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Article

  • The EMBO Journal (2004) 23, 2800 - 2810
  • doi:10.1038/sj.emboj.7600289

Published online: 1 July 2004

VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis

Jianying Dong1, Jeremy Grunstein1,a, Max Tejada1, Frank Peale2, Gretchen Frantz2, Wei-Ching Liang3, Wei Bai2, Lanlan Yu1, Joe Kowalski1, Xiaohuan Liang1, Germaine Fuh3, Hans-Peter Gerber1 and Napoleone Ferrara1

  1. Department of Molecular Oncology, Genentech Inc., South San Francisco, CA, USA
  2. Department of Pathology, Genentech Inc., South San Francisco, CA, USA
  3. Department of Protein Engineering, Genentech Inc., South San Francisco, CA, USA

Correspondence to:

Napoleone Ferrara, Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Tel.: +1 650 225 2968; Fax: +1 650 225 6443; E-mail: nf@gene.com

aPresent address: Amgen Inc., 1 Amgen Center drive, Thousand Oaks, CA 91320, USA

Received 26 February 2004; Accepted 28 May 2004

We generated VEGF-null fibrosarcomas from VEGF-loxP mouse embryonic fibroblasts to investigate the mechanisms of tumor escape after VEGF inactivation. These cells were found to be tumorigenic and angiogenic in vivo in spite of the absence of tumor-derived VEGF. However, VEGF derived from host stroma was readily detected in the tumor mass and treatment with a newly developed anti-VEGF monoclonal antibody substantially inhibited tumor growth. The functional significance of stroma-derived VEGF indicates that the recruitment of stromal cells is critical for the angiogenic and tumorigenic properties of these cells. Here we identified PDGF AA as the major stromal fibroblast chemotactic factor produced by tumor cells, and demonstrated that disrupting the paracrine PDGFR alpha signaling between tumor cells and stromal fibroblasts by soluble PDGFR alpha-IgG significantly reduced tumor growth. Thus, PDGFR alpha signaling is required for the recruitment of VEGF-producing stromal fibroblasts for tumor angiogenesis and growth. Our findings highlight a novel aspect of PDGFR alpha signaling in tumorigenesis.

  • Keywords:

    • angiogenesis,
    • fibrosarcoma,
    • PDGF,
    • stroma,
    • VEGF