity, recurrence and prognosis are currently clinically available. In this review, we provide an overview of recently published articles addressing HCC-related genes and microRNAs to update what is currently known regarding genetic and epigenetic aspects of the pathogenesis of HCC and propose novel promising candidates for use as diagnostic and therapeutic targets in HCC.

• Hepatocellular carcinoma
• Oncogene
• Tumor suppressor gene
• MicroRNA
• DNA methylation

• Animals
• Carcinoma, Hepatocellular/genetics
• Cell Cycle Proteins/genetics
• DNA Methylation
• Disease Progression
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Humans
• Interleukin-6/genetics
• Liver Neoplasms/genetics
• Membrane Glycoproteins/genetics
• Microtubule-Associated Proteins/genetics
• Neoplasm Recurrence, Local
• Niacinamide/analogs & derivatives
• Niacinamide/therapeutic use
• Nuclear Proteins/genetics
• Oncogenes
• Phenylurea Compounds/therapeutic use
• Prognosis
• Receptors, Immunologic/genetics
• Sirtuin 1/genetics
• Sorafenib
• Trans-Activators
• Transcription Factors/genetics
• Treatment Outcome
• Triggering Receptor Expressed on Myeloid Cells-1

• Apoptosis
• Cell cycle
• Gene-gene interaction
• Inflammation
• Transcription factor

Chronic inflammation has been considered an important risk factor for development of prostate cancer. Toll-like receptors (TLRs) recognize microbial moieties or endogenous molecules and play an important role in the triggering and promotion of inflammation. In this study, we examined whether expression of TLR4 and TLR5 was associated with progression of prostate transformation in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The expression of TLR4 and TLR5 was evaluated by immunohistochemisty in formalin-fixed paraffin-embedded prostate tissue from wild-type (WT) and TRAMP mice. Normal prostate tissue from WT mice showed strong expression of TLR4 and TLR5. However, TLR4 expression in the prostate tissue from TRAMP mice gradually decreased as pathologic grade became more aggressive. TLR5 expression in the prostate tissue from TRAMP mice also decreased in low-grade prostate intraepithelial neoplasia (PIN), high-grade PIN and poorly differentiated adenocarcinoma. Overall, our results suggest that decreased expression of TLR4 and TLR5 may contribute to prostate tumorigenesis.

• Toll-like receptor 4
• Toll-like receptor 5
• prostate cancer
• transgenic adenocarcinoma of mouse prostate

• Toll-like receptors
• drug delivery
• immunotherapy
• multifunctional nanoparticles
• multimodal imaging
• theranostics

• Animals
• Cell Line
• Drug Carriers
• Ferric Compounds/administration & dosage
• Immune System/drug effects
• Immune System/immunology
• Lymph Nodes/drug effects
• Mice
• Mice, Inbred BALB C
• Nanoparticles
• RNA, Double-Stranded/administration & dosage

Toll-like receptors (TLRs) are a family of highly conserved transmembrane proteins expressed in epithelial and immune cells that recognize pathogen associated molecular patterns. Besides their role in immune response against infections, numerous studies have shown an important role of different TLRs in cancer, indicating these receptors as potential targets for cancer therapy. We previously demonstrated that the activation of TLR3 by the synthetic double-stranded RNA analogue poly I:C induces apoptosis of androgen-sensitive prostate cancer (PCa) LNCaP cells and, much less efficiently, of the more aggressive PC3 cell line. Therefore, in this study we selected LNCaP cells to investigate the mechanism of TLR3-mediated apoptosis and the in vivo efficacy of poly I:C-based therapy. We show that interferon regulatory factor-3 (IRF-3) signalling plays an essential role in TLR3-mediated apoptosis in LNCaP cells through the activation of the intrinsic and extrinsic apoptotic pathways. Interestingly, hardly any apoptosis was induced by poly I:C in normal prostate epithelial cells RWPE-1. We also demonstrate for the first time the direct anticancer effect of poly I:C as a single therapeutic agent in a well-established human androgen-sensitive PCa xenograft model, by showing that tumour growth is highly impaired in poly I:C-treated immunodeficient mice. Immunohistochemical analysis of PCa xenografts highlights the antitumour role of poly I:C in vivo both on cancer cells and, indirectly, on endothelial cells. Notably, we show the presence of TLR3 and IRF-3 in both human normal and PCa clinical samples, potentially envisaging poly I:C-based therapy for PCa.

• IRF-3
• apoptosis
• poly I:C
• prostate cancer
• toll-like receptor

Prostate cancer is the second leading cause of cancer-related death in men after lung cancer. Immune responses clearly play a critical role in the tumorigenesis and in the efficacy of radiation therapy and chemotherapy in prostate cancer; however, the underlying molecular mechanisms are still poorly understood. Toll-like receptors (TLRs) are a well-known family of pattern recognition receptors that play a key role in host immune system. Recent studies demonstrate that there are links between TLRs and cancer; however, the function and biological importance of TLRs in prostate cancer seems complex. To elucidate the role of TLRs and innate immunity in prostate cancer might provide us with a better understanding of the molecular mechanisms of this disease. Moreover, utilizing the agonists or antagonists of TLRs might represent a promising new strategy against prostate cancer. In this review, we summarize recent advances on the studies of association between TLR signaling and prostate cancer, TLR polymorphisms and prostate cancer risk, and provide some insights about TLRs as potential targets for prostate cancer immunotherapy.

• TLR signaling
• immunotherapy
• innate immunity
• prostate cancer
• toll-like receptor

Many types of tumors are organized in a hierarchy of heterogeneous cell populations with different molecular signature. Such heterogeneity may be associated with different responsiveness to microenvironment stimuli. In the present study, the effects of lipopolysaccharide (LPS) and lipoteichoic acid (LTA), as well-known mediators of inflammation, on cancerous behavior of three prostate tumor cells, LNCaP, PC3 and DU145, were investigated.

Expression of TLR1-10, CD14 and MyD88 transcripts was investigated by RT-PCR. Protein expression of TLR2 and 4 was scrutinized by flow cytometry, immunofluorescent staining and Western blotting. Experiments were set up to assess the effects of LPS and LTA at different concentrations and times on cell proliferation, extracellular matrix invasion, adhesion and cytokine production.

We showed that prostate cancer cell lines differentially express TLR1-10, MyD88 and CD14 transcripts. DU145 failed to express TLR4 gene. Positively-identified TLR2 protein in all prostate cancer cells and TLR4 protein in PC3 and LNCaP by Western blotting was not accompanied by cell surface expression, as judged by flow cytometry. Immunofluorescent staining clearly demonstrated predominantly perinuclear localization of TLR2 and TLR4. LTA activation of all prostate cancer cells significantly increased cell proliferation. Regardless of lacking TLR4, DU145 cells proliferated in response to LPS treatment. While LPS caused increased invasiveness of LNCaP, invasive capacity of PC3 was significantly reduced after LPS or LTA stimulation. Stimulation of all prostate tumor cells with LTA was associated with increased cell adhesion and IL-8 production. IL-6 production, however, was differentially regulated by LPS stimulation in prostate tumor cells.

The data shows that cancer cells originated from the same histologically origin exhibit heterogeneous response to the same TLR ligand. Therefore, a thorough and comprehensive judgment on how and to what extent a particular cancer is affected by TLR agonist could not be inferred by studying an individual cell line.

• Adhesion
• Inflammation
• Invasion
• Pro-inflammatory cytokine
• Proliferation
• Prostate cancer
• Toll like receptor

• Adoptive T cell therapy;
• Bacterial lipoprotein;
• Glioma;
• Toll-like receptor 2;
• Tumor microenvironment

• Colony formation
• TLR7
• growth inhibition
• prostate cancer
• transgenic adenocarcinoma of mouse prostate mice

• combined chemotherapy
• inflammation

• Animals
• Apoptosis/drug effects
• Apoptosis/genetics
• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• Cell Line, Tumor
• DNA (Cytosine-5-)-Methyltransferases/genetics
• DNA (Cytosine-5-)-Methyltransferases/metabolism
• DNA Methylation
• Female
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Immunoblotting
• Male
• Mice
• Mice, Nude
• MicroRNAs/genetics
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Poly I-C/pharmacology
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/pathology
• Prostatic Neoplasms/prevention & control
• Receptors, Retinoic Acid/genetics
• Receptors, Retinoic Acid/metabolism
• Reverse Transcriptase Polymerase Chain Reaction
• Toll-Like Receptor 3/agonists
• Toll-Like Receptor 3/genetics
• Toll-Like Receptor 3/metabolism
• Tretinoin/pharmacology
• Xenograft Model Antitumor Assays

• U01 CA166905 NCI NIH HHS
• U01 CA152758 NCI NIH HHS
• RC2 CA148302 NCI NIH HHS
• P30 CA016058 NCI NIH HHS
• RC2CA148302 NCI NIH HHS
• UO1CA152758 NCI NIH HHS