Phospholipase Cε promotes intestinal tumorigenesis of ApcMin/+ mice through augmentation of inflammation and angiogenesis
Phospholipase Cε promotes intestinal tumorigenesis of ApcMin/+ mice through augmentation of inflammation and angiogenesis
复制标题
DOI：
10.1093/carcin/bgp125
复制
发表时间：
2009-08-01
期刊：
影响因子：
4.7
通讯作者：
Kataoka, Tohru
中科院分区：
文献类型：
--
作者：
Li, Mingzhen;Edamatsu, Hironori;Kataoka, Tohru
Apc(Min/+)小鼠携带腺瘤性息肉病大肠杆菌基因的失活等位基因，被广泛用作人类结直肠肿瘤发生的动物模型，已知肿瘤环境（例如炎症）在肿瘤进展中发挥关键作用。我们之前证明，磷脂酶 C (PLC)epsilon 是 Ras 和 Rap 小 GTP 酶的效应子，通过增强 TPA 诱导的炎症，在使用 12-O-十四烷酰基佛硼-13-乙酸酯 (TPA) 作为启动子的两阶段皮肤化学致癌作用中发挥着至关重要的作用。在这里，我们发现，与具有 PLC epsilon(+/+) 背景的小鼠相比，缺乏 PLC epsilon (PLC epsilon(-/-)) 的 Apc(Min/+) 小鼠表现出对自发性肠道肿瘤发生的显着抵抗力。肿瘤（在组织病理学上分为低级别和高级别腺瘤，不典型增生和大小不断增加）和腺癌的发展时间过程表明，在 PLC epsilon(-/-);Apc(Min/+) 小鼠中，不仅低级别腺瘤的形成而且向高级别腺瘤的进展也受到抑制。 PLC epsilon(-/-);Apc(Min/+)小鼠的低度腺瘤表现出细胞凋亡加速和细胞增殖减少。它们还表现出肿瘤血管生成的显着减弱和血管内皮生长因子表达的减少。相比之下，PLC epsilon(-/-);Apc(Min/+)小鼠的高级腺瘤表现出肿瘤相关炎症的显着减弱，而细胞凋亡和增殖没有显着差异。这些结果表明，PLC epsilon 通过两种不同的机制（增强血管生成和炎症）在肠道肿瘤发生中发挥关键作用，具体取决于肿瘤阶段。
Apc(Min/+) mice, carrying an inactivated allele of the adenomatous polyposis coli gene, are widely used as an animal model for human colorectal tumorigenesis, where tumor environment, such as inflammation, is known to play a critical role in tumor progression. We previously demonstrated that phospholipase C (PLC)epsilon, an effector of Ras and Rap small GTPases, plays a crucial role in two-stage skin chemical carcinogenesis using 12-O-tetradecanoyl-phorbor-13-acetate (TPA) as a promoter through augmentation of TPA-induced inflammation. Here, we show that Apc(Min/+) mice lacking PLC epsilon (PLC epsilon(-/-)) exhibit marked resistance to spontaneous intestinal tumorigenesis compared with those with the PLC epsilon(+/+) background. Time course of the development of tumors, which are histopathologically classified into low- and high-grade adenomas with increasing dysplasia and size, and adenocarcinomas indicates that not only the low-grade adenoma formation but also the progression to high-grade adenoma are suppressed in PLC epsilon(-/-);Apc(Min/+) mice. Low-grade adenomas of PLC epsilon(-/-);Apc(Min/+) mice exhibit accelerated apoptosis and reduced cellular proliferation. They also show marked attenuation of tumor angiogenesis and reduction in expression of vascular endothelial growth factor. In contrast, high-grade adenomas of PLC epsilon(-/-);Apc(Min/+) mice exhibit marked attenuation of tumor-associated inflammation without significant differences in apoptosis and proliferation. These results suggest that PLC epsilon plays crucial roles in intestinal tumorigenesis through two distinct mechanisms, augmentation of angiogenesis and inflammation, depending on the tumor stage.