Nucleic acid-sensing toll-like receptors 3, 7 and 8 in esophageal epithelium, barrett’s esophagus, dysplasia and adenocarcinoma

Abstract

Toll-like receptors (TLRs) are immunological receptors recognizing various microbial and endogenous ligands, such as DNA, RNA, and other microbial and host components thus activating immunological responses. The expression of TLRs in esophageal adenocarcinoma is not well known. The aim of this study was to evaluate expression patterns of those TLRs that sense nucleic acids in Barrett's esophagus with and without dysplasia and in esophageal adenocarcinoma. TLRs 3, 7 and 8 were stained immunohistochemically and evaluated in a cohort of patients with esophageal adenocarcinoma or dysplasia. Specimens with normal esophagus (n D 88), gastric (n D 67) or intestinal metaplasia (n D 51) without dysplasia, and low-grade (n D 42) or high-grade dysplasia (n D 37) and esophageal adenocarcinoma (n D 99) were studied. We used immunofluorescence to confirm the subcellular localization of TLRs. We found abundant expression of TLR3, 7 and 8 in esophageal squamous epithelium, columnar metaplasia, dysplasia and adenocarcinoma. Cytoplasmic expression of TLR3, TLR7 or TLR8 did not associate to clinicopathological parameters or prognosis in esophageal cancer. High nuclear expression of TLR8, confirmed with immunofluorescence, in cancer cells was observed in tumors of high T-stage (p < 0.01) and in tumors with organ metastasis (p < 0.001). High nuclear TLR8 expression was associated with poor prognosis (p < 0.001). The expression of TLR3, TLR7 and TLR8 increased toward dysplasia and adenocarcinoma. We demonstrated nuclear localization of TLR8, which associates with metastasis and poor prognosis. TLR3 and TLR7 do not seem to have prognostic significance in esophageal adenocarcinoma.

Alternative MyD88 -Cyclin D1 signaling in breast cancer cells regulates TLR3 mediated cell proliferation

“…Though, regulation of this translocation is reported to be controlled by UNC93B1 protein, its inhibition has only a partial effect on TLR3 mediated signaling (Bugge et al, 2017). Further, cell surface expression of TLR3 has been reported in a variety of cells such as pulmonary cells, hepatocytes, breast cancer, prostate cancer and epithelial adenocarcinoma (Salaun et al, 2006; Gambara et al, 2014; Helminen et al, 2016) indicate that it signaling occurs through the plasma membrane. Dynasore, a dynamin inhibitor that inhibits endocytosis of the receptors, only partially affects the poly(I:C) mediated TLR3 signaling.…”

“…TLR3 induces a potent antigen-specific CD8+ T-cell responses that directly induces effector CD8+ T-cell and natural killer (NK) cells for IFN-γ release (Conforti et al, 2010). TLR3 was reported to be expressed not only by immune cells but also in the various cancer cells, such as breast cancers (Salaun et al, 2006), prostate cancer (Gambara et al, 2014), epithelial adenocarcinoma (Helminen et al, 2016), and others. Classically TLR3 signaling is mediated through the endosomal compartment of the cells.…”

Toll-like receptors TLR-2, TLR-4, TLR-7, and TLR-9 in tumor tissue and serum of the patients with esophageal squamous cell carcinoma and gastro-esophageal junction cancer

“…Although a possible association might be obscured by the limited number of observations in subgroup analysis, analogous results were presented by Helminen et al, who evaluated TLR-7 expression in esophageal adenocarcinoma, using immunohistochemistry. 20 Much research points at a dual or controversial role of TLR-7 in cancer development. [20][21][22][23] Whereas Lin et al showed down-regulation of TLR-7 gene expression in hepatocellular adenocarcinoma and hepatitis, Vaz and Andersson demonstrated its overexpression in pancreatic ductal adenocarcinoma.…”

“…20 Much research points at a dual or controversial role of TLR-7 in cancer development. [20][21][22][23] Whereas Lin et al showed down-regulation of TLR-7 gene expression in hepatocellular adenocarcinoma and hepatitis, Vaz and Andersson demonstrated its overexpression in pancreatic ductal adenocarcinoma. 21,23 In summary, the role of TLR-7 expression and activation in adenocarcinomas remains unclear and requires further studies.…”

Development of immune-modulatory RNAS to regulate RIG-I-like receptors mediated antiviral immune response for therapy and vaccination

“…Toll like receptors 1, 2 and 6 recognise the cell wall lipid in bacteria and fungus (Chau et al, 2009;Talreja et al, 2003). Whereas, Toll like receptors 3, 7, 8 and 9 have been reported to recognise of viral nucleic acids (Alexopoulou et al, 2001;Helminen et al, 2016;Pohar et al, 2018). Other Toll like receptors such as TLR 4 and 5 recognise the envelope proteins and polysaccharides in bacterial and fungal cell walls (such as lipopolysaccharide, mannan and flagellin) (Akira & Takeda, 2004;Poltorak et al, 2000).…”