Matrix metalloproteinase/integrin interactions as target for anti-angiogenic treatment strategies.
Modulation of the balance between pro- and antiangiogenic factors holds great promise for the treatment of a broad spectrum of human disease ranging from ischemic heart disease to cancer. This requires both the identification of angiogenic regulators and their efficient delivery to target organs. Here, we demonstrate the use of a noncatalytic fragment of matrix metalloproteinase 2 (termed PEX) delivered by lentiviral vectors in different angiogenesis models. Transduction of human endothelial cells with PEX virus suppressed endothelial invasion and formation of capillary-like structures without affecting chemotaxis in vitro. Lentiviral delivery of PEX blocked basic fibroblast growth factor-induced matrix metalloproteinase 2 activation and angiogenesis on chicken chorioallantoic membranes. PEX expression also inhibited tumor-induced angiogenesis and tumor growth in a nude mouse model. Thus, our study shows that lentiviral vectors can deliver sufficient quantities of antiangiogenic substances to achieve therapeutic effects in vivo.
Kessler
T A
TA
Department of Medicine/Hematology and Oncology, University of Münster, Münster, Germany.
Pfeifer
A
A
Silletti
S
S
Mesters
R M
RM
Berdel
W E
WE
Verma
I
I
Cheresh
D
D
D000482:Allantois / Q000098:blood supply; D000818:Animals; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply; D004730:Endothelium, Vascular / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D016023:Integrins / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000502:physiology; D008545:Melanoma / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018919:Neovascularization, Physiologic; D010446:Peptide Fragments / Q000235:genetics; D014162:Transfection
D016023:Integrins; D010446:Peptide Fragments; D020778:Matrix Metalloproteinase 2