Toll-Like Receptor 9 Is a Novel Biomarker for Esophageal Squamous Cell Dysplasia and Squamous Cell Carcinoma Progression

Takala, Heikki; Kauppila, Joonas H.; Soini, Ylermi; Selander, Katri S.; Vuopala, Katri; Lehenkari, Petri; Saarnio, Juha; Karttunen, Tuomo J.

doi:10.1159/000329115

Cited by 44 publications

(38 citation statements)

References 61 publications

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“…TLR9 overexpression by cancer epithelial [35][36][37][38][39][40][41]. Results from our study are in agreement with those reported in the literature [42].…”

Section: Discussionsupporting

confidence: 92%

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

Meseure

Vacher

Alsibai

et al. 2016

Cancer Microenvironment

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Toll-like receptors (TLRs) are pattern recognition receptors mainly expressed by cells of the immune system but also by epithelial tumor cells. Little is known about expression patterns of TLR genes in breast tumors, and their clinical significance is unclear. The aim of our study was to investigate expression of TLRs pathway components in pre-invasive breast lesions and invasive breast carcinomas (IBCs). We used RT-PCR assays to quantify mRNA levels of the 10 TLR genes and genes involved in TLR pathways in 350 breast tumors from patients with known clinical/pathological status and long-term outcome. Sets of 158 breast samples were also analyzed by immunochemistry including; 40 early noninvasive breast lesions, 38 IBCs and 80 triple negative carcinomas subtype (TNCs). We identified TLR9 as the major TLR gene family member upregulated in breast tumors and more particularly in TNCs. Immunohistochemical studies demonstrated that TLR9 protein was expressed in tumor epithelial and stromal cells of the TLR9 mRNA-overexpressing tumors. TLR9 overexpression appears very early during breast carcinogenesis. High TLR9 levels were associated with favorable outcome in the TNC sub-group. TLR9 overexpression was associated with alterations of down-stream components of the TLR9 signaling pathway, epithelio-mesenchymal transition (EMT) induction and EGFR pathway deregulation. TNCs with TLR9 overexpression were significantly correlated with development of a fibrous and inflammatory microenvironment with variable status of nuclear phosphoSTAT3. Our results suggest that TLR9 could play a role in TNC carcinogenesis and could be useful as predictive biomarker and therapeutic target.Keywords Toll-like receptor 9 . Breast cancer subtypes .

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“…TLR9 overexpression by cancer epithelial [35][36][37][38][39][40][41]. Results from our study are in agreement with those reported in the literature [42].…”

Section: Discussionsupporting

confidence: 92%

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

Meseure

Vacher

Alsibai

et al. 2016

Cancer Microenvironment

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“…These signaling pathways are all involved in pathways expressing various types of pattern recognition receptors (PRRs). Recently, many studies have confirmed that glioma, breast, prostate, lung, ovarian and esophageal cancer cells are all related to the 'Toll-like receptor signaling pathway' (28)(29)(30)(31). These studies used microorganism-derived TLR ligand to indicate that the TLR expressed in the tumor cells had functional activities (32).…”

Section: Discussionmentioning

confidence: 99%

Screening for transcription factors and their regulatory small molecules involved in regulating the functions of CL1-5 cancer cells under the effects of macrophage-conditioned medium

Xue

Gao

et al. 2013

Oncology Reports

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Abstract. Many reports have inferred that macrophages can interact with tumor cells in the tumor microenvironment (TME) in a vicious cycle of tumor development; however, the changes in gene expression in tumor cells under the effects of macrophages are still largely unknown. The present study was carried out to illustrate the changes in the gene expression profile in lung cancer cells under the effects of macrophageconditioned medium. Gene expression profile data were derived from the GEO database GSE9315. The GSM234968 sample was derived from a highly invasive human pulmonary adenocarcinoma cell line, CL1-5, and was treated with conditioned medium (supernatant of a culture solution of human monocyte THP-1). The GSM234967 sample that was not treated with the conditioned medium was used as a control. GO and KEGG enrichment analyses were carried out using DAVID software, and visualization networks were constructed using Cytoscape software. The results showed that 40 differentially expressed genes were annotated. Five differentially expressed transcription factors were identified, EIF2B4, EIF2B5, JUNB, GNG11 and HMGB2, which were all related to 'stress' and 'responses'. The gene cluster of JUNB was mainly enriched in cancer-related pathways, 'Wnt signaling pathway' and 'MAPK signaling pathway'. Finally, 10 small molecules, thioridazine, resveratrol, astemizole, ciclopirox, calmidazolium, etoposide, anisomycin, pyrvinium, azacyclonol and terfenadine, which may act on transcription factors, were identified using the CMap database. In conclusion, we identified transcription factors playing key roles in tumor cells under the effects of macrophages in order to provide new clues for blocking this vicious cycle of tumor development.

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“…4 TLR9, which recognizes CpG-oligodeoxynucleotides, has been associated with survival in esophageal squamous cell carcinoma and adenocarcinoma. 5,6 Stimulation of TLR9 induced invasion of esophageal cancer cells and its expression increases in metaplasia-dysplasia sequence. 7,8 No published information, however, on TLRs 3, 7 or 8 in esophageal adenocarcinoma could be found.…”

Section: Introductionmentioning

confidence: 99%

Nucleic acid-sensing toll-like receptors 3, 7 and 8 in esophageal epithelium, barrett’s esophagus, dysplasia and adenocarcinoma

et al. 2016

Self Cite

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Toll-like receptors (TLRs) are immunological receptors recognizing various microbial and endogenous ligands, such as DNA, RNA, and other microbial and host components thus activating immunological responses. The expression of TLRs in esophageal adenocarcinoma is not well known. The aim of this study was to evaluate expression patterns of those TLRs that sense nucleic acids in Barrett's esophagus with and without dysplasia and in esophageal adenocarcinoma. TLRs 3, 7 and 8 were stained immunohistochemically and evaluated in a cohort of patients with esophageal adenocarcinoma or dysplasia. Specimens with normal esophagus (n D 88), gastric (n D 67) or intestinal metaplasia (n D 51) without dysplasia, and low-grade (n D 42) or high-grade dysplasia (n D 37) and esophageal adenocarcinoma (n D 99) were studied. We used immunofluorescence to confirm the subcellular localization of TLRs. We found abundant expression of TLR3, 7 and 8 in esophageal squamous epithelium, columnar metaplasia, dysplasia and adenocarcinoma. Cytoplasmic expression of TLR3, TLR7 or TLR8 did not associate to clinicopathological parameters or prognosis in esophageal cancer. High nuclear expression of TLR8, confirmed with immunofluorescence, in cancer cells was observed in tumors of high T-stage (p < 0.01) and in tumors with organ metastasis (p < 0.001). High nuclear TLR8 expression was associated with poor prognosis (p < 0.001). The expression of TLR3, TLR7 and TLR8 increased toward dysplasia and adenocarcinoma. We demonstrated nuclear localization of TLR8, which associates with metastasis and poor prognosis. TLR3 and TLR7 do not seem to have prognostic significance in esophageal adenocarcinoma.

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Toll-Like Receptor 9 Is a Novel Biomarker for Esophageal Squamous Cell Dysplasia and Squamous Cell Carcinoma Progression

Cited by 44 publications

References 61 publications

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

Screening for transcription factors and their regulatory small molecules involved in regulating the functions of CL1-5 cancer cells under the effects of macrophage-conditioned medium

Nucleic acid-sensing toll-like receptors 3, 7 and 8 in esophageal epithelium, barrett’s esophagus, dysplasia and adenocarcinoma

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