Decorin suppresses tumor cell-mediated angiogenesis.
The progressive growth of most neoplasms is dependent upon the establishment of new blood vessels, a process regulated by tumor-secreted factors and matrix proteins. We examined the in vitro and in vivo angiogenic ability of conditioned media obtained from fibrosarcoma, carcinoma, and osteosarcoma cells and their decorin-transfected counterparts. Human endothelial cells were investigated in vitro by evaluating three essential steps of angiogenesis: migration, attachment, and differentiation. On the whole, wild-type tumor cell-secretions enhanced endothelial cell attachment, migration, and differentiation, whereas their decorin-expressing forms inhibited these processes. Similarly, decorin-containing media suppressed endothelial cell sprouting in an ex vivo aortic ring assay. Since angiogenesis is an important component of tumor expansion, the growth rate of these cells as tumor xenografts was examined by implantation in nude mice. In vivo, the decorin-expressing tumor xenografts grew at markedly lower rates and showed a significant suppression of neovascularization. Immunohistochemical, Northern and Western blot analyses indicated that the decorin-expressing cells produced vascular endothelial growth factor (VEGF) at markedly reduced rates vis-á-vis their wild-type counterparts. Specificity of this process was confirmed by experiments where addition of recombinant decorin to the wild-type tumor cells caused 80-95% suppression of VEGF mRNA and protein. These results provide a novel mechanism of action for decorin, and indicate that decorin could adversely affect in vivo tumor growth by suppressing the endogenous tumor cell production of a powerful angiogenic stimulus.
Grant
Derrick S
DS
Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Room 812 Curtis Building, 1015 Walnut Street, Philadelphia, Pennsylvania, PA 19107, USA.
Yenisey
Cigdem
C
Rose
R Wesley
RW
Tootell
Mason
M
Santra
Manoranjan
M
Iozzo
Renato V
RV
D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000254:growth & development; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division; D002478:Cells, Cultured; D002633:Chemotaxis; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D046508:Culture Techniques; D058575:Decorin; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D016326:Extracellular Matrix Proteins; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D011509:Proteoglycans / Q000032:analysis / Q000502:physiology*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays
D017077:Culture Media, Conditioned; C546878:DCN protein, human; C546879:Dcn protein, mouse; D058575:Decorin; D016228:Endothelial Growth Factors; D016326:Extracellular Matrix Proteins; D007797:Laminin; D008222:Lymphokines; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors