MMP-9 production by T cells from mammary tumor bearers is upregulated by tumor-derived VEGF

Matrix metalloproteinase-9 (MMP-9) has been shown to be important in tumor invasion and metastasis, and may be implicated in lymphoreticular cell extravasation. T cells from D1-DMBA-3 mammary tumor-bearing mice exhibit an overproduction of MMP-9 compared with the levels expressed in T cells from normal mice, both at the transcriptional and translational levels. This upregulation is more pronounced in animals bearing large tumors. We have previously characterized several tumor derived factors in our system using the in vitro DA-3 tumor cells derived from the in vivo D1-DMBA-3 tumors (ie PGE₂, GM-CSF and phosphatidyl serine). Treatment of normal T lymphocytes with these factors yielded no increased production of MMP-9. TNF-α and IL-6, although not expressed by the tumor cells themselves, are greatly increased in the tumor bearers' lymphoreticular cells and in their sera. Exposure of normal T cells to these two cytokines also failed to upregulate MMP-9 production. Vascular endothelial growth factor (VEGF) has been shown to be produced by many tumors. Using a VEGF-specific ELISA, we determined that the DA-3 tumor cells, as well as the T lymphocytes from tumor bearers, express high levels of this growth factor. Treatment of normal T cells with VEGF resulted in an overproduction of MMP-9. These results indicate that VEGF may be responsible for the elevated levels of MMP-9 observed in T cells from tumor-bearing mice.