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  • The EMBO Journal (2003) 22, 4091 - 4102
  • doi:10.1093/emboj/cdg408

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

Alicia Viloria-Petit1, Lucile Miquerol2, Joanne L. Yu3, Marina Gertsenstein2, Capucine Sheehan1, Linda May3, Jack Henkin4, Corrinne Lobe1, Andras Nagy2, Robert S. Kerbel1 and Janusz Rak3

  1. Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre and Department of Medical Biophysics, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada
  2. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
  3. Henderson Research Centre, Experimental Thrombosis Research, McMaster University, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada
  4. Abbott Laboratories, 100 Abbott Park Road, North Chicago, IL 60064-4000, USA

Correspondence to:

Janusz Rak, E-mail: jrak@thrombosis.hhscr.org

Received 28 August 2002; Accepted 30 June 2003; Revised 26 June 2003

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.

  • Keywords:

    • neu,
    • PEDF,
    • ras,
    • TSP-1,
    • VEGF