Simultaneous inhibition of glioma angiogenesis, cell proliferation, and invasion by a naturally occurring fragment of human metalloproteinase-2.
Angiogenesis, tumor cell proliferation, and migration are the hallmarks of solid tumors, such as gliomas. This study demonstrates that a fragment derived from the autocatalytic digestion of matrix metalloproteinase (MMP)-2, called PEX, acts simultaneously as an inhibitor of glioma angiogenesis, cell proliferation, and migration. PEX is detected in the cultured medium of various human glioma, endothelial, breast, and prostate carcinoma cell lines. PEX is purified from the medium of glioma cell lines by chromatography, where PEX is constitutively expressed as a free and a TIMP-2-bound form. In human glioma tissue, PEX expression correlates with histological subtype and grade and with alpha v beta 3 integrin expression to which it is bound. Systemic administration of PEX to s.c. and intracranial human glioma xenografts results in a 99% suppression of tumor growth with no signs of toxicity. Thus, PEX is a very promising candidate for the treatment of human malignant gliomas.
Bello
L
L
Neurosurgery, Department of Neurological Sciences, University of Milan, Ospedale Maggiore Policlinico, Instituto di Ricovero E Cura a Carattere Scientifico, Milan, Italy.
Lucini
V
V
Carrabba
G
G
Giussani
C
C
Machluf
M
M
Pluderi
M
M
Nikas
D
D
Zhang
J
J
Tomei
G
G
Villani
R M
RM
Carroll
R S
RS
Bikfalvi
A
A
Black
P M
PM
D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003470:Culture Media; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005910:Glioma / Q000098:blood supply* / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D019030:Receptors, Vitronectin / Q000096:biosynthesis / Q000378:metabolism; D019096:Vitronectin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D003470:Culture Media; D010446:Peptide Fragments; D019030:Receptors, Vitronectin; D019096:Vitronectin; D016222:Fibroblast Growth Factor 2; D020778:Matrix Metalloproteinase 2