TLR4-mediated skin carcinogenesis is dependent on immune and radioresistant cells

Abstract

Skin cancers are the most commonly diagnosed cancers. Understanding what are the factors contributing to skin tumour development can be instrumental to identify preventive therapies. The myeloid differentiation primary response gene (MyD)88, the downstream adaptor protein of most Toll-like receptors (TLR), has been shown to be involved in seve ral mouse tumourigenesis models. We show here that TLR4, but not TLR2 or TLR9, is upstream of MyD88 in skin tumourigenesis. TLR4 triggering is not dependent on lipopolysaccharide associated to skincolonizing bacteria, but on the high mobility group box-1 protein (HMGB1), an endogenous ligand of TLR4. HMGB1 is released by necrotic keratinocytes and is required for the recruitment of inflammatory cells and for the initiation of inflammation. The expression of TLR4 on both bone marrow-derived and radioresistant cells is necessary for carcinogenesis. Consistently, a human tissue microarray analysis showed that melanoma and colon cancer display an over-expression of TLR4 and its downstream adaptor protein MyD88 within tumours. Together, our results suggest that the initial release of HMGB1 triggers a TLR4-dependent inflammatory response that leads to tumour development.

Age-associated inflammation connects RAS-induced senescence to stem cell dysfunction and epidermal malignancy

“…Moreover, old skin displayed pronounced TLR signaling and NF-κB signatures, both implicated in inflammation-driven cancer progression. 38,39 Indeed, the old H-Ras-challenged skin was markedly enriched for T cells (CD3+, Figure 3e) and macrophages ( Figure 3f). NF-κB is a master regulator of inflammation, whose role in driving tumorigenesis through chronic inflammation is well established.…”

Low doses of ionizing radiation induce immune-stimulatory responses in isolated human primary monocytes

“…1C and 7). It has been reported that the interaction between HMGB1 and TLR2 is structurally and mechanistically different to TLR4 as TLR2 interacts only with nucleosome-bound HMGB1 proteins (26).…”

Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells

“…Viral infection (HBV or HCV) and environmental factors (alcohol, obesity) give rise to chronic liver inflammation and increase the risk for HCC. The link between inflammation and cancer is supported by the fact that TLR4, the pathogen-associated molecular pattern, which mediates an inflammatory response to endotoxin and other ligands, is implicated in lung (5), colon (6), and skin carcinomas (7). Although we usually consider macrophages and lymphocytes to be the primary cell types that express TLR4 to mediate immune and inflammatory response, an increasing body of evidence points to the role of TLR4 ectopically expressed in epithelial parenchymal cells in oncogenesis (8,9).…”