T cell-derived matrix metalloproteinase-9 in breast cancer: Friend or foe?

It has been reported that in epithelial cancer invasion, most matrix metalloproteinases (MMPs) are made by stromal cells of the host, and not the neoplasm itself. Findings from several laboratories indicate that immune cell-derived MMPs may be advantageous to developing tumors by promoting angiogenesis, neoplastic cell proliferation, and progression to malignancy. We have found a dramatic up-regulation of MMP-9 secretion by splenic and tumor-infiltrating T lymphocytes from D1-DMBA-3 mammary tumor-bearing mice compared to T cells from normal animals. Furthermore, tumor-derived vascular endothelial growth factor induced the up-regulation of MMP-9 in T cells, corroborating the suggestion that tumor cells may "conscript" inflammatory cells to make contributions to the tumor phenotype. Some investigators propose that the resulting degradation of the extracellular matrix by lymphocyte-derived proteases might be used by tumor cells to establish a blood supply and to metastasize. The outcome of MMP activity in the tumor microenvironment may be dependent on a variety of factors including tumor phenotype; the presence of other proteases and cytokines; and the time, level, and site of MMP production. In light of recent findings that MMPs are also capable of generating anti-angiogenic molecules, further investigation will bear out whether inflammatory cell-derived MMPs are friend or foe to developing tumors.