The effect of Vasohibin-1 expression and tumor-associated macrophages on the angiogenesis in vitro and in vivo

• Published in: Tumor biology Vol. 37; no. 6; pp. 7267 - 7276
• Main Authors: Shen, Zhanlong, Yan, Yichao, Ye, Chunxiang, Wang, Bo, Jiang, Kewei, Ye, Yingjiang, Mustonen, Harri, Puolakkainen, Pauli, Wang, Shan
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.06.2016; Springer Nature B.V
• Subjects: Aged; Angiogenesis; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma - blood supply; Carcinoma - genetics; Carcinoma - pathology; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - physiology; Cell Line; Cell Line, Tumor; Coculture Techniques; Disease-Free Survival; Female; Gastric cancer; Gene expression; Heterografts; Human Umbilical Vein Endothelial Cells; Humans; Macrophages - physiology; Male; Medical prognosis; Mice; Mice, Inbred BALB C; Mice, Nude; Microvessels - pathology; Middle Aged; Neoplasm Metastasis; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - physiopathology; Original Article; Random Allocation; RNA Interference; RNA, Small Interfering - genetics; Single-Blind Method; Specific Pathogen-Free Organisms; Stomach Neoplasms - blood supply; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Vascular Endothelial Growth Factor A - analysis; Vasohibin-1; Angiogenesis; Prognosis; TAMs; Gastric cancer
• ISSN: 1010-4283; 1423-0380
• DOI: 10.1007/s13277-015-4595-4

Vasohibin-1 is an intrinsic inhibitor of angiogenesis induced by VEGF-A. However, there little is known about the relationship between Vasohibin-1 expression, angiogenesis, and tumor-associated macrophages (TAMs). Vasohibin-1 expression, VEGF-A expression, microvessel density (MVD) marked with CD34, and density of cells marked with CD68 were measured in 111 paraffin-embedded tissues of gastric cancer by immunohistochemistry. The length of tube forming structures of endothelial cells and mobility rate of gastric cancer cells in Matrigel were tested by three-dimensional live cell imaging system. The effect of TAMs on the tumor growth, MVD, and Vasohibin-1 expression was measured by nude mice tumor genesis assay in vivo. We found that high Vasohibin-1 protein expression correlated significantly with worse TNM stage ( P  = 0.002), metastatic lymph node ( P  = 0.014), distant metastasis ( P  = 0.022), overall survival ( P  < 0.001), and progression-free survival ( P  < 0.001) compared to those with low Vasohibin-1 expression. Vasohibin-1 protein expression had statistical correlation with the MVD ( r  = 0.860, P  < 0.001), density of CD68 + cells ( r  = 0.882, P  < 0.001), and VEGF-A expression ( r  = 0.719, P  < 0.001) in the gastric cancer tissues. Decreasing Vasohibin-1 expression with siRNA increased the length of tube forming structures of endothelial cells in co-culture with endothelial cells (EA-hy923), macrophages, and gastric cancers (Hs746T). Tumor volume ( P  = 0.001), Vasohibin-1 ( P  < 0.001), and VEGF-A ( P  < 0.001) expression in mice inoculated with AGS and THP (10:1) was significantly higher than that with AGS alone ( P  = 0.001). Vasohibin-1 protein expression had statistical correlation with VEGF expression ( r  = 0.786, P  < 0.001) and MVD ( r  = 0.496, P  = 0.014) in gastric xenografted tumor. Therefore, Vasohibin-1 might be a potential marker of worse prognosis and therapeutic target in gastric cancer. Vasohibin-1 might play an important role in the process of angiogenesis regulated by TAMs.