Vasohibin-1 Expression in Endothelium of Tumor Blood Vessels Regulates Angiogenesis

Tomoko Hosaka^*, Hiroshi Kimura^*, Takahiro Heishi^*, Yasuhiro Suzuki^*, Hiroki Miyashita^*, Hideki Ohta, Hikaru Sonoda, Takuya Moriya, Satoshi Suzuki, Takashi Kondo and Yasufumi Sato^*

From the Departments of Vascular Biology,^* and Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai; the Discovery Research Laboratories, Shionogi & Co, Ltd, Osaka; and the Department of Pathology, Tohoku University Hospital, Sendai, Japan

In this study, we characterized the significance of the vascularendothelial growth factor-inducible angiogenesis inhibitor vasohibin-1to tumors. In pathological sections of non-small cell lung carcinoma,vasohibin-1 was present in the endothelial cells of blood vesselsof the tumor stroma, but not in the lymphatics. In cancer cells,the presence of vasohibin-1 was associated with hypoxia-induciblefactor 1 ${alpha}$ /vascular endothelial growth factor and fibroblast growthfactor-2 expression. We then examined the function of vasohibin-1in the mouse by subcutaneously inoculating with Lewis lung carcinomacells. Resultant tumors in vasohibin-1^–/– mice containedmore immature blood vessels and fewer apoptotic tumor cellsthan tumors in wild-type mice. In wild-type mice that had beeninoculated with Lewis lung carcinoma cells, tail vein injectionof adenovirus containing the human vasohibin-1 gene inhibitedtumor growth and tumor angiogenesis. Moreover, the remainingtumor vessels in adenoviral human vasohibin-1 gene-treated micewere small, round, and mature, surrounded by mural cells. Theaddition of adenoviral human vasohibin-1 gene to cisplatin treatmentimproved cisplatin’s antitumor activity in mice. Theseresults suggest that endogenous vasohibin-1 is not only involvedin tumor angiogenesis, but when sufficient exogenous vasohibin-1is supplied, it blocks sprouting angiogenesis by tumors, maturesthe remaining vessels, and enhances the antitumor effect ofconventional chemotherapy.