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首页> 外文期刊>The journal of clinical investigation >Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice
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Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice

机译：乙酰肝素酶促进慢性炎症循环，促进小鼠结肠炎相关的肿瘤发生

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Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is closely associated with colon cancer. Expression of the enzyme heparanase is clearly linked to colon carcinoma progression, but its role in UC is unknown. Here we demonstrate for what we believe to be the first time the importance of heparanase in sustaining the immune-epithelial crosstalk underlying colitis-associated tumorigenesis. Using histological specimens from UC patients and a mouse model of dextran sodium sulfate–induced colitis, we found that heparanase was constantly overexpressed and activated throughout the disease. We demonstrate, using heparanase-overexpressing transgenic mice, that heparanase overexpression markedly increased the incidence and severity of colitis-associated colonic tumors. We found that highly coordinated interactions between the epithelial compartment (contributing heparanase) and mucosal macrophages preserved chronic inflammatory conditions and created a tumor-promoting microenvironment characterized by enhanced NF-κB signaling and induction of STAT3. Our results indicate that heparanase generates a vicious cycle that powers colitis and the associated tumorigenesis: heparanase, acting synergistically with the intestinal flora, stimulates macrophage activation, while macrophages induce production (via TNF-α–dependent mechanisms) and activation (via secretion of cathepsin L) of heparanase contributed by the colon epithelium. Thus, disruption of the heparanase-driven chronic inflammatory circuit is highly relevant to the design of therapeutic interventions in colitis and the associated cancer.
机译：溃疡性结肠炎（UC）是与结肠癌密切相关的慢性炎症性肠病。乙酰肝素酶的表达显然与结肠癌的进展有关，但在UC中的作用尚不清楚。在这里，我们首次证明了乙酰肝素酶在维持与结肠炎相关的肿瘤发生的免疫上皮串扰中的重要性。使用来自UC患者的组织学标本和右旋糖酐硫酸钠诱发的结肠炎的小鼠模型，我们发现乙酰肝素酶在整个疾病中一直被过度表达和激活。我们证明，使用过表达乙酰肝素酶的转基因小鼠，乙酰肝素酶的过表达显着增加了结肠炎相关结肠肿瘤的发生率和严重性。我们发现，上皮区室（促乙酰肝素酶）与粘膜巨噬细胞之间高度协调的相互作用保留了慢性炎症条件，并创造了以NF-κB信号传导增强和STAT3诱导为特征的肿瘤促进微环境。我们的结果表明，乙酰肝素酶产生恶性循环，加剧结肠炎和相关的肿瘤发生：乙酰肝素酶与肠道菌群协同作用，刺激巨噬细胞活化，而巨噬细胞诱导产生（通过TNF-α依赖性机制）和活化（通过组织蛋白酶的分泌）。 L）乙酰肝素酶由结肠上皮引起。因此，乙酰肝素酶驱动的慢性炎症回路的破坏与结肠炎和相关癌症的治疗干预的设计高度相关。

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