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Contrasting effects of VEGF gene disruption in embryonic stem cell-derived versus oncogene-induced tumors.

Authors
  • Viloria-Petit, Alicia
  • Miquerol, Lucile
  • Yu, Joanne L
  • Gertsenstein, Marina
  • Sheehan, Capucine
  • May, Linda
  • Henkin, Jack
  • Lobe, Corrinne
  • Nagy, Andras
  • Kerbel, Robert S
  • Rak, Janusz
Type
Published Article
Journal
The EMBO journal
Publication Date
Aug 15, 2003
Volume
22
Issue
16
Pages
4091–4102
Identifiers
PMID: 12912908
Source
Medline
License
Unknown

Abstract

Previous gene targeting studies have implicated an indispensable role of vascular endothelial growth factor (VEGF) in tumor angiogenesis, particularly in tumors of embryonal or endocrine origin. In contrast, we report here that transformation of VEGF-deficient adult fibroblasts (MDF528) with ras or neu oncogenes gives rise to highly tumorigenic and angiogenic fibrosarcomas. These aggressive VEGF-null tumors (528ras, 528neu) originated from VEGF(-/-) embryonic stem cells, which themselves were tumorigenically deficient. We also report that VEGF production by tumor stroma has a modest role in oncogene-driven tumor angiogenesis. Both ras and neu oncogenes down-regulated at least two endogenous inhibitors of angiogenesis [pigment epithelium derived factor (PEDF) and thrombospondin 1 (TSP-1)]. This is functionally important as administration of an antiangiogenic TSP-1 peptide (ABT-526) markedly inhibited growth of VEGF(-/-) tumors, with some ingress of pericytes. These results provide the first definitive genetic demonstration of the dispensability of tumor cell-derived VEGF in certain cases of 'adult' tumor angiogenesis, and thus highlight the importance of considering VEGF-independent as well as VEGF-dependent pathways when attempting to block this process pharmacologically.

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