Matrix metalloproteinases and metastatic cancer.
The rationale for matrix metalloproteinase (MMP) inhibition as a means to treat disease progression in breast cancer stems from the apparent involvement of MMPs in the hydrolysis of basement membranes during tumour cell invasion and subsequent metastasis. MMP-mediated matrix remodelling also appears to promote the growth of tumour cells, possibly by facilitating the proliferation and migration of endothelial cells and the neovascularization of tumour tissue. We found that transfection of the C127 breast cancer cell line by MMP-2 (gelatinase A), but not by MMP-1 or MMP-3 (collagenase and stromelysin respectively), gave rise to an invasive and metastatic phenotype. We were surprised to find that this phenotype depended not only on the catalytic properties of MMP-2 but also on properties associated with the MMP-2 non-catalytic C-terminal domain. Experiments with a synthetic gelatinase inhibitor revealed that a single dose could prevent the lungs of nude mice being colonized by the MMP-2 transfectants, and that the inhibitor had to be administered during or shortly after injection of the cells, indicating that an early event, such as the extravasation of the cells into the lung, is gelatinase-dependent in this system. In other studies employing long-term treatment with CT1746, an orally active gelatinase inhibitor, we have previously demonstrated a reduction in primary tumour growth rates, localized spread, and spontaneous metastasis, even when the treatment was commenced several days after tumour implantation. Furthermore, additive effects were recorded when gelatinase inhibitor therapy was combined with cytotoxic drug treatment. Since the gelatinase inhibitors can also inhibit bone resorption in vitro, these observations point to their potential for delaying disease recurrence and reducing rates of bone loss following conventional therapeutic strategies, in metastatic breast cancer.
Cockett
M I
MI
Strangeways Research Laboratory, Cambridge, U.K.
Murphy
G
G
Birch
M L
ML
O'Connell
J P
JP
Crabbe
T
T
Millican
A T
AT
Hart
I R
IR
Docherty
A J
AJ
D000818:Animals; D018093:Gelatinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured
D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2