VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis.
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.
Dong
Jianying
J
Department of Molecular Oncology, Genentech Inc., South San Francisco, CA 94080, USA.
Grunstein
Jeremy
J
Tejada
Max
M
Peale
Frank
F
Frantz
Gretchen
G
Liang
Wei-Ching
WC
Bai
Wei
W
Yu
Lanlan
L
Kowalski
Joe
J
Liang
Xiaohuan
X
Fuh
Germaine
G
Gerber
Hans-Peter
HP
Ferrara
Napoleone
N
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002461:Cell Line, Transformed; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D002633:Chemotaxis; D005347:Fibroblasts / Q000502:physiology*; D005354:Fibrosarcoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D011905:Genes, ras; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000503:physiopathology; D019899:Paracrine Communication; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D015398:Signal Transduction; D042442:Vascular Endothelial Growth Factors / Q000172:deficiency / Q000235:genetics*
D000911:Antibodies, Monoclonal; D010982:Platelet-Derived Growth Factor; D042442:Vascular Endothelial Growth Factors; C075278:platelet-derived growth factor A; D020796:Receptor, Platelet-Derived Growth Factor alpha