The toll‐like receptor pathway: A novel mechanism of infection‐induced carcinogenesis of prostate epithelial cells

Kundu, Shilajit; Lee, Chung; Billips, Benjamin K.; Habermacher, Geoffrey; Zhang, Qiang; Liu, Victoria; Wong, Larry; Klumpp, David J.; Thumbikat, Praveen

doi:10.1002/pros.20710

Cited by 118 publications

(105 citation statements)

References 17 publications

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“…Moreover, the induction of TLRs on tumor cells may directly promote proliferation, such as in human prostate cancer and in head and neck cancer. This reaction is time-and dose-dependent and is reflected by NF-κB induction and the subsequent upregulation of oncoprotein c-Myc [64,65]. However, there are studies suggesting a protective role of TLR stimulation and possible therapeutic options exploiting TLR ligation.…”

Section: The Results Of Tlr Activation -Tlrs In Carcinogenesismentioning

confidence: 99%

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

Wolska

Lech‐Marańda

Robak

2009

Cellular and Molecular Biology Letters

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Toll-like receptors (TLRs) have been described as major components of the innate immune system, recognizing the conserved molecular structures found in the large groups of pathogens called pathogen-associated molecular patterns (PAMPs). TLR expression is ubiquitous, from epithelial to immunocompetent cells. TLR ligation triggers several adapter proteins and downstream kinases, leading to the induction of key pro-inflammatory mediators but also anti-inflammatory and anti-tumor cytokines. The result of this activation goes beyond innate immunity to shape the adaptive responses against pathogens and tumor cells, and maintains host homeostasis via cell debris utilization. TLRs have already become potent targets in infectious disease treatment and vaccine therapy and in neoplastic disease treatment, due to their ability to enhance antigen presentation. However, some studies show the dual effect of TLR stimulation on malignant cells: they can be proapoptotic or promote survival under different conditions. It is therefore crucial to design further studies assessing the biology of these receptors in normal and transformed cells. The established role of TLRs in human disease therapy is based on TLR7 and TLR4 agonists, respectively for the novel treatment of some types of skin cancer and for the anti-hepatitis B virus vaccine. Some clinical trials involving TLR agonists as potent enhancers of the anti-tumor response in solid tumors have begun.

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Section: The Results Of Tlr Activation -Tlrs In Carcinogenesismentioning

confidence: 99%

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

Wolska

Lech‐Marańda

Robak

2009

Cellular and Molecular Biology Letters

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“…Several studies indicated that these infectious agents may elicit an immune response, creating a cytokine tissue environment that leads to chronic inflammation, DNA damage, cell proliferation, angiogenesis and ultimately prostate cancer (32)(33)(34)(35)). An in vitro study suggested that components of viral and other infectious agents may shift the balance towards altered homeostasis in cells that have already deviated from normal gene expression and may thus play a role in malignant transformation (36). Several epidemiological studies evaluated the association between herpes virus infection and prostate cancer risk, although results were inconsistent (9,14,16,17).…”

Section: Discussionmentioning

confidence: 99%

Herpes simplex virus type 2 or human herpesvirus 8 infection and prostate cancer risk: A meta-analysis

Wang

Shen

2013

Biomedical Reports

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Abstract. Prostate cancer is the second most frequently diagnosed type of cancer and the sixth leading cause of cancer mortality among males worldwide. The aim of this study was to investigate the association between the infection by herpes simplex virus type 2 (HSV-2) or human herpesvirus 8 (HHV-8) and the risk of prostate cancer. A systematic literature search was performed using PubMed, Cochrane Library, Web of Science, Scopus, CNKI and CBM. The association of HSV-2 or HHV-8 infection with the risk of prostate cancer was separately assessed. Estimates of the odds ratio (OR) with 95% confidence interval (CI) were pooled by the fixed-or random-effects model. A total of 11 articles with 2,996 cases and 3,875 controls were included in this meta-analysis. HSV-2 infection was associated with increased prostate cancer risk (OR=1.209; 95% CI, 1.003-1.456). Results of the stratified analysis suggested that such an association existed among participants from North and South America (OR=1.226; 95% CI, 1.000-1.503). No significant correlation was observed in the HHV-8 group (OR=1.106; 95% CI, 0.765-1.598). Further investigations and large-sample studies are required to elucidate the possible mechanism underlying viral carcinogenesis and the association between herpes virus infection and the risk of prostate cancer.

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“…Helicobacter pylori acting through TLR2/TLR9 on gastric epithelial cells activated both Src and NF-kB, resulting in an increased expression of cyclooxygenase-2 (Cox-2), which may contribute to gastric cancer progression (Chang et al, 2004). The triggering of TLR4 and TLR9 on prostate cancer cells has also been shown to promote tumour cell proliferation through increased NF-kB activation (Kundu et al, 2008).…”

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confidence: 99%

High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer

et al. 2010

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BACKGROUND: The Toll-like receptor (TLR) 4 signalling pathway has been shown to have oncogenic effects in vitro and in vivo. To demonstrate the role of TLR4 signalling in colon tumourigenesis, we examined the expression of TLR4 and myeloid differentiation factor 88 (MyD88) in colorectal cancer (CRC). METHODS: The expression of TLR4 and MyD88 in 108 CRC samples, 15 adenomas, and 15 normal mucosae was evaluated by immunohistochemistry, and the correlations between their immunoscores and clinicopathological variables, including disease-free survival (DFS) and overall survival (OS), were analysed. RESULTS: Compared with normal mucosae and adenomas, 20% cancers displayed high expression of TLR4, and 23% cancers showed high expression of MyD88. The high expression of TLR4 and MyD88 was significantly correlated with liver metastasis (P ¼ 0.0001, P ¼ 0.0054). In univariate analysis, the high expression of TLR4 was significantly associated with shorter OS (hazard ratio (HR): 2.17; 95% confidence interval (95% CI): 1.15 -4.07; P ¼ 0.015). The high expression of MyD88 expression was significantly associated with poor DFS and OS (HR: 2.33; 95% CI: 1.31 -4.13; P ¼ 0.0038 and HR: 3.03; 95% CI: 1.67 -5.48; P ¼ 0.0002). The high combined expression of TLR4 and MyD88 was also significantly associated with poor DFS and OS (HR: 2.25; 95% CI: 1.27 -3.99; P ¼ 0.0053 and HR: 2.97; 95% CI: 1.64 -5.38; P ¼ 0.0003). Multivariate analysis showed that high expressions of TLR4 (OS: adjusted HR: 1.88; 95% CI: 0.99 -3.55; P ¼ 0.0298) and MyD88 (DFS: adjusted HR: 1.93; 95% CI: 1.01 -3.67; P ¼ 0.0441; OS: adjusted HR: 2.25; 95% CI: 1.17 -4.33; P ¼ 0.0112) were independent prognostic factors of OS. Furthermore, high co-expression of TLR4/MyD88 was strongly associated with both poor DFS and OS. CONCLUSION: Our findings suggest that high expression of TLR4 and MyD88 is associated with liver metastasis and is an independent predictor of poor prognosis in patients with CRC.

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The toll‐like receptor pathway: A novel mechanism of infection‐induced carcinogenesis of prostate epithelial cells

Abstract: Our study has identified a unique mechanism that describes how components of pathogens common in the urinary system may contribute to the malignant transformation of benign prostate epithelia.

Cited by 118 publications

References 17 publications

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

Herpes simplex virus type 2 or human herpesvirus 8 infection and prostate cancer risk: A meta-analysis

High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer

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