Journal Article

Phospholipase Cε promotes intestinal tumorigenesis of <i>Apc<sup>Min/+</sup></i> mice through augmentation of inflammation and angiogenesis

Mingzhen Li, Hironori Edamatsu, Riko Kitazawa, Sohei Kitazawa and Tohru Kataoka

in Carcinogenesis

Volume 30, issue 8, pages 1424-1432
Published in print August 2009 | ISSN: 0143-3334
Published online May 2009 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgp125
Phospholipase Cε promotes intestinal tumorigenesis of ApcMin/+ mice through augmentation of inflammation and angiogenesis

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ApcMin/+ 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)ε, 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 ApcMin/+ mice lacking PLCε (PLCε−/−) exhibit marked resistance to spontaneous intestinal tumorigenesis compared with those with the PLCε+/+ 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 PLCε−/−;ApcMin/+ mice. Low-grade adenomas of PLCε−/−;ApcMin/+ 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 PLCε−/−;ApcMin/+ mice exhibit marked attenuation of tumor-associated inflammation without significant differences in apoptosis and proliferation. These results suggest that PLCε plays crucial roles in intestinal tumorigenesis through two distinct mechanisms, augmentation of angiogenesis and inflammation, depending on the tumor stage.

Journal Article.  6099 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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