W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, United States of America.
PLoS One. 2010 Feb 5;5(2):e9070. doi: 10.1371/journal.pone.0009070.
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.
METHODOLOGY/PRINCIPAL FINDINGS: In the present study, a variant of the Apc(Min/+) mouse, a model for the human condition, Familial Adenomatous Polyposis (FAP), was generated with an additional deficiency of Fas (Apc(Min/+)/Fas(lpr)) by cross-breeding Apc(Min/+) mice with Fas deficient (Fas(lpr)) mice. One of the main limitations of the Apc(Min/+) mouse model is that it only develops benign polyps. However, Apc(Min/+)/Fas(lpr) mice presented with a dramatic increase in tumor burden relative to Apc(Min/+) 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 Apc(Min/+)/Fas(lpr) mice relative to Apc(Min/+) cohorts, which resulted in enhanced inflammation.
CONCLUSIONS/SIGNIFICANCE: This study demonstrated that imposition of a Fas deletion in an Apc(Min/+) background results in a more aggressive phenotype of the Apc(Min/+) mouse model, with more rapid development of invasive intestinal tumors and a decrease in Fas-L levels.
Fas 是肿瘤坏死家族的一员，当与配体 Fas-L 结合时，负责启动凋亡途径。在结直肠癌中已经报道了 Fas 介导的凋亡途径的缺陷。
方法/主要发现：在本研究中，通过将 Fas 缺陷（Fas(lpr)）小鼠与 Apc(Min/+) 小鼠杂交，生成了一种 Apc(Min/+) 小鼠的变体，即人类家族性腺瘤性息肉病（FAP）的模型，该变体还存在 Fas 的变异（Apc(Min/+)/Fas(lpr))。Apc(Min/+) 小鼠模型的主要局限性之一是它仅发展良性息肉。然而，Apc(Min/+)/Fas(lpr) 小鼠在高龄时表现出与 Apc(Min/+) 小鼠相比肿瘤负担显著增加和侵袭性病变。增殖和凋亡标志物显示细胞增殖增加，但凋亡变化可忽略不计，而 p53 在早期增加。与 Apc(Min/+) 队列相比，Apc(Min/+)/Fas(lpr) 小鼠中的 Fas-L 降低，导致炎症增强。
结论/意义：这项研究表明，在 Apc(Min/+) 背景下施加 Fas 缺失会导致 Apc(Min/+) 小鼠模型更具侵袭性表型，更快速地发展为侵袭性肠道肿瘤，并降低 Fas-L 水平。
