Phospholipase Cepsilon promotes intestinal tumorigenesis of Apc(Min/+) mice through augmentation of inflammation and angiogenesis.
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 PLCepsilon (PLCepsilon(-/-)) exhibit marked resistance to spontaneous intestinal tumorigenesis compared with those with the PLCepsilon(+/+) 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 PLCepsilon(-/-);Apc(Min/+) mice. Low-grade adenomas of PLCepsilon(-/-);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 PLCepsilon(-/-);Apc(Min/+) mice exhibit marked attenuation of tumor-associated inflammation without significant differences in apoptosis and proliferation. These results suggest that PLCepsilon plays crucial roles in intestinal tumorigenesis through two distinct mechanisms, augmentation of angiogenesis and inflammation, depending on the tumor stage.
Li
Mingzhen
M
Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Edamatsu
Hironori
H
Kitazawa
Riko
R
Kitazawa
Sohei
S
Kataoka
Tohru
T
D000230:Adenocarcinoma / Q000098:blood supply / Q000209:etiology / Q000473:pathology; D000236:Adenoma / Q000098:blood supply / Q000209:etiology / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation; D005260:Female; D005756:Gastritis / Q000209:etiology* / Q000473:pathology; D017491:Genes, APC / Q000502:physiology*; D007124:Immunoenzyme Techniques; D007414:Intestinal Neoplasms / Q000098:blood supply* / Q000209:etiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000209:etiology*; D054801:Phosphoinositide Phospholipase C / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D002273:Carcinogens; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon; D013755:Tetradecanoylphorbol Acetate