The response of VEGF-stimulated endothelial cells to angiostatic molecules is substrate-dependent.
BACKGROUND
The microenvironment surrounding cells can exert multiple effects on their biological responses. In particular the extracellular matrix surrounding cells can profoundly influence their behavior. It has been shown that the extracellular matrix composition in tumors is vastly different than that found in normal tissue with increased amounts of certain matrices such as collagen I. It has been previously demonstrated that VEGF stimulation of endothelial cells growing on type I collagen results in the induction of bcl-2 expression and enhanced endothelial cell survival. We sought to investigate whether this increased endothelial cell survival resulted in the failure of angiostatic molecules to inhibit angiogenesis.


RESULTS
We now demonstrate that VEGF-induced survival on collagen I impairs the ability of three known angiostatic molecules, TSP-1, IP-10 and endostatin to inhibit endothelial cell proliferation. Apoptosis of endothelial cells, growing on collagen I, induced by TSP-1 and IP-10 was also inhibited following VEGF stimulation. In contrast, endostatin induced apoptosis in these same cells. Further analysis determined that endostatin did not decrease the expression of bcl-2 nor did it increase activation of caspase-3 in the presence of VEGF. Alternatively, it appeared that in the presence of VEGF, endostatin induced the activation of caspase-8 in endothelial cells grown on collagen I. Furthermore, only endostatin had the ability to inhibit VEGF-induced sprout formation in collagen I gels.


CONCLUSIONS
These data suggest that TSP-1, IP-10 and endostatin inhibit endothelial cells via different mechanisms and that only endostatin is effective in inhibiting angiogenic activities in the presence of collagen I. Our results suggest that the efficacy of angiostatic treatments may be impaired depending on the context of the extracellular matrix within the tumor environment and thus could impede the efficacy of angiostatic therapies.
Addison
Christina L
CL
Centre for Cancer Therapeutics, Ottawa Health Research Institute, 501 Smyth Rd., Ottawa, Ontario, K1H 8L6, Canada. caddison@ohri.ca
Nör
Jacques E
JE
Zhao
Huijun
H
Linn
Stephanie A
SA
Polverini
Peter J
PJ
Delaney
Christie E
CE
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D024042:Collagen Type I / Q000494:pharmacology; D043169:Endostatins / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects*; D016326:Extracellular Matrix Proteins / Q000494:pharmacology; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D019700:Thrombospondin 1 / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D054357:Chemokine CXCL10; D024042:Collagen Type I; D043169:Endostatins; D016326:Extracellular Matrix Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D020169:Caspases