Up-regulation of matrix metalloproteinase-9 and monocyte chemoattractant protein-1 in T lymphocytes of mammary tumor-bearing mice: Role of tumor-associated factors

Altered cytokine production has been implicated in the down-regulated cell-mediated immunity in mice with mammary tumors. The cellular and molecular mechanisms involved in the up-regulation of MMP-9 and MCP-1 by T cells in tumor-bearing mice were evaluated. Matrix metalloproteinase-9 (MMP-9), a matrix-degrading enzyme, is crucial in tumor invasion and metastasis and is implicated in leukocyte extravasation. In this report, we demonstrate that during growth of the D1-DMBA-3 mammary tumor in BALB/c mice there is progressive up-regulation of MMP-9 in splenic T-cells at both the transcriptional and translational levels. Our previous work has identified several factors produced by this tumor including PGE2, GM-CSF, and phosphatidyl serine, however, none of these agents induces increased production of MMP-9 by normal splenic T cells. Although not produced by the tumor, TNF-alpha and IL-6 are up-regulated in both macrophages and B cells in tumor-bearing mice. Exposure of normal T cells to these two cytokines, however, also fails to up-regulate MMP-9 production. Vascular endothelial growth factor (VEGF) is produced by many tumors and we determined that the mammary tumor used in our studies expresses high levels of this angiogenic growth factor. Importantly, splenic T cells from tumor bearers constitutively produce increased amounts of VEGF and treatment of normal T cells with VEGF results in up-regulated MMP-9 production. Of crucial importance is the finding that tumor-infiltrating T cells also produce high levels of VEGF and MMP-9. Our studies indicate that VEGF can act directly on T lymphocytes and that elevated VEGF levels may contribute to the aberrant MMP-9 secretion by mammary tumor bearers\u27 T cells.Continued investigation of other factors capable of modulating MMP-9 found that the chemokine monocyte chemoattractant protein-1 (MCP-1) could also up-regulate MMP-9 secretion by splenic T cells. Furthermore, it was shown that tumor bearers\u27 T cells produce high levels of MCP-1 and the tumor-derived factor GM-CSF was able to induce secretion of MCP-1 by T lymphocytes. This factor was found to be involved in the up-regulation at both the transcriptional and translational levels. Additionally, GM-CSF receptor-alpha expression was elevated in T cells from tumor-bearing mice. The results of this study emphasize the complexity of the cytokine network and give insight into the cellular and molecular mechanisms involved in the altered production of cytokines and proteases during neoplasia