Philippe Birembaut

Induction of membrane-type matrix metalloproteinase 1 (MT1-MMP) expression in human fibroblasts by breast adenocarcinoma cells.

Membrane-type matrix metalloproteinase 1 (MT1-MMP) has been recently described as an activator of proMMP-2 (MMP-2) which is involved in tumor invasion. We have shown by in situ hybridization that MT1-MMP is produced by stromal cells in close contact to preinvasive and invasive tumor cells of breast carcinomas. Of particular interest was the observation that some fibroblasts express this enzyme in focal areas in preinvasive lesions, suggesting that particular tumor cells may stimulate fibroblasts to produce MT1-MMP. We have therefore compared the ability of two different breast cancer cell lines, one non-invasive (MCF7) and one invasive (MDA-MB-231) to stimulate MT1-MMP production in human fibroblasts with consequent proMMP-2-activation. The MDA-MB-231 conditioned medium induced MT1-MMP mRNAs in human fibroblasts and a parallel activation of proMMP-2 whereas MCF7 conditioned medium did not have any effect. These results suggest the existence of soluble factor(s) secreted by invasive or some preinvasive breast tumor cells which stimulate fibroblasts to produce and activate MMPs, and emphasize the cooperation between cancer and stromal cells in tumor invasion.

Clinical Aspects of Matrix Metalloproteinases

Tumor metastasis is ultimately responsible for most cancer deaths. Tumor invasion and metastasis represent a multistep process including basement membrane disruption, stromal infiltration, angiogenesis, intravasation and extravasation and invasion of target organs by tumor cells. All these events require degradation and remodeling of the extracellular matrix (ECM) by various proteolytic enzymes. Among these enzymes, matrix metalloproteinases (MMPs) play a key role at various levels. These enzymes are associated with degradation of a broad spectrum of ECM components. MMPs are also implicated in the remodeling the ECM by creating and maintaining a microenvironment that facilitates angiogenesis and growth of tumors. Thus, in the last years, the exploration of MMPs expression has led to a large bunch of studies on their biological activities and their clinical implications.