VEGF-D is an X-linked/AP-1 regulated putative onco-angiogen in human glioblastoma multiforme.

Abstract

BACKGROUND:

Glioblastoma multiforme (GBM) is a hypervascularized and locally infiltrating brain tumor of astroglial origin with a very poor prognosis. An X-linked c-fos oncogene-inducible mitogenic, morphogenic, and angiogenic factor, endothelial growth factor-D (VEGF-D), is the newest mammalian member of VEGF family. We analyzed VEGF-D in GBM because of its high angiogenic potential and its linkage to the X chromosome.

MATERIALS AND METHODS:

Nonmalignant brain and GBM tissue sections as well as GBM cell lines were analyzed by immunofluorescence for the expression of VEGF-D, factor VIII (endothelial cell marker), glial-fibrillary acidic protein (GFAP) (astrocytic cell lineage cytoplasmic marker), and several Fos family transcription factors, including c-Fos and Fra-1. The proteins were also detected by Western blots. The differences between genotypes of normal brain and GBM cells were examined by cDNA microarrays.

RESULTS AND CONCLUSIONS:

GBM expressed ubiquitously VEGF-D, which colocalized with GFAP. Contrary to our expectations, low levels of c-Fos were detected in GBM cells. However, we identified another Fos family member, Fra-1, together with its transcriptional activation partner, c-Jun, as being stably up-regulated in GBM cells. Furthermore, we demonstrated that a fra-1 transgene induced VEGF-D expression in cultured cells and GBM cell stimulation evoked a sustained increase in both Fra-1 and VEGF-D levels. This study reveals that an up-regulation of AP-1 factors may be a hallmark of GBM. Because VEGF-D activates VEGF receptor 2 and 3, receptors important for tumor angiogenesis, it may represent an X-linked/AP-1-regulated onco-angiogen in human GBM. The VEGF-D system and AP-1 activity appear to be very attractive targets for new molecular diagnostics and rational molecular anti-cancer therapies.

• Authors: W Debinski, B Slagle-Webb, M G Achen, S A Stacker, E Tulchinsky, G Y Gillespie, D M Gibo
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) Vol. 7 Issue 9 Pg. 598-608 (Sep 2001) ISSN: 1076-1551 [Print] England
• PMID: 11778649 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelial Growth Factors
• Proto-Oncogene Proteins c-fos
• Proto-Oncogene Proteins c-jun
• Transcription Factor AP-1
• Vascular Endothelial Growth Factor D
• fos-related antigen 1

Topics

• Animals
• Brain (metabolism, pathology)
• Endothelial Growth Factors (genetics, metabolism)
• Genetic Linkage
• Glioblastoma (blood supply, genetics, metabolism, pathology)
• Humans
• Immunohistochemistry
• Mice
• Neovascularization, Pathologic
• Proto-Oncogene Proteins c-fos (genetics, metabolism)
• Proto-Oncogene Proteins c-jun (genetics, metabolism)
• Transcription Factor AP-1 (metabolism)
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor D
• X Chromosome (genetics)