title: Vasohibin-2 modulates tumor onset in the gastrointestinal tract by normalizing tumor angiogenesis.
abstract: BACKGROUND
  Vasohibin-2 (VASH2) has been identified as an endogenous and vascular endothelial growth factor (VEGF)-independent angiogenic factor that is highly expressed in tumor cells. In the present study, we aimed to determine whether pre-existing vascular changes can be used to predict tumor transformation as benign or malignant. We sought to characterize microvascular changes and tumor development in the intestinal tract of ApcMin/+ mice and ApcMin/+/Vash2-/- mice.
  
  
  METHODS
  ApcMin/+ mice provide a unique orthotopic model for the development of spontaneous adenomatous polyposis and subsequent carcinomas, a phenomenon termed the adenoma-carcinoma sequence. ApcMin/+ mice were mated with Vash2-/- mice with a mixed C57BL/6 background and the resulting pups were screened for the Min mutation and for the Vash2-/- gene by PCR. Intestinal tumors from ApcMin/+ mice and ApcMin/+/Vash2-/- mice were removed and either frozen or epon-embedded for subsequent analyses. For 3-dimensional imaging using confocal laser-scanning microscopy and transmission electron microscopy, cryosections were made, and immunofluorescent staining for various markers was performed.
  
  
  RESULTS
  We found that structural abnormalities in tumor vessels from benign tumors resembled those in malignant tumors. In addition, a novel angiogenic factor, vasohibin-2 (VASH2) protein, was detected around tumor blood vessels in late-stage adenomas and adenocarcinomas, but was absent from early-stage adenomas in ApcMin/+ mice. Tumors used to examine endogenous VASH2 (derived from CMT93 colon carcinomas) were less vascularized in Vash2-/- mice and were more regular than those seen in wild-type (WT) mice. In addition, tumors in Vash2-/- mice were smaller than those in WT mice. Furthermore, cross-breeding of mice homozygous for a deletion of Vash2 with mice heterozygous for the APC mutation resulted in animals that showed a significant decrease in the number of polyps in the small intestine.
  
  
  CONCLUSIONS
  We propose that VASH2 may modulate the onset of tumors in the gastrointestinal tract by regulating tumor angiogenesis.
authors.forename: Shuji
authors.initials: S
authors.lastname: Kitahara
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Masae
authors.initials: M
authors.lastname: Morishima
authors.forename: Asuka
authors.initials: A
authors.lastname: Yoshii
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kikuta
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Shimizu
authors.forename: Shunichi
authors.initials: S
authors.lastname: Morikawa
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Anatomy and Developmental Biology, School of Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. ezakit@research.twmu.ac.jp.
authors.forename: Taichi
authors.initials: T
authors.lastname: Ezaki
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D042501:Angiogenic Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003433:Crosses, Genetic; D018450:Disease Progression; D005260:Female; D041981:Gastrointestinal Tract / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D015398:Signal Transduction
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D042501:Angiogenic Proteins; C000594357:VASH2 protein, mouse