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First published online 26 April 2005
doi: 10.1242/jcs.02334

Journal of Cell Science 118, 2143-2153 (2005)
Published by The Company of Biologists 2005
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Research Article

Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-{alpha} and TGF-ß

Christina H. Stuelten1, Stacey DaCosta Byfield1, Praveen R. Arany1, Tatiana S. Karpova2, William G. Stetler-Stevenson3 and Anita B. Roberts1,*

1 Laboratory of Cell Regulation and Carcinogenesis, CCR, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
2 Laboratory of Receptor Biology and Gene Expression, CCR, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
3 Cancer and Cell Biology Branch, CCR, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

* Author for correspondence (e-mail: robertsa{at}dce41.nci.nih.gov)

Accepted 16 February 2005

We used 2D-cocultures employing fibroblasts of different genetic backgrounds and MCF10A-derived human breast epithelial cells of increasingly malignant potential to investigate tumor-stroma interactions in breast cancer and to identify possible signaling pathways involved. Tumor cells induced expression of matrix-metalloproteinase 9 (MMP-9) in fibroblasts in a pattern dependent on the degree of their malignancy. In-situ zymography localized the main gelatinolytic activity around stromal cells in cocultures and xenografted tumors. Use of Smad3 knockout fibroblasts, small molecule inhibitors, and neutralizing antibodies showed that MMP-9 expression was induced by tumor cell-derived TNF-{alpha} and TGF-ß, dependent on Smad-, Ras-, and PI3-kinase-signaling, and likewise modulated by subsequent HGF- and EGF-signaling. Together, our results indicate that MMP-9 levels in tumor fibroblasts are regulated by a complex tumor-stroma cross-talk, involving multiple ligands and cellular signaling pathways.

Key words: Breast cancer, Coculture, MMP-9, TGF-ß, TNF-{alpha}




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