Activation of the
platelet-derived growth factor (
PDGF)-receptors is critically involved into various stromal cell functions including recruitment of stromal cells and
vascular endothelial growth factor (
VEGF) induction in
tumor and perivascular cells. To evaluate the effects of combined
PDGFRalpha and -beta inhibition in a
non-small cell lung cancer model, we stably transfected A549
lung cancer cells with the
PDGF-A mutant PDGF-0. PDGF-0 has been generated by substituting
amino acids in the binding region of
PDGF-A with the corresponding
VEGF-A region, leading to a decreased receptor-binding affinity and activation. Compared with control vector transfected cells, transfection with PDGF-0 had no impact on monolayer growth and apoptosis in vitro, but significantly impaired the number of colony formation in soft
agar. After
subcutaneous injections, all mice developed
tumors within 5 days. While control vector transfected A549 cells were characterized by constant
tumor growth, PDGF-0 transfected A549 revealed a reduced
tumor mass (p < 0.001) with no further growth beyond 14 days (2 months observation time) and complete regressions in 7 of 13 cases. Immunohistochemical analyses revealed that PDGF-0 transfected
tumors demonstrated decreased recruitment of periendothelial cells, while the
tumor invasion zone was similar to control vector transfectants. Similarly,
conditioned medium from PDGF-0 transfected cells induced significantly less migration of smooth muscle cells and fibroblasts in vitro. Interestingly, in PDGF-0 transfectants, neither total vessel count nor
VEGF expression were significantly altered. These studies demonstrate that combined inhibition of
PDGFRalpha and -beta results in markedly decreased
tumor growth in vivo because of impaired recruitment of periendothelial cells.