Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases.
The balance between levels of metalloproteinases and their corresponding inhibitors is a critical factor in tumor invasion and metastasis. Down-regulation of the activity of these proteases was achieved by transfection of invasive and metastatic rat cells with the complementary DNA for metalloproteinase inhibitor/tissue inhibitor of metalloproteinase 2 (MI/TIMP-2), a novel inhibitor of metalloproteinases recently described. (Y. A. DeClerck et al., J. Biol. Chem., 264: 17445-17453, 1989; W. G. Stetler-Stevenson et al., J. Biol. Chem., 264: 17374-17378, 1989). Secretion of functional MI/TIMP-2 protein in stably transfected cells resulted in a marked decrease in metalloproteinase activity. Partial suppression of the formation of lung colonies after i.v. injection in nude mice was observed in a transfected clone expressing high levels of MI/TIMP-2. Production of MI/TIMP-2 in four clones markedly reduced tumor growth rate in vivo after s.c. injection and completely suppressed local tissue invasion. Thus, down-regulation of metalloproteinase activity has a striking effect on local invasion and partially suppresses hematogenous metastasis.
DeClerck
Y A
YA
Department of Pediatrics, University of Southern California, Los Angeles 90033.
Perez
N
N
Shimada
H
H
Boone
T C
TC
Langley
K E
KE
Taylor
S M
SM
D000818:Animals; D011905:Genes, ras; D005822:Genetic Vectors; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000473:pathology*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D015183:Restriction Mapping; D019714:Tissue Inhibitor of Metalloproteinases; D014162:Transfection; D014183:Transplantation, Heterologous
D006023:Glycoproteins; D011994:Recombinant Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D008666:Metalloendopeptidases