Fas/CD95 deficiency in ApcMin/+ mice increases intestinal tumor burden.
Fas/CD95 deficiency in ApcMin/+ mice increases intestinal tumor burden.
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DOI：
10.1371/journal.pone.0009070
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发表时间：
2010-02-05
期刊：
影响因子：
3.7
通讯作者：
Ploplis VA
中科院分区：
文献类型：
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作者：
Guillen-Ahlers H;Suckow MA;Castellino FJ;Ploplis VA
Fas是肿瘤坏死家族的成员，当与其配体Fas-L结合时负责启动细胞凋亡途径。Fas介导的凋亡途径的缺陷已在结直肠癌中报道。在本研究中，通过将ApcMin/+小鼠与Fas缺陷型（Faslpr）小鼠杂交，产生了具有额外的Fas缺陷型（ApcMin/+/Faslpr）的ApcMin/+小鼠的变体，其是人类疾病家族性腺瘤性息肉病（FAP）的模型。ApcMin/+小鼠模型的主要局限性之一是它只产生良性息肉。然而，相对于ApcMin/+小鼠，ApcMin/+/Faslpr小鼠呈现出肿瘤负荷的显著增加以及在高龄时的侵袭性病变。增殖和凋亡标志物显示细胞增殖增加，但凋亡的变化可以忽略不计，而p53在早期增加。相对于ApcMin/+组群，ApcMin/+/Faslpr小鼠中的Fas-L较低，这导致炎症增强。这项研究表明，在ApcMin/+背景下实施Fas缺失导致ApcMin/+小鼠模型更具侵袭性的表型，侵袭性肠道肿瘤的发展更快，Fas-L水平降低。
Fas, a member of the tumor necrosis family, is responsible for initiating the apoptotic pathway when bound to its ligand, Fas-L. Defects in the Fas-mediated apoptotic pathway have been reported in colorectal cancer. In the present study, a variant of the ApcMin/+ mouse, a model for the human condition, Familial Adenomatous Polyposis (FAP), was generated with an additional deficiency of Fas (ApcMin/+/Faslpr) by cross-breeding ApcMin/+ mice with Fas deficient (Faslpr) mice. One of the main limitations of the ApcMin/+ mouse model is that it only develops benign polyps. However, ApcMin/+/Faslpr mice presented with a dramatic increase in tumor burden relative to ApcMin/+ mice and invasive lesions at advanced ages. Proliferation and apoptosis markers revealed an increase in cellular proliferation, but negligible changes in apoptosis, while p53 increased at early ages. Fas-L was lower in ApcMin/+/Faslpr mice relative to ApcMin/+ cohorts, which resulted in enhanced inflammation. This study demonstrated that imposition of a Fas deletion in an ApcMin/+ background results in a more aggressive phenotype of the ApcMin/+ mouse model, with more rapid development of invasive intestinal tumors and a decrease in Fas-L levels.