A breast carcinoma biopsy showed cytochemical evidence of epithelial mesenchymal transition and an α-smooth muscle actin-positive stromal reaction. To study the lineage, and the nature of the cells in the stromal reaction, we derived a novel cell line, HBFL-1, from the explanted biopsy. HBFL-1 cells are immortal and exhibit a shared non-random X-chromosome inactivation pattern with the epithelial tumor of origin. Yet they closