Stromelysin-3 expression by mammary tumor-associated fibroblasts under in vitro breast cancer cell induction.

To understand better the influence of the host stromal phenotype on stromal expression of stromelysin-3 (ST3) in breast cancer, we have investigated ST3 expression by host stromal cells isolated from 9 different primary breast carcinomas. These tumor-associated fibroblasts were cocultivated with 3 epithelial cancer cell lines of mammary origin (MDA-MB-231, SK-BR-3 and MCF-7), as well as with normal human mammary epithelial cells (NME and 184A1) and keratinocytes, using both direct and indirect coculture systems. ST3 expression was demonstrated by both in situ hybridization and immunocytochemistry. The results showed that ST3 expression by stromal cells was cancer-specific. Indeed, ST3 expression by tumor-associated stromal cells was induced by 3 malignant cancer cell lines (MDA-MB-231, SK-BR-3 and MCF-7), whereas no ST3 was expressed under normal mammary epithelial cell stimulation. ST3 expression was weak or absent in unstimulated tumor-associated fibroblasts. However, after direct coculture with cancer cells, expression of ST3 transcripts reappeared in 8 of the 9 cases and was observed only in fibroblasts located in close contact with tumor cells. Under similar coculture conditions and using the same cancer cell line stimulation, ST3 expression was, however, quite variable among these 9 cases, reflecting the difference of protease expression observed on the sections of the original tumors. Tumor induction of ST3 expression was much more important by direct cell-cell contact than by indirect stimulation and was not influenced by the addition of basic fibroblast growth factor (bFGF) and anti-bFGF to the culture medium. Our results suggest that the host stromal cell phenotype may significantly influence host stromal cell protease expression under cancer cell stimulation.