Increased Toll-like receptor 9 expression indicates adverse prognosis in oesophageal adenocarcinoma

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

doi:10.1111/j.1365-2559.2011.03991.x

Cited by 56 publications

(58 citation statements)

References 23 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: 83%

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

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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: 83%

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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“…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

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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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“…4,6 Although initially thought to be limited only to the innate immune system, it is now well established that TLR9 is widely expressed also in various cancer types, such as in breast, brain, gastric, lung, ovarian, prostate and kidney cancers as well as in cancers of the GI tract. [7][8][9][10][11][12][13][14][15][16][17] Stimulation of TLR9 expressing cancer cells with bacterial DNA-like, synthetic TLR9 ligands induces MMP-13-mediated invasion in vitro. 7,10,18,19 Based on these findings, it was expected that tumor TLR9 mediates invasion and metastasis and that high tumor TLR9 expression would be associated with worse survival.…”

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confidence: 99%

“…Such an association has indeed been made in brain, prostate and esophageal cancers. 9,14,16,20 However, in TNBC and in RCC, the prognostic value of tumor TLR9 expression is the opposite. In these cancers, low tumor TLR9 expression has been shown to predict poor prognosis and short disease-specific survival.…”

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confidence: 99%

Tumor infiltrating CD8⁺T lymphocyte count is independent of tumor TLR9 status in treatment naïve triple negative breast cancer and renal cell carcinoma

et al. 2015

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Toll-like receptor 9 (TLR9) is a cellular DNA-receptor of the innate immune system that is widely expressed in cancers. We demonstrated that low tumor TLR9 expression predicts poor disease-specific survival in triple negative breast cancer (TNBC) and renal cell carcinoma (RCC). We hypothesized that this is because TLR9 expression affects tumor immunophenotype. To begin to test this, we compared the number of tumor infiltrating CD8 C T lymphocytes with TLR9 expression in treatment na€ ıve breast cancer (n D 197) and RCC (n D 94) cohorts with known TLR9 expression status. CD8 C T lymphocyte counts were assayed with image analysis after immunohistochemistry (IHC). Tumor TLR9 expression was not correlated with CD8C T cell counts in breast cancer or RCC. CD8 C T cell counts were significantly associated with tumor proliferation index in TNBC, but not in non-TNBC. CD8C T cell counts were also significantly associated with tumor grade in non-TNBC, but not in TNBC. In RCC, CD8C T cell counts were significantly associated with tumor stage. CD8 C T cell counts were significantly associated with prognosis in TNBC and RCC, but the presence of CD8 C T cells in these tumors had opposite effects on disease-specific survival: High CD8 C counts were associated with better prognosis in TNBC and worse prognosis in RCC. Among TNBC patients, those with low tumor TLR9 and low CD8 C T cell counts had the poorest prognosis (log-rank p D 0.0002 vs. high tumor TLR9 and high CD8 C T cell count). In conclusion, pre-treatment tumor TLR9 status is not associated with tumor infiltrating CD8 C T lymphocytes in TNBC or RCC. The combination of TLR9 and CD8 C TIL count might be a novel composite prognostic marker in TNBC.

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Increased Toll-like receptor 9 expression indicates adverse prognosis in oesophageal adenocarcinoma

Abstract: High TLR-9 expression is associated with poor differentiation, a high proliferation rate and disseminated disease. Accordingly, increased TLR-9 expression may contribute to the growth and metastatic properties of oesophageal adenocarcinoma.

Cited by 56 publications

References 23 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

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

Tumor infiltrating CD8⁺T lymphocyte count is independent of tumor TLR9 status in treatment naïve triple negative breast cancer and renal cell carcinoma

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Increased Toll-like receptor 9 expression indicates adverse prognosis in oesophageal adenocarcinoma

Abstract: High TLR-9 expression is associated with poor differentiation, a high proliferation rate and disseminated disease. Accordingly, increased TLR-9 expression may contribute to the growth and metastatic properties of oesophageal adenocarcinoma.

Cited by 56 publications

References 23 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

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

Tumor infiltrating CD8+T lymphocyte count is independent of tumor TLR9 status in treatment naïve triple negative breast cancer and renal cell carcinoma

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Tumor infiltrating CD8⁺T lymphocyte count is independent of tumor TLR9 status in treatment naïve triple negative breast cancer and renal cell carcinoma