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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.

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