MMP-2 and MMP-9 expression in breast cancer-derived human fibroblasts is differentially regulated by stromal-epithelial interactions.
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.
Singer
Christian F
CF
Division of Senology, Vienna University Medical Center, and Ludwig-Boltzmann-Institute for Clinical Experimental Oncology, Austria. Christian.Singer@univie.ac.at
Kronsteiner
Nicole
N
Marton
Erika
E
Kubista
Marion
M
Cullen
Kevin J
KJ
Hirtenlehner
Kora
K
Seifert
Michael
M
Kubista
Ernst
E
D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002450:Cell Communication; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000378:metabolism
D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9