Inhibition of AIDS-Kaposi's sarcoma cell induced endothelial cell invasion by TIMP-2 and a synthetic peptide from the metalloproteinase propeptide: implications for an anti-angiogenic therapy.
In the initial phases of angiogenesis, endothelial cells must degrade and cross the vessel basement membrane, as do tumor cells during invasion and metastasis formation. Various metalloproteinases have been implicated in tumor cell invasion, in particular MMP-2 (72 kDa collagenase IV, gelatinase A), which has been demonstrated to be associated with tumor metastasis formation. Supernatants from AIDS-Kaposi sarcoma (KS) cells induce normal endothelial cells to invade through a reconstituted basement membrane (Matrigel) in vitro, which correlates with the angiogenic potential of KS cells in vivo. Here we demonstrate that two specific inhibitors of MMP-2, TIMP-2 and a peptide from the MMP-2 propeptide region (peptide 74), inhibit endothelial cell invasion induced by AIDS-KS cell supernatants. Smooth muscle cells were much less sensitive to these inhibitors. These data suggest that MMP-2 activation is a key event in endothelial cell invasion, the initial phase of tumor-associated neoangiogenesis. Inhibition of this enzyme could be an effective treatment for KS and tumor-associated angiogenesis.
Benelli
R
R
Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Adatia
R
R
Ensoli
B
B
Stetler-Stevenson
W G
WG
Santi
L
L
Albini
A
A
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications*; D000595:Amino Acid Sequence; D002633:Chemotaxis / Q000187:drug effects; D003094:Collagen; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D018093:Gelatinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010455:Peptides / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology*; D011509:Proteoglycans; D012514:Sarcoma, Kaposi / Q000098:blood supply / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D019716:Tissue Inhibitor of Metalloproteinase-2; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins
D017077:Culture Media, Conditioned; D004338:Drug Combinations; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin; D009363:Neoplasm Proteins; D010455:Peptides; D011506:Proteins; D011509:Proteoglycans; C059485:matrigel; D019716:Tissue Inhibitor of Metalloproteinase-2; C073977:peptide 74; D003094:Collagen; D003513:Cycloheximide; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2