VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis |
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| Authors: | Dong Jianying Grunstein Jeremy Tejada Max Peale Frank Frantz Gretchen Liang Wei-Ching Bai Wei Yu Lanlan Kowalski Joe Liang Xiaohuan Fuh Germaine Gerber Hans-Peter Ferrara Napoleone |
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| Affiliation: | Department of Molecular Oncology, Genentech Inc., South San Francisco, CA 94080, USA. |
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| Abstract: | 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. |
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| Keywords: | angiogenesis fibrosarcoma PDGF stroma VEGF |
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