Department of Experimental Oncology, European Institute of Oncology, Milano, Italy.
EMBO J. 2010 Jul 7;29(13):2242-52. doi: 10.1038/emboj.2010.94. Epub 2010 Jun 4.
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 several 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 skin-colonizing 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.
皮肤癌是最常见的癌症。了解导致皮肤肿瘤发展的因素对于确定预防疗法至关重要。髓样分化初级反应基因（MyD）88 是大多数 Toll 样受体（TLR）的下游衔接蛋白，已被证明参与了几种小鼠肿瘤发生模型。我们在这里表明，TLR4 而不是 TLR2 或 TLR9，是皮肤肿瘤发生中 MyD88 的上游。TLR4 的触发不依赖于与皮肤定植细菌相关的脂多糖，而是依赖于高迁移率族蛋白 B1（HMGB1），这是 TLR4 的内源性配体。HMGB1 由坏死角质形成细胞释放，是招募炎症细胞和引发炎症所必需的。TLR4 在骨髓衍生细胞和耐辐射细胞上的表达对于致癌作用是必需的。一致地，人类组织微阵列分析显示黑色素瘤和结肠癌在肿瘤内过度表达 TLR4 及其下游衔接蛋白 MyD88。总之，我们的结果表明，HMGB1 的最初释放触发了 TLR4 依赖性炎症反应，导致肿瘤的发展。
