Distinct functionality of tumor cell-derived gelatinases during formation of liver metastases.
The specific spatiotemporal role of the matrix metalloproteinase 2 (MMP-2) and MMP-9 (gelatinase) during metastasis is still under debate. Host cells have been described as major contributors to these MMPs during metastasis. Here, we show strong overexpression of MMP-2 and MMP-9 by tumor cells of clinical liver specimen of recurrent metachronous metastases, leading us to address the importance of tumor cell-derived MMP-2 or MMP-9 during liver metastasis. Thus far, distinction of their roles was impossible due to lack of inhibitors which can act exclusively on tumor cells or distinguish MMP-2 from MMP-9. We therefore used short hairpin RNA interference technology in the well-established syngeneic L-CI.5s lymphoma model, in which we could analyze the time course of experimental liver colonization (arrest/invasion of single tumor cells, outgrowth, and invasion within the parenchyma) in immunocompetent mice and correlate these steps with MMP-2 or MMP-9 expression levels. In parental tumor cells, MMP-9 expression closely correlated with the invasive phases of liver colonization, whereas MMP-2 expression remained unaltered. Specific knockdown of MMP-9 revealed a close correlation between invasion-dependent events and tumor cell-derived MMP-9 expression. In contrast, knockdown of MMP-2 did not significantly alter the metastatic potential of the cells but led to a marked inhibition of metastatic foci growth. These findings explain the efficacy of gelatinase-specific synthetic inhibitors on invasion and growth of tumor cells and attribute distinct functions of MMP-2 and MMP-9 to aspects of liver metastasis.
Gerg
Michael
M
Klinikum rechts der Isar der Technischen Universität München, Institut für Experimentelle Onkologie und Therapieforschung, Munich, Germany.
Kopitz
Charlotte
C
Schaten
Susanne
S
Tschukes
Alexander
A
Kahlert
Christoph
C
Stangl
Manfred
M
von Weyhern
Claus W Hann
CW
Brücher
Björn L D M
BL
Edwards
Dylan R
DR
Brand
Karsten
K
Krüger
Achim
A
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D017931:DNA Primers; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D012334:RNA, Neoplasm / Q000235:genetics; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D012334:RNA, Neoplasm; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9