Colitis-associated cancer is dependent on the interplay between the hemostatic and inflammatory systems and supported by integrin alpha(M)beta(2) engagement of fibrinogen.
Colitis-associated cancer is dependent on the interplay between the hemostatic and inflammatory systems and supported by integrin alpha(M)beta(2) engagement of fibrinogen.
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DOI：
10.1158/0008-5472.can-09-3465
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发表时间：
2010-04-01
期刊：
影响因子：
11.2
通讯作者：
Palumbo JS
中科院分区：
文献类型：
--
作者：
Steinbrecher KA;Horowitz NA;Blevins EA;Barney KA;Shaw MA;Harmel-Laws E;Finkelman FD;Flick MJ;Pinkerton MD;Talmage KE;Kombrinck KW;Witte DP;Palumbo JS
结肠炎和结肠癌之间的联系已经建立，但在这种情况下调节炎症的机制尚未完全确定。鉴于大量证据表明止血系统成分是炎症和肿瘤进展的有力调节剂，我们采用基因靶向小鼠直接测试凝血因子纤维蛋白原导致小鼠结肠炎相关结肠癌的假设。这种基本的临时基质蛋白被发现是结肠癌的重要决定因素。纤维蛋白原缺乏导致氧化偶氮甲烷/葡聚糖硫酸钠激发后形成的结肠腺瘤数量急剧减少。在表达保留凝血功能但缺乏白细胞整联蛋白受体α M β 2结合基序（Fib γ 390 - 396 A）的纤维蛋白原突变体的小鼠中进行的更详细的分析显示，α M β 2介导的纤维蛋白（原）参与与局部炎症过程（例如，IL-6的产生）和上皮细胞的改变，这些改变有助于腺瘤的形成。与这些发现一致，大多数Fib γ 390 - 396A小鼠没有出现可辨别的腺瘤，而对照组的腺瘤率为100%。此外，基于有丝分裂指数的定量分析，从Fib γ 390 - 396 A小鼠收获的腺瘤显著小于对照小鼠的腺瘤，并且增殖性较低，表明纤维蛋白（原）在已建立的腺瘤生长中的额外作用。这些研究首次证明了纤维蛋白（原）与炎症驱动的恶性肿瘤的发展之间的独特联系。鉴于前驱炎症在许多癌症进展中的重要性，这些研究表明，靶向纤维蛋白（原）-α M β 2相互作用的治疗可能有助于预防和/或治疗这一重要的恶性肿瘤亚组。
A link between colitis and colon cancer is well established, but the mechanisms regulating inflammation in this context are not fully defined. Given substantial evidence that hemostatic system components are powerful modulators of both inflammation and tumor progression, we employed gene-targeted mice to directly test the hypothesis that the coagulation factor fibrinogen contributes to colitis-associated colon cancer in mice. This fundamental provisional matrix protein was found to be an important determinant of colon cancer. Fibrinogen deficiency resulted in a dramatic diminution in the number of colonic adenomas formed following azoxymethane/dextran sodium sulfate challenge. More detailed analyses in mice expressing a mutant form of fibrinogen that retains clotting function, but lacks the leukocyte integrin receptor αMβ2 binding motif (Fibγ390-396A) revealed αMβ2-mediated engagement of fibrin(ogen) is mechanistically coupled to local inflammatory processes (e.g., IL-6 elaboration) and epithelial alterations which contribute to adenoma formation. Consistent with these findings, the majority of Fibγ390-396A mice developed no discernable adenomas, whereas penetrance was 100% in controls. Furthermore, the adenomas harvested from Fibγ390-396A mice were significantly smaller than those from control mice and less proliferative based on quantitative analyses of mitotic indices, suggesting an additional role for fibrin(ogen) in the growth of established adenomas. These studies demonstrate, for the first time, a unique link between fibrin(ogen) and the development of inflammation-driven malignancy. Given the importance of antecedent inflammation in the progression of numerous cancers, these studies suggest that therapies targeting fibrin(ogen)-αMβ2 interactions may be useful in preventing and/or treating this important subset of malignancies.