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Molecular Cancer
Published in: Molecular Cancer 1/2014

Open Access 01-12-2014 | Research

Vasohibin-2 modulates tumor onset in the gastrointestinal tract by normalizing tumor angiogenesis

Authors: Shuji Kitahara, Yasuhiro Suzuki, Masae Morishima, Asuka Yoshii, Sachiko Kikuta, Kazuhiko Shimizu, Shunichi Morikawa, Yasufumi Sato, Taichi Ezaki

Published in: Molecular Cancer | Issue 1/2014

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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 Apc Min/+ mice and Apc Min/+ /Vash2 -/- mice.

Methods

Apc Min/+ mice provide a unique orthotopic model for the development of spontaneous adenomatous polyposis and subsequent carcinomas, a phenomenon termed the adenoma-carcinoma sequence. Apc Min/+ 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 Apc Min/+ mice and Apc Min/+ /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 Apc Min/+ 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.

Conclusion

We propose that VASH2 may modulate the onset of tumors in the gastrointestinal tract by regulating tumor angiogenesis.
Appendix
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Metadata
Title
Vasohibin-2 modulates tumor onset in the gastrointestinal tract by normalizing tumor angiogenesis
Authors
Shuji Kitahara
Yasuhiro Suzuki
Masae Morishima
Asuka Yoshii
Sachiko Kikuta
Kazuhiko Shimizu
Shunichi Morikawa
Yasufumi Sato
Taichi Ezaki
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2014
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-13-99

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