Abstract
Patient treatment for oral squamous cell carcinoma (OSCC) not associated with Human papillomavirus remains problematic. OSCC microenvironment is typically inflamed and colonized by microorganisms, providing ligands for toll-like receptors (TLR). In immune cells TLR2 and TLR4 activate NF-kB and extracellular signal regulated kinase (ERK)1/2 pathways, leading to upregulation of inhibitory adenosine receptors A2a and A2b, and reduction in stimulatory A1 and A3. How TLR and adenosine receptors function in SCC cells is not understood. To address this gap, we evaluated TLR and adenosine receptor expression and function in human OSCC cells and keratinocytes. TLR2 and A2a were co-expressed in pre-cancer and SCC cells of 17 oral specimens. In vitro, 5/6 OSCC lines expressed more TLR2 than TLR1, 4 or 6 mRNA. TLR2 ligands stimulated A2a expression in TLR2-high cell lines, but no A1 or A3 was detected with or without stimuli. In TLR2-high OSCC, TLR2/1, 2/6 and adenosine receptor agonists activated ERK1/2. TLR2-mediated ERK1/2 phosphorylation resulted in accumulation of c-FOS, ERK-dependent cell proliferation and reduced caspase-3 activity. Similar ERK1/2-dependent proliferation and decreased caspase-3 activity were caused by combined TLR2 and adenosine receptor stimuli. We conclude that TLR2 and adenosine receptor agonists, known to be present in the tumor microenvironment, may contribute to OSCC progression in part via direct effects on the ERK1/2 pathway in squamous carcinoma cells.
Highlights
Squamous cell carcinoma (SCC) is a tenacious and aggressive cancer of epithelial cells that occurs in many organs, and is especially prevalent at mucosal and skin surfaces
We found that oral squamous cell carcinoma (OSCC) cell lines were more likely to secrete nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB)-driven factors in response to TLR2/1 than TLR4 stimuli
These observations are important for the understanding of OSCC biology, because these cancers are raised in a microenvironment rich in products of microorganisms and inflammation
Summary
Squamous cell carcinoma (SCC) is a tenacious and aggressive cancer of epithelial cells that occurs in many organs, and is especially prevalent at mucosal and skin surfaces. We focus on the major group of Human papillomavirus (HPV)-negative oral (O)SCC, which represent >90% of oral cancer [2]. OSCC develop in the context of surface-associated microbes, and several studies have identified various commensal and pathogenic Gram-positive (Gpos) and Gram-negative (Gneg) bacteria that colonized these cancers [4,5,6,7,8,9], while OSCC cells were deficient in the production of several anti-microbial www.impactjournals.com/oncotarget peptides [10]. Continuous bathing of a developing carcinoma in microbial products is a potentially important factor, in part because they can trigger and/or support chronic inflammation. The role of colonizing microbes in OSCC pathogenesis has not been defined
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