We have previously documented that adoptively transferred IL-2-activat
ed NK (A-NK) cells can accumulate within cancer metastases, Electron m
icroscopic studies of pulmonary metastases have revealed that adoptive
ly transferred A-NK cells that accumulate within metastases bind to en
dothelial cells and are able to traverse basement membranes. We have n
ow extended these morphologic studies. We report that rat A-NK cells p
roduce two matrix metalloproteinases: MMP-2 and MMP-9, as determined b
y SDS-PAGE gelatin zymography, These activities are inhibited followin
g incubation with BB-94 (batimastat), a specific inhibitor of matrix m
etalloproteinases but not with 3,4-dichloroisocoumarin, an inhibitor o
f neutral serine proteases, The identity of MMP-2 was confirmed by Wes
tern blots using a polyclonal Ab against human MMP-9, whereas reverse
transcriptase-PCR analysis of mRNA extracts of A-NK cells has confirme
d the presence of MMP-9. In addition, we report for the first time tha
t A-NK cells can migrate through a model basement membrane-like extrac
ellular matrix, Moreover, the ability of A-NK cells to migrate through
this model basement membrane was partially inhibited by BB-94; howeve
r, BB-94 has no effect on A-NK cell-mediated cytotoxicity, suggesting
that matrix metalloproteinases do not contribute to cytolytic function
of A-NK cells. In sum, our studies show that A-NK cells employ BB-94-
inhibitable matrix metalloproteinases to degrade extracellular matrice
s. This suggests that matrix metalloproteinases may play a role in the
accumulation of A-NK cells within cancer metastases.