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Tumor Biology

, Volume 37, Issue 6, pp 7267–7276 | Cite as

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

  • Zhanlong ShenEmail author
  • Yichao Yan
  • Chunxiang Ye
  • Bo Wang
  • Kewei Jiang
  • Yingjiang Ye
  • Harri Mustonen
  • Pauli PuolakkainenEmail author
  • Shan WangEmail author
Original Article

Abstract

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.

Keywords

Vasohibin-1 TAMs Angiogenesis Prognosis Gastric cancer 

Notes

Acknowledgments

This study was supported by grants from National Science Foundation of China (81372290, 81372291).

Compliance with ethical standards

Conflicts of interest

None

Supplementary material

13277_2015_4595_MOESM1_ESM.doc (38 kb)
Supplementary table 1 Clinicopathological data of 111 cases of gastric cancer patients (DOC 38 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Gastroenterological Surgery, Laboratory of Surgical OncologyPeking University People’s HospitalBeijingChina
  2. 2.Department of Surgery, Helsinki University Central HospitalUniversity of HelsinkiHelsinkiFinland

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