Carcinogenesis Advance Access originally published online on May 20, 2009
Carcinogenesis 2009 30(8):1424-1432; doi:10.1093/carcin/bgp125
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Phospholipase C
promotes intestinal tumorigenesis of ApcMin/+ mice through augmentation of inflammation and angiogenesis
Division of Molecular Biology, Department of Biochemistry and Molecular Biology
1 Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
* To whom corresponding should be addressed. Tel: +81 78 382 5390; Fax: +81 78 382 5399; Email: kataoka{at}people.kobe-u.ac.jp
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)
, 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 PLC (PLC–/–) exhibit marked resistance to spontaneous intestinal tumorigenesis compared with those with the PLC+/+ 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–/–;ApcMin/+ mice. Low-grade adenomas of PLC–/–;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 PLC–/–;ApcMin/+ mice exhibit marked attenuation of tumor-associated inflammation without significant differences in apoptosis and proliferation. These results suggest that PLC plays crucial roles in intestinal tumorigenesis through two distinct mechanisms, augmentation of angiogenesis and inflammation, depending on the tumor stage.
Abbreviations: APC, adenomatous polyposis coli; COX-2, cyclooxygenase-2; mRNA, messenger RNA; PCR, polymerase chain reaction; PLC, phospholipase C; TPA, 12-O-tetradecanoyl-phorbor-13-acetate; VEGF, vascular endothelial growth factor
These authors contributed equally to this work. Received February 6, 2009; revised April 19, 2009; accepted May 14, 2009.