Toll-like Receptor-4 Expression by Stromal Fibroblasts Is Associated With Poor Prognosis in Colorectal Cancer

Eiró, Noemí; González, Lucía; González, Luis O.; Fernández-García, Belén; Andicoechea, Alejandro; Barbón, Esther; García-Muñiz, José L.; Vizoso, F

doi:10.1097/cji.0b013e31829d85e6

Cited by 29 publications

(31 citation statements)

References 49 publications

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“…Similarly, high expression of TLR7 on stromal fibroblasts was associated with good prognosis in oral squamous cell carcinoma (OSCC)49. Conversely, expression of TLR4 on stromal fibroblasts was associated with poor prognosis in colorectal cancer14. Similar data were reported for hepatocellular carcinoma, where TLR9 expression on tumour-associated fibroblasts was associated with reduced overall survival50.…”

Section: Discussionmentioning

confidence: 66%

“…Some studies suggest tumour-promoting effects of TLR expression on cancer-associated fibroblasts. For example, TLR4 expression by stromal fibroblasts in colorectal cancer was associated with poor prognosis14 and overexpression of TLR3 in fibroblasts results in upregulation of the oncoprotein c-Myc15. Other studies showed that high TLR9 messenger RNA expression on fibroblast-like cells in breast or oesophageal squamous cell carcinoma was associated with reduced metastasis and invasion1617.…”

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confidence: 99%

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Combined toll-like receptor 3/7/9 deficiency on host cells results in T-cell-dependent control of tumour growth

et al. 2017

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Toll-like receptors (TLRs) are located either on the cell surface or intracellularly in endosomes and their activation normally contributes to the induction of protective immune responses. However, in cancer their activation by endogenous ligands can modulate tumour progression. It is currently unknown how endosomal TLRs regulate endogenous anti-tumour immunity. Here we show that TLR3, 7 and 9 deficiencies on host cells, after initial tumour growth, result in complete tumour regression and induction of anti-tumour immunity. Tumour regression requires the combined absence of all three receptors, is dependent on both CD4 and CD8 T cells and protects the mice from subsequent tumour challenge. While tumours in control mice are infiltrated by higher numbers of regulatory T cells, tumour regression in TLR-deficient mice is paralleled by altered vascular structure and strongly induced influx of cytotoxic and cytokine-producing effector T cells. Thus, endosomal TLRs may represent a molecular link between the inflamed tumour cell phenotype, anti-tumour immunity and the regulation of T-cell activation.

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Section: Discussionmentioning

confidence: 66%

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confidence: 99%

Combined toll-like receptor 3/7/9 deficiency on host cells results in T-cell-dependent control of tumour growth

et al. 2017

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“…The increased TLR4 expression compared to normal tissue also has been reported in sporadic CRC[23], and another study demonstrated a correlation between high expression of TLR4 and advanced disease[10]. Yet results also have been published showing that the loss of TLR4 correlates with increased metastatic status[24], and TLR4 expression by tumour cells has been significantly associated with a lower rate of tumour recurrence[25]. Nihon-Yanagi et al[8] showed equally weak TLR4 expression in both cancerous and noncancerous tissue in general, but higher expression in the cancer of the proximal colon.…”

Section: Discussionmentioning

confidence: 78%

Divergent expression of bacterial wall sensing Toll-like receptors 2 and 4 in colorectal cancer

Paarnio¹,

Väyrynen²,

Klintrup³

et al. 2017

WJG

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AIMTo characterize the expression of toll-like receptors (TLR) 2 and 4 in colorectal cancer (CRC) and in normal colorectal mucosa.METHODSWe analysed tissue samples from a prospective series of 118 unselected surgically treated patients with CRC. Sections from formalin fixed, paraffin embedded specimens were analysed for TLR2 and TLR4 expression by immunohistochemistry. Two independent assessors evaluated separately expression at the normal mucosa, at the invasive front and the bulk of the carcinoma, and in the lymph node metastases when present. Expression levels in different locations were compared and their associations with clinicopathological features including TNM-stage and the grade of the tumour and 5-year follow-up observations were analysed.RESULTSNormal colorectal epithelium showed a gradient of expression of both TLR2 and TLR4 with low levels in the crypt bases and high levels in the surface. In CRC, expression of both TLRs was present in all cases and in the major proportion of tumour cells. Compared to normal epithelium, TLR4 expression was significantly weaker but TLR2 expression stronger in carcinoma cells. Weak TLR4 expression in the invasive front was associated with distant metastases and worse cancer-specific survival at 5 years. In tumours of the proximal colon the cancer-specific survival at 5 years was 36.9% better with strong TLR4 expression as compared with those with weak expression (P = 0.044). In contrast, TLR2 expression levels were not associated with prognosis. Tumour cells in the lymph node metastases showed higher TLR4 expression and lower TLR2 expression than cells in primary tumours.CONCLUSIONTumour cells in CRC show downregulation of TLR4 and upregulation of TLR2. Low expression of TLR4 in the invasive front predicts poor prognosis and metastatic disease.

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“…To date, 13 mammalian TLRs have been described, 11 of which are expressed in humans. TLR3, TLR4 , and TLR9 are found in breast, prostate, and colon cancer [20, 21, 22]. TLR7 expression has also been reported in esophageal squamous cell carcinoma [23].…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between the HIF-1 and Toll-like receptor/nuclear factor-κB pathways in the oral squamous cell carcinoma microenvironment

Han

Wang

et al. 2016

Oncotarget

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Hypoxia is a prominent feature of the microenvironment of solid tumors and may contribute to tumor progression through the oxygen-sensitive transcriptional regulator hypoxia-inducible factor-1 (HIF-1). Chronic inflammation is another typical feature. Inflammatory mediators, including Toll-like receptors (TLRs) and nuclear factor-κB (NF-κB), play an important role in cancer development. Recent studies have revealed extensive cross-talk between hypoxia and inflammation signaling, though the mechanisms remain unclear. Our results confirm that TLR3 and TLR4 are highly expressed in oral squamous cell carcinoma (OSCC). Activation of TLR3 and TLR4 stimulated the expression of HIF-1 through NF-κB. In addition, HIF-1 increased the expression of TLR3 and TLR4 through direct promoter binding. Thus, the TLR/NF-κB pathway forms a positive feedback loop with HIF-1. These results indicate a novel cross-talk between the TLR/NF-κB and HIF-1 signaling, which may contribute to OSCC initiation and progression. With the elucidation of this novel mechanism, it might serve as a basis for future microenvironment targeted cancer therapy.

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Toll-like Receptor-4 Expression by Stromal Fibroblasts Is Associated With Poor Prognosis in Colorectal Cancer

Cited by 29 publications

References 49 publications

Combined toll-like receptor 3/7/9 deficiency on host cells results in T-cell-dependent control of tumour growth

Combined toll-like receptor 3/7/9 deficiency on host cells results in T-cell-dependent control of tumour growth

Divergent expression of bacterial wall sensing Toll-like receptors 2 and 4 in colorectal cancer

Crosstalk between the HIF-1 and Toll-like receptor/nuclear factor-κB pathways in the oral squamous cell carcinoma microenvironment

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