TLR4 Activates the B-Catenin Pathway to Cause Intestinal Neoplasia

Santaolalla, Rebeca; Ruiz, Jose; Davies, Joan E.; Sussman, Daniel A.; Pastorini, Cristhine; España, Cecilia; Burlingame, Oname; Bejarano, P.A.; Rassaei, Negar; Ko, Justine S.; Dirisina, Ramanarao; Shang, Limin; Lira, Sérgio A.; Fukata, Masayuki; Abreu, María T.

doi:10.1097/00054725-201212001-00032

Cited by 7 publications

(14 citation statements)

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“…In novel studies, we now report that these putative human colonic stem cells express TLR-2, TLR-4 and TLR-5. Wnt signalling is important in regulating stem cell function and a recent study has reported the ability of TLR-4 to activate the canonical Wnt pathway in colonic epithelial cell lines [34]. Expression of TLR-4 in Lgr5-positive murine small intestinal stem cells has also been reported [35].…”

Section: Discussionmentioning

confidence: 97%

Toll-like receptor expression in crypt epithelial cells, putative stem cells and intestinal myofibroblasts isolated from controls and patients with inflammatory bowel disease

Brown

Hughes

Moossavi

et al. 2014

Clinical and Experimental Immunology

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The aim of our studies was to investigate the expression of Toll-like receptor (TLR)-2 and TLR-4 (and in some studies TLR-5) in myofibroblasts and small and large intestinal crypt epithelial cells from control patients and those affected by Crohn’s disease and ulcerative colitis. Isolated and disaggregated crypt epithelial cells and monolayers of myofibroblasts were used for studies by reverse transcription–polymerase chain reaction (RT–PCR), real-time RT–PCR, flow cytometry, immunocytochemistry and Western blot analysis. Compared to control cells, crypt epithelial cells isolated from active ulcerative colitis and Crohn’s disease colonic mucosal samples showed significantly higher expression of TLR-2 and TLR-4 transcripts and protein (on the cell surface). There was also enhanced expression of TLR-4 in crypt cells from ileal Crohn’s disease. Expression of TLR-2 and TLR-4 transcripts in crypt epithelial cells isolated from inflamed mucosa of distal ulcerative colitis did not differ significantly from such cells obtained from the normal proximal colon. Crypt epithelial cells with side population characteristics (putative stem cells) also expressed transcripts and protein for TLR-2, TLR-4 and TLR-5. Colonic myofibroblast expression of these TLRs was much weaker than in crypt epithelial cells. In conclusion, enhanced TLR-2 and TLR-4 expression by crypt epithelial cells in active inflammatory bowel disease likely reflects greater ability to respond to microbial products. Results from our studies using mucosal samples from patients with distal ulcerative colitis suggest that the enhanced expression of these TLRs could be constitutive. TLR-2, TLR-4 and TLR-5 expression by stem cells imply ability to respond to distinct bacterial products.

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Section: Discussionmentioning

confidence: 97%

Toll-like receptor expression in crypt epithelial cells, putative stem cells and intestinal myofibroblasts isolated from controls and patients with inflammatory bowel disease

Brown

Hughes

Moossavi

et al. 2014

Clinical and Experimental Immunology

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“…TLR4 incites inflammation by interacting with the adaptor protein MyD88 then activating Ikkb and finally NF-jB to activate the expression of inflammatory cytokines including TNF-a, IL-1b, IL-6 and IL-8. 14 Observations that TLR4 is upregulated in human CRCs 31,32 and that TLR4 overexpression promotes, 20 while knockout attenuates 33 tumorigenesis in mice, implicate this pathway in colorectal tumorigenesis. Further, constitutive activation of Ikkb and NF-jB has also been shown to promote colonic inflammation and tumorigenesis in mice.…”

Section: Cancer Therapy and Preventionmentioning

confidence: 99%

“…Tumor incidence and colonic cytokine concentrations of AOM-treated mice by group SEM (n 5[15][16][17][18][19][20]. Mean values across the row with different letters are differ, p 0.05.…”

mentioning

confidence: 98%

“…In fact, it is demonstrated that overexpression of TLR4 promotes systemic inflammation and intestinal neoplasia in mice. 19,20 Compelling evidence indicates that elevated inflammation constitutes a major mechanistic link between obesity and increased tumor risk. 21,22 Further, our laboratory has demonstrated a distinct colonic transcriptome in obese mice that converge on Akt signaling pathway, 23 a critical mediator of carcinogenesis.…”

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confidence: 99%

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Parabacteroides distasonis attenuates toll‐like receptor 4 signaling and Akt activation and blocks colon tumor formation in high‐fat diet‐fed azoxymethane‐treated mice

