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

Alicia Viloria-Petit, Lucile Miquerol, Joanne L. Yu, Marina Gertsenstein, Capucine Sheehan, Linda May, Jack Henkin, Corrinne Lobe, Andras Nagy, Robert S. Kerbel, Janusz Rak

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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 anti-angiogenic TSP-1 peptide (ABT-526) markedly inhibited growth of VEGF4-/- 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.

Original languageEnglish
Pages (from-to)4091-4102
Number of pages12
JournalThe EMBO Journal
Issue number16
Publication statusPublished - 15 Aug 2003
Externally publishedYes


  • Neu
  • PEDF
  • Ras
  • TSP-1
  • VEGF

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