The prognostic role of tissue TLR2 and TLR4 in colorectal cancer

Beilmann-Lehtonen, Ines; Böckelman, Camilla; Mustonen, Harri; Koskensalo, Selja; Hagström, Jaana; Haglund, Caj

doi:10.1007/s00428-020-02833-5

Cited by 26 publications

(20 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Very few studies exist describing the role of TLRs in CRC. We previously demonstrated that patients with lymph node-positive disease with a strong tissue expression of TLR2 exhibited a better DSS [11]. The current study supports this finding, since CRC cases with a high TLR2 expression exhibited a better prognosis across the entire cohort.…”

Section: Discussionsupporting

confidence: 88%

“…TLRs have not been extensively investigated in CRC, with TLR4 representing the most studied TLR in CRC. In a previous study, we revealed that Dukes B patients with strong TLR4 tissue immunoexpression exhibited a worse prognosis, while a strong TLR2 tissue immunoexpression was associated with a favorable prognosis in Dukes C patients [11]. In another study, we demonstrated that a strong TLR5 tissue expression represents an independent positive prognostic factor among CRC patients [12].…”

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 97%

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…patients was associated with a worse disease (48). Another study showed that stimulation of TLR2 promotes TLR2 positive squamous carcinoma cell growth (49).…”

Section: Oncogenic Nature Of Grp94 Clientsmentioning

confidence: 98%

Molecular Chaperone GRP94/GP96 in Cancers: Oncogenesis and Therapeutic Target

et al. 2021

View full text Add to dashboard Cite

During tumor development and progression, intrinsic and extrinsic factors trigger endoplasmic reticulum (ER) stress and the unfolded protein response, resulting in the increased expression of molecular chaperones to cope with the stress and maintain tumor cell survival. Heat shock protein (HSP) GRP94, also known as GP96, is an ER paralog of HSP90 and has been shown to promote survival signaling during tumor-induced stress and modulate the immune response through its multiple clients, including TLRs, integrins, LRP6, GARP, IGF, and HER2. Clinically, elevated expression of GRP94 correlates with an aggressive phenotype and poor clinical outcome in a variety of cancers. Thus, GRP94 is a potential molecular marker and therapeutic target in malignancies. In this review, we will undergo deep molecular profiling of GRP94 in tumor development and summarize the individual roles of GRP94 in common cancers, including breast cancer, colon cancer, lung cancer, liver cancer, multiple myeloma, and others. Finally, we will briefly review the therapeutic potential of selectively targeting GRP94 for the treatment of cancers.

show abstract

“…In CRC patients, TLRs have not been widely investigated. In our previous study, Dukes B CRC patients with a strong TLR4 tissue expression exhibited a worse prognosis, while Dukes C CRC patients with a strong TLR2 expression experienced a better prognosis [14].…”

Section: Introductionmentioning

confidence: 83%

High Tissue TLR5 Expression Predicts Better Outcomes in Colorectal Cancer Patients

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background: Colorectal cancer (CRC), the third most common cancer globally, caused 881,000 cancer deaths in 2018. Toll-like receptors (TLRs), the primary sensors of pathogen-associated molecular patterns and damage-associated molecular patterns, activate innate and adaptive immune systems and participate in the development of an inflammatory tumor microenvironment. We aimed to explore the prognostic value of TLR3, TLR5, TLR7, and TLR9 tissue expressions in CRC patients. Methods: Using immunohistochemistry, we analyzed tissue microarray samples from 825 CRC patients who underwent surgery between 1982 and 2002 at the Department of Surgery, Helsinki University Hospital, Finland. After analyzing a pilot series of 205 tissue samples, we included only TLR5 and TLR7 in the remainder of the patient series. We evaluated the associations between TLR5 and TLR7 tissue expressions, clinicopathologic variables, and survival. Using the Kaplan-Meier method, we generated survival curves, determining significance using the log-rank test. Univariate and multivariate survival analyses relied on the Cox proportional hazards model. Results: The 5-year disease-specific survival was 55.9% among TLR5-negative (95% confidence interval [CI] 50.6–61.2%) and 61.9% (95% CI 56.6–67.2%; p = 0.011, log-rank test) among TLR5-positive patients. In the Cox multivariate survival analysis adjusted for age, sex, stage, location, and grade, positive TLR5 immunoexpression (hazard ratio [HR] 0.74; 95% CI 0.59–0.92; p = 0.007) served as an independent positive prognostic factor. TLR7 immunoexpression exhibited no prognostic value in the survival analysis across the entire cohort (HR 0.97; 95% CI 0.78–1.20; p = 0.754) nor in subgroup analyses. Conclusions: We show for the first time that a high TLR5 tumor tissue expression associates with a better prognosis in CRC patients.

show abstract

The prognostic role of tissue TLR2 and TLR4 in colorectal cancer

Cited by 26 publications

References 48 publications

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

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

Molecular Chaperone GRP94/GP96 in Cancers: Oncogenesis and Therapeutic Target

High Tissue TLR5 Expression Predicts Better Outcomes in Colorectal Cancer Patients

Contact Info

Product

Resources

About