MMP-2 and MMP-9 expression in breast cancer-derived human fibroblasts is differentially regulated by stromal-epithelial interactions

被引:127
作者
Singer, CF
Kronsteiner, N
Marton, E
Kubista, M
Cullen, KJ
Hirtenlehner, K
Seifert, M
Kubista, E
机构
[1] Univ Vienna, Med Ctr, Div Senol, A-1090 Vienna, Austria
[2] Ludwig Boltzmann Inst Clin Expt Oncol, Vienna, Austria
[3] Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA
关键词
breast cancer; co-culture; gelatinases; MMP; stroma-epithelial interactions;
D O I
10.1023/A:1014918512569
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 Zn-2+-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.
引用
收藏
页码:69 / 77
页数:9
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