The role of MMP-9 in the anti-angiogenic effect of secreted protein acidic and rich in cysteine.
BACKGROUND
Secreted protein acidic and rich in cysteine (SPARC), a matricellular glycoprotein, modulates cellular interaction with the extracellular matrix and is capable of altering the growth of various cancers. We therefore sought to determine the effect of SPARC expression on medulloblastoma tumour growth and angiogenesis.


METHODS
To this extent, we selected three SPARC full-length cDNA overexpressed clones (Daoy-SP). Consequences of SPARC overexpression were studied in terms of cell growth, angiogenesis using co-culture assay in vitro, dorsal skin-fold chamber assay in vivo, PCR Array for human angiogenic genes, as well as western blotting for angiogenic molecules and tumour growth, in an orthotopic tumour model.


RESULTS
The SPARC protein and mRNA levels were increased by approximately three-fold in Daoy-SP cells compared with parental (Daoy-P) and vector (Daoy-EV) controls. Daoy-SP clones reduced tumour cell-induced angiogenesis in vitro and in vivo, and formed small tumours with fewer blood vessels when compared with controls. Matrix metalloprotease-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression were decreased in Daoy-SP clones. Further, inhibition of MMP-9 expression caused SPARC-mediated inhibition of angiogenesis and tumour growth as MMP-9 rescued SPARC-mediated anti-angiogenic effect in vitro and tumour growth inhibition in vivo.


CONCLUSIONS
Overexpression of SPARC decreases angiogenesis, which leads to decreased tumour growth. Further, the role of MMP-9 could be attributed to the anti-angiogenic effect of SPARC.
Bhoopathi
P
P
Program of Cancer Biology, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL 61605, USA.
Chetty
C
C
Gujrati
M
M
Dinh
D H
DH
Rao
J S
JS
Lakka
S S
SS
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000502:physiology*; D008527:Medulloblastoma / Q000098:blood supply / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D015676:Osteonectin / Q000032:analysis / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D015676:Osteonectin; D042461:Vascular Endothelial Growth Factor A; D020780:Matrix Metalloproteinase 9