Serum TLR2 and TLR4 levels in colorectal cancer and their association with systemic inflammatory markers, tumor characteristics, and disease outcome

Paarnio, Karoliina; Tuomisto, Anne; Väyrynen, Sara A.; Klintrup, Kai; Ohtonen, Pasi; Mäkinen, Markus J.; Mäkelä, Jyrki; Karttunen, Tuomo J.

doi:10.1111/apm.12971

Cited by 14 publications

(12 citation statements)

References 25 publications

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“…TLR 1, 2, 5, 6, and 10 are extracellular TLRs, whereas TLR3, 7, 8, and 9 are localized in intracellular organelles (12). TLR2 and TLR4 are two major TLRs that have been widely investigated for their involvement in inflammatory responses and cancers (13). The expression and clinical significance of TLR4 have been reported in patients with BCa (14).…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of TLR2 Serves as a Prognostic Biomarker in Breast Cancer and Predicts Resistance to Endocrine Therapy in the Luminal B Subtype

2020

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Background: Breast cancer (BCa) is a serious global health burden among females, and the development of resistance represents an important challenge to BCa treatment. Here, we examined the expression of toll-like receptor 2 (TLR2) in BCa patients and the prognostic value of TLR2 for predicting endocrine resistance. Methods: The study included 150 BCa patients, of which 82 underwent endocrine therapy. TLR2 mRNA expression was measured by quantitative Real-Time PCR, and its prognostic value was determined by Kaplan-Meier survival analysis. Changes in the expression of TLR2 in BCa patients with endocrine resistance were assessed, and the value of TLR2 for predicting endocrine resistance was evaluated using the receiver operating characteristic curve analysis. Results: TLR2 expression was higher in BCa tissue than in normal tissue and associated with tumor size, HER2 status, tumor subtype, and TNM stage. TLR2 upregulation was associated with poor prognosis in patients with BCa, as well as endocrine resistance, and TLR2 upregulation was more prevalent among HER2-positive BCa cases. The predictive performance of TLR2 for endocrine resistance was higher in HER2-positive BCa than in other hormone receptor-positive BCa cases. Conclusion: TLR2 upregulation is a promising biomarker for prognosis and predicting resistance to endocrine therapy. The relationship between TLR2 and HER2 indicates that TLR2 may be involved in endocrine resistance through the HER2 signaling pathway in BCa.

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Section: Introductionmentioning

confidence: 99%

Dysregulation of TLR2 Serves as a Prognostic Biomarker in Breast Cancer and Predicts Resistance to Endocrine Therapy in the Luminal B Subtype

2020

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“…One of the core enriched genes of the present analysis was the co-chaperon HSP90B1, which directly influences the functionality of most TLRs (Graustein 2018). Recently, it was demonstrated that TLR2 was highly upregulated in CRC compared to normal mucosa (Paarnio et al 2019) and TLRs might even prove to be important as diagnostic markers. Furthermore, TLRs correlate with high inflammation and poor prognosis in CRC patients (Paarnio et al 2017).…”

Section: Hep Vs M0: Reactome Toll-like Receptor-cascadementioning

confidence: 79%

The association of immunosurveillance and distant metastases in colorectal cancer

Jacob

Jurinović

Lampert

et al. 2021

J Cancer Res Clin Oncol

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Background Colorectal cancer (CRC) is the third most common malignancy worldwide, but the key driver to distant metastases is still unknown. This study aimed to elucidate the link between immunosurveillance and organotropism of metastases in CRC by evaluating different gene signatures and pathways. Material and methods CRC patients undergoing surgery at the Department of General, Visceral and Transplantation Surgery at the Ludwig-Maximilian University Hospital Munich (Munich, Germany) were screened and categorized into M0 (no distant metastases), HEP (liver metastases) and PER (peritoneal carcinomatosis) after a 5-year follow-up. Six patients of each group were randomly selected to conduct a NanoString analysis, which includes 770 genes. Subsequently, all genes were further analyzed by gene set enrichment analysis (GSEA) based on seven main cancer-associated databases. Results Comparing HEP vs. M0, the gene set associated with the Toll-like receptor (TLR) cascade defined by the Reactome database was significantly overrepresented in HEP. HSP90B1, MAPKAPK3, PPP2CB, PPP2R1A were identified as the core enrichment genes. The immunologic signature pathway GSE6875_TCONV_VS_FOXP3_KO_TREG_DN with FOXP3 as downstream target was significantly overexpressed in M0. RB1, TMEM 100, CFP, ZKSCAN5, DDX50 were the core enrichment genes. Comparing PER vs. M0 no significantly differentially expressed gene signatures were identified. Conclusion Chronic inflammation might enhance local tumor growth. This is the first study identifying immune related gene sets differentially expressed between patients with either liver or peritoneal metastases. The present findings suggest that the formation of liver metastases might be associated with TLR-associated pathways. In M0, a high expression of FOXP3 + tumor infiltrating lymphocytes (TILs) seemed to prevent at least in part metastases. Thus, these correlative findings lay the cornerstone to further studies elucidating the underlying mechanisms of organotropism of metastases.

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“…Among many malignancies including CRC, local and systemic inflammation has been studied separately, with very few studies assessing the association between local inflammation and SIR. Paarnio et al [13] studied both the serum and tumoral expression of TLR2 and TLR4 finding no association with each other, although patients with detectable serum TLR2 levels exhibited higher TLR2 immunoexpression in the normal colorectal mucosa. They found that patients with undetectable TLR2 serum levels had higher CRP values, indicative of some connection between local and systemic inflammation [13].…”

Section: Discussionmentioning

confidence: 99%

“…To our knowledge, this was the first study to describe the role of TLR5 in CRC. In addition, a low serum TLR2 associated with a high serum C-reactive protein (CRP) in another published study [13].…”

Section: Introductionmentioning

confidence: 99%

The Relationship between the Tissue Expression of TLR2, TLR4, TLR5, and TLR7 and Systemic Inflammatory Responses in Colorectal Cancer Patients

et al. 2021

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Background: Colorectal cancer (CRC) is the third most commonly diagnosed malignancy globally. CRC patients with elevated plasma C-reactive protein (CRP) levels exhibit compromised prognoses. Toll-like receptors (TLRs), activating the innate and adaptive immune systems, may contribute to pro- and antitumorigenic inflammatory responses. We aimed to identify a possible link between local and systemic inflammatory responses in CRC patients by investigating the association between tissue TLRs and plasma CRP. Methods: Tissue expressions of TLR2, TLR4, TLR5, and TLR7 were assessed using immunohistochemistry of tissue microarray slides from 549 CRC patients surgically treated between 1998 and 2005. Blood samples were drawn preoperatively, centrifuged, aliquoted, and stored at −80°C until analysis. Plasma CRP was determined through high-sensitivity time-resolved immunofluorometric assay. We investigated the association of TLRs to clinicopathologic variables, plasma CRP, and survival. Results: High TLR2 expression (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.41–0.85; p = 0.005), high TLR5 expression (HR 0.60; 95% CI 0.45–0.83; p = 0.002), positive TLR7 expression (HR 0.49; 95% CI 0.33–0.72; p < 0.001), and low CRP (HR 1.48; 95% CI 1.08–2.11; p = 0.017) were associated with a better prognosis. A high TLR2 immunoexpression was associated with a better prognosis among low-CRP patients (HR 0.53; 95% CI 0.35–0.80; p = 0.002), high TLR4 expression among high-CRP patients (HR 2.04; 95% CI 1.04–4.00; p = 0.038), high TLR5 expression among low-CRP patients (HR 0.059; 95% CI 0.37–0.92; p = 0.021), and positive TLR7 expression among low-CRP patients (HR 0.53; 95% CI 0.28–1.00; p = 0.049). In multivariate analyses, no biomarkers emerged as significant independent variables. Conclusions: High tissue TLR2, TLR5, and TLR7 levels were associated with a better prognosis. Among low-CRP patients, those with high TLR2, TLR5, and TLR7 immunoexpressions exhibited a better prognosis. Among high CRP patients, a high TLR4 immunoexpression was associated with a better prognosis.

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Serum TLR2 and TLR4 levels in colorectal cancer and their association with systemic inflammatory markers, tumor characteristics, and disease outcome

Cited by 14 publications

References 25 publications

Dysregulation of TLR2 Serves as a Prognostic Biomarker in Breast Cancer and Predicts Resistance to Endocrine Therapy in the Luminal B Subtype

Dysregulation of TLR2 Serves as a Prognostic Biomarker in Breast Cancer and Predicts Resistance to Endocrine Therapy in the Luminal B Subtype

The association of immunosurveillance and distant metastases in colorectal cancer

The Relationship between the Tissue Expression of TLR2, TLR4, TLR5, and TLR7 and Systemic Inflammatory Responses in Colorectal Cancer Patients

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