Epithelial Vanin-1 Controls Inflammation-Driven Carcinogenesis in the Colitis-Associated Colon Cancer Model
Epithelial Vanin-1 Controls Inflammation-Driven Carcinogenesis in the Colitis-Associated Colon Cancer Model
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DOI：
10.1002/ibd.21031
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发表时间：
2010-01-01
影响因子：
4.9
通讯作者：
Galland, Franck
中科院分区：
文献类型：
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作者：
Pouyet, Laurent;Roisin-Bouffay, Celine;Galland, Franck
背景：Vanin-1是一种上皮性泛氨酸酶，为组织提供半胱胺，调节应激反应。Vaninl是由肠细胞表达的，它的缺失限制了肠上皮细胞产生促炎信号。慢性活动性炎症和癌症之间的联系在溃疡性结肠炎患者中得到了说明，他们患结直肠癌的风险增加。事实上，持续的炎症为肿瘤的生长提供了有利的条件。方法：我们对Vanin-1(-/-)小鼠应用结肠炎相关癌症(CAC)方案，该方案结合注射偶氮甲烷(AOM)和反复给予葡聚糖硫酸钠(DSS)。我们对肿瘤进行了编号，并对巨噬细胞的浸润以及细胞死亡和增殖的分子标志物进行了量化。我们还测试了DSS诱导的结肠炎。我们对存活率、组织损伤、促炎细胞因子的产生和组织再生进行评分。结果：在CAC方案中，Vanin-1(-/-)小鼠的结直肠癌发病率显著降低，并表现出轻微的DSS诱导的结肠炎的临床症状。Vanin-1缺乏对肿瘤诱导的早期影响与炎症程度和随后的上皮细胞增殖直接相关，而不是与细胞死亡率相关；所有这些都与CEC中NF-kappa B通路的激活调节有关。结论：这些结果强调了肠上皮作为癌变过程中的辅助因素在控制粘膜炎症中的重要性。这可能导致在癌症治疗中有用的新的抗炎策略。
Background: Vanin-1 is an epithelial pantetheinase that provides cysteamine to tissue and regulates response to stress. Vaninl is expressed by enterocytes, and its absence limits intestinal epithelial cell production of proinflammatory signals. A link between chronic active inflammation and cancer is illustrated in patients with ulcerative colitis, who have an augmented risk of developing colorectal cancer. Indeed, sustained inflammation provides advantageous growth conditions to tumors. We examined whether epithelial cells affect tumorigenesis through vanin-1-dependent modulation of colonic inflammation.Methods: To vanin-1(-/-) mice, we applied the colitis-associated cancer (CAC) protocol, which combines injection of azoxymethane (AOM) with repeated administrations of dextran sodium sulfate (DSS). We numbered tumors and quantified macrophage infiltration and molecular markers of cell death and proliferation. We also tested DSS-induced colitis. We scored survival, tissue damages, proinflammatory cytokine production, and tissue regeneration. Finally, we explored activation pathways by biochemical analysis on purified colonic epithelial cells (CECs) and in situ immunofluorescence.Results: Vanin-1(-/-) mice displayed a drastically reduced incidence of colorectal cancer in the CAC protocol and manifested mild clinical signs of DSS-induced colitis. The early impact of vanin-1 deficiency on tumor induction was directly correlated to the amount of inflammation and subsequent epithelial proliferation rather than cell death rate; all this wits linked to the modulation of NF-kappa B pathway activation in CECs.Conclusions: These results emphasize the importance of the intestinal epithelium in the control of mucosal inflammation actining as a cofactor in carcinogenesis. This might lead to novel anti-inflammatory strategies useful in cancer therapy.