Correlation of tumor- and stromal-derived MT1-MMP expression with progression of human ovarian tumors in SCID mice.
OBJECTIVE
Human ovarian carcinoma samples were orthotopically implanted into SCID mice to investigate the contribution of matrix metalloproteases (MMPs) to the spread of ovarian tumors.


METHODS
Mice were inoculated with patient tumor samples, and developed ovarian tumors over a 16-week period with metastasis occurring in some mice. Species-specific quantitative RT-PCR was used to identify the source of tumor-associated MMPs.


RESULTS
Membrane-type (MT)1-MMP mRNA was significantly increased in high-grade tumors, tumors with evidence of serosal involvement, and tumors in which distant metastases were detected. The increase in MT1-MMP expression was predominantly from the human tumor cells, with a minor contribution from the mouse ovarian stroma. Neither human nor mouse MT2-MMP were correlated with tumor progression and MT3-MMP levels were negligible. While tumor cells did not produce significant amounts of MMP-2 or MMP-9, the presence of tumor was associated with increased levels of MMP-2 expression by mouse ovarian stroma. Stromal-derived MT1-MMP was greater in large tumors and was associated with stromal MMP-2 expression but neither was significantly linked with metastasis.


CONCLUSIONS
These studies indicate that tumor-derived MT1-MMP, more so than other gelatinolytic MMPs, is strongly linked to aggressive tumor behavior. This orthotopic model of human ovarian carcinoma is appropriate for studying ovarian tumor progression, and will be valuable in the further investigation of the metastatic process.
Drew
A F
AF
Gynaecological Cancer Research Centre, Royal Women's Hospital, Carlton 3053, Melbourne, Australia. angela.drew@uc.edu
Blick
T J
TJ
Lafleur
M A
MA
Tim
E L M
EL
Robbie
M J
MJ
Rice
G E
GE
Quinn
M A
MA
Thompson
E W
EW
D000818:Animals; D001706:Biopsy; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053511:Matrix Metalloproteinase 14; D053517:Matrix Metalloproteinase 15; D053513:Matrix Metalloproteinase 16; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics; D000090023:Metallothionein 3; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D014183:Transplantation, Heterologous
C507098:MMP15 protein, human; C507102:MMP16 protein, human; D000090023:Metallothionein 3; C507096:Mmp14 protein, mouse; C507100:Mmp15 protein, mouse; C507104:Mmp16 protein, mouse; C000715430:Mt3 protein, mouse; D012333:RNA, Messenger; D053517:Matrix Metalloproteinase 15; D053513:Matrix Metalloproteinase 16; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14