Koh

Kane

Lee

et al. 2018

Intl Journal of Cancer

100

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Gut dysbiosis may play an etiological role in colorectal tumorigenesis. We previously observed that the abundance of Parabacteroides distasonis (Pd) in stool was inversely associated with intestinal tumor burden and IL-1β concentrations in mice. Here, we assessed the anti-inflammatory capacity of Pd membrane fraction (PdMb) in colon cancer cell lines. In addition, we tested whether Pd could suppress colon tumorigenesis in mice. Six-week old male A/J mice were fed a low-fat diet (LF), high-fat diet (HF), or HF+ whole freeze-dried Pd (HF+Pd, 0.04% w/w) for 24 weeks. After 1 week on diet, mice received 4 weekly injections of azoxymethane (AOM). PdMb robustly suppressed the production of pro-inflammatory cytokines and lowered the abundance of MyD88 and pAkt (ser473) induced by E. coli lipopolysaccharide in colon cancer cell lines. Moreover, PdMb induced apoptosis in colon cancer cell lines and blocked TLR4 activation in a reporter line. Colon tumors were observed in 0% of LF (0 of 19), 25% of HF (5 of 20) and 0% of HF+Pd mice (0 of 20) (P = 0.005). The latter group also displayed a lower abundance of MyD88 and pAkt (ser473) in colonic mucosa than HF mice. Taken together, these data suggest that Pd has anti-inflammatory and anti-cancer properties that are likely mediated by the suppression of TLR4 and Akt signaling, as well as promotion of apoptosis. Further work is needed to confirm these findings in additional models and fully elaborate the mechanism of action. This article is protected by copyright. All rights reserved.

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“…Loss-of-function alleles in TLR4 has been shown to affect metastasis-free survival and overall survival rates after treatment with anthracycline-based adjuvant chemotherapy in breast cancer patients (Vacchelli et al, 2016). Moreover, TLR4 has also been shown to promote metastasis in nonsmall cell lung cancer (Liu et al, 2015b), hepatocellular carcinoma (Liu et al, 2015a), oral squamous cell carcinoma (He et al, 2015), breast cancer (Yang et al, 2014), and colon cancer (Santaolalla et al, 2013). The mechanisms by which TLR4 promotes metastasis include the facilitation of an epithelial-mesenchymal transition (EMT) and the elevation of cytokines (IL-6, IL-10) that boost matrix metalloproteinase (MMP2 and MMP9) expression (Yang et al, 2014).…”

mentioning

confidence: 99%

TLR4 Promotes Breast Cancer Metastasis via Akt/GSK3β/β‐Catenin Pathway upon LPS Stimulation

Yin

Shen

et al. 2017

The Anatomical Record

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Bacteria/virus-induced chronic inflammation is involved in both tumor initiation and tumor progression. Toll-like receptor 4 (TLR4) has been implicated in the development of several types of cancer. In this study, we explored the impact of TLR4 activation by lipopolysaccharide (LPS) on breast cancer metastasis and associated signaling molecules. We first examined TLR4 expression levels in breast tissue using a human breast tissue microarray and breast cell lines. We then studied the role of TLR4 activation by LPS stimulation in breast cancer metastasis using both in vitro and in vivo models. Finally, we investigated signaling molecules involved in the process using Western blotting and fluorescent immunohistochemistry staining. The results showed that TLR4 expression levels increased in breast cancer tissue compared to normal breast tissue. In addition, our results also showed that TLR4 pathway activation by LPS stimulation in MCF7 and MDA-MB-231 breast cancer cells caused the following actions: (1) promotes migration of breast cancer cells, (2) triggers the β-catenin signaling pathway via PI3K/Akt/GSK3β, and (3) promotes transcription of downstream β-catenin target genes leading to breast cancer metastasis. This study substantiates and further extends the relationship between TLR4 activation by LPS and breast cancer using both in vitro and in vivo models. The results suggest that the Akt/GSK3β/β-catenin signal transduction pathway may serve as a viable clinical treatment target in breast cancer. Anat Rec, 300:1219-1229, 2017. © 2017 Wiley Periodicals, Inc.

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TLR4 Activates the B-Catenin Pathway to Cause Intestinal Neoplasia

Cited by 7 publications

References 0 publications

Toll-like receptor expression in crypt epithelial cells, putative stem cells and intestinal myofibroblasts isolated from controls and patients with inflammatory bowel disease

Toll-like receptor expression in crypt epithelial cells, putative stem cells and intestinal myofibroblasts isolated from controls and patients with inflammatory bowel disease

Parabacteroides distasonis attenuates toll‐like receptor 4 signaling and Akt activation and blocks colon tumor formation in high‐fat diet‐fed azoxymethane‐treated mice

TLR4 Promotes Breast Cancer Metastasis via Akt/GSK3β/β‐Catenin Pathway upon LPS Stimulation

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