Overcoming fas-mediated apoptosis accelerates Helicobacter-induced gastric cancer in mice
Overcoming fas-mediated apoptosis accelerates Helicobacter-induced gastric cancer in mice
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DOI：
10.1158/0008-5472.can-05-1802
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发表时间：
2005-12-01
期刊：
影响因子：
11.2
通讯作者：
Houghton, JM
中科院分区：
文献类型：
--
作者：
Cai, X;Stoicov, C;Houghton, JM
螺旋杆菌诱导的胃癌发生的起始分子事件尚不清楚。在感染早期，Fas抗原介导的细胞凋亡耗尽壁细胞和主细胞群，导致建筑变形。随着感染的进展，出现化生和发育不良的腺体，这些腺体对Fas介导的细胞凋亡具有抗性。这些异常谱系发生在胃癌之前，被认为是胃癌的前驱病变。在细胞转化之前获得抗凋亡表型表明Fas敏感性的丧失可能是胃癌早期所需的特征。我们推断，在我们的小鼠模型中，强制的Fas-apoptosis抵抗将导致更早、更具侵袭性的胃癌。Fas抗原缺陷型（1 pr）小鼠或C57 BL/6野生型小鼠进行照射，并用C57 BL/6骨髓形成部分1 pr/wt嵌合体或wt/wt对照小鼠重建，延长1 pr的寿命，并确保对猫螺杆菌感染的有效免疫应答。感染的1 pr/ wt小鼠早在感染后7个月就发生了胃癌（而wt/wt小鼠为15个月）。在10个月（90%）和15个月（100%）时，小鼠出现侵袭性浸润性病变。这种较早发病和更具侵袭性的组织学强有力地证明Fas-凋亡抵抗是胃癌形成的早期和重要特征。
The initiating molecular events in Helicobacter-induced gastric carcinogenesis are not known. Early in infection, Fas antigen-mediated apoptosis depletes parietal and chief cell populations, leading to architectural distortion. As infection progresses, metaplastic and dysplastic glands appear, which are resistant to Fas-mediated apoptosis. These abnormal lineages precede, and are thought to be the precursor lesions of, gastric cancer. Acquisition of an antiapoptotic phenotype before transformation of cells suggests that loss of Fas sensitivity may be an early required trait for gastric cancer. We reasoned that forced Fas-apoptosis resistance would result in earlier and more aggressive gastric cancer in our mouse model. Fas antigen-deficient (1pr) mice or C57BL/6 wild-type mice were irradiated and reconstituted with C57BL/6 marrow forming partial 1pr/wt chimera or wt/wt control mice, extending the life span of the 1pr and ensuring a competent immune response to Helicobacter felis infection. Infected 1pr/ wt mice developed gastric cancer as early as 7 months after infection (compared with 15 months in wt/wt mice). At 10 months (90%) and 15 months (100%), mice developed aggressive invasive lesions. This earlier onset and more aggressive histology strongly argues that Fas-apoptosis resistance is an early and important feature of gastric cancer formation.