Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15

FASEB J. 2019 Sep;33(9):10505-10514. doi: 10.1096/fj.201802758RRR. Epub 2019 Jun 26.


Hemangioblastoma (HB) is an abnormal intracranial buildup of blood vessels that exhibit a great potential for hemorrhage. Surgical options are limited, and few medications are available for treatment. We show here by immunohistochemical analysis that HB lesions display highly increased levels of VEGF expression and macrophage/microglia infiltration compared with those in normal brain tissues. In the meantime, TNF superfamily 15 (TNFSF15) (also known as vascular endothelial growth inhibitor), an antiangiogenic cytokine, is highly expressed in normal brain blood vessels but diminished in HB lesions. We set up a brain hemangioma model by using mouse bEnd.3 cells of a T antigen-transformed endothelial cell line that produce a large amount of VEGF. When implanted in mouse brains, these cells form lesions that closely resemble the pathologic characteristics of HB. Retroviral infection of bEnd.3 cells with TNFSF15 leads to inhibition of VEGF production and retardation of hemangioma formation. Similar results are obtained when wild-type bEnd.3 cells are implanted in the brains of transgenic mice overexpressing TNFSF15. Additionally, TNFSF15 treatment results in enhanced pericyte coverage of the blood vessels in the lesions together with reduced inflammatory cell infiltration and decreased hemorrhage. These findings indicate that the ability of TNFSF15 to counterbalance the abnormally highly angiogenic and inflammatory potential of the microenvironment of HB is of therapeutic value for the treatment of this disease.-Yang, G.-L., Han, Z., Xiong, J., Wang, S., Wei, H., Qin, T.-T., Xiao, H., Liu, Y., Xu, L.-X., Qi, J.-W., Zhang, Z.-S., Jiang, R., Zhang, J., Li, L.-Y. Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15.

Keywords: TNF superfamily; VEGF; hemangioblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Proliferation
  • Cell- and Tissue-Based Therapy*
  • Disease Models, Animal*
  • Endothelial Cells / cytology
  • Endothelial Cells / transplantation*
  • Hemangioma / metabolism
  • Hemangioma / pathology
  • Hemangioma / prevention & control*
  • Humans
  • Intracranial Hemorrhages / metabolism
  • Intracranial Hemorrhages / pathology
  • Intracranial Hemorrhages / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Prognosis
  • Tumor Cells, Cultured
  • Tumor Microenvironment
  • Tumor Necrosis Factor Ligand Superfamily Member 15 / administration & dosage
  • Tumor Necrosis Factor Ligand Superfamily Member 15 / genetics*


  • TNFSF15 protein, human
  • Tumor Necrosis Factor Ligand Superfamily Member 15