Vasohibin-1 expression in endothelium of tumor blood vessels regulates angiogenesis

Am J Pathol. 2009 Jul;175(1):430-9. doi: 10.2353/ajpath.2009.080788. Epub 2009 Jun 4.


In this study, we characterized the significance of the vascular endothelial growth factor-inducible angiogenesis inhibitor vasohibin-1 to tumors. In pathological sections of non-small cell lung carcinoma, vasohibin-1 was present in the endothelial cells of blood vessels of the tumor stroma, but not in the lymphatics. In cancer cells, the presence of vasohibin-1 was associated with hypoxia-inducible factor 1alpha/vascular endothelial growth factor and fibroblast growth factor-2 expression. We then examined the function of vasohibin-1 in the mouse by subcutaneously inoculating with Lewis lung carcinoma cells. Resultant tumors in vasohibin-1(-/-) mice contained more immature blood vessels and fewer apoptotic tumor cells than tumors in wild-type mice. In wild-type mice that had been inoculated with Lewis lung carcinoma cells, tail vein injection of adenovirus containing the human vasohibin-1 gene inhibited tumor growth and tumor angiogenesis. Moreover, the remaining tumor vessels in adenoviral human vasohibin-1 gene-treated mice were small, round, and mature, surrounded by mural cells. The addition of adenoviral human vasohibin-1 gene to cisplatin treatment improved cisplatin's antitumor activity in mice. These results suggest that endogenous vasohibin-1 is not only involved in tumor angiogenesis, but when sufficient exogenous vasohibin-1 is supplied, it blocks sprouting angiogenesis by tumors, matures the remaining vessels, and enhances the antitumor effect of conventional chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Carcinoma, Lewis Lung
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cisplatin / administration & dosage
  • Combined Modality Therapy
  • Endothelium, Vascular / metabolism*
  • Female
  • Fibroblast Growth Factor 2 / metabolism
  • Genetic Therapy
  • Humans
  • Immunohistochemistry
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Neoplasms / blood supply*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism*
  • Vascular Endothelial Growth Factor A / metabolism


  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Vascular Endothelial Growth Factor A
  • Vash1 protein, mouse
  • Fibroblast Growth Factor 2
  • Cisplatin