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Authors: | Singer Christian F Kronsteiner Nicole Marton Erika Kubista Marion Cullen Kevin J Hirtenlehner Kora Seifert Michael Kubista Ernst |
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Institution: | (1) Division of Senology, Vienna University Medical Center, and Ludwig-Boltzmann-Institute for Clinical Experimental Oncology, Waehringer Guertel 18-20, A-1090 Vienna, Austria;(2) Vincent T. Lombardi Cancer Research Center, Georgetown University Medical Center, 3800 Reservoir Rd, NW, Washington, DC, 20007, USA |
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Abstract: | Tissue remodeling is a key element in the local invasion and metastasis of malignant breast tumors. The degradation of extracellular matrix that is associated with this process is thought to be mediated by a number of Zn2+-dependent matrix metalloproteinases (MMPs). In most cases these enzymes are not produced by the malignant epithelium itself but by adjacent breast stroma, suggesting an important role for cell-cell interactions. We have analyzed Gelatinase A (MMP-2) and Gelatinase B (MMP-9) gene expression in a panel of six breast cancer cell lines and six primary cultures of stromal cells deriving from breast cancer biopsies. With one exception we did not detect MMP-2 or MMP-9 gene expression in any of the established tumor cell lines. Conversely, tumor stroma-derived fibroblasts expressed MMP-2 mRNA, although no MMP-9 mRNA was seen in RNase protection assays. When fibroblasts were cultured in the presence of media conditioned by MCF-7 tumor cells, MMP-2 enzyme production increased but MMP-9 activity remained undetectable. However, when fibroblasts and MCF-7 tumor cells were co-cultured together, MMP-9 was induced. These observations were confirmed by immunocytochemical analysis of co-cultures of MCF-7 and tumor-derived fibroblasts in which MMP-2 and MMP-9 protein expression was confined to stromal cells adjacent to MCF-7 tumor cells. No MMP-2 or MMP-9 staining was detected in monocultures of the two respective cell types. We conclude that MMP-2 expression is present in the stroma of malignant tumors and is increased by paracrine stimulation mediated by soluble factors. In contrast, MMP-9 expression tumor-derived fibroblasts requires direct contact with malignant tumor epithelium. |
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Keywords: | breast cancer co-culture gelatinases MMP stroma-epithelial interactions |
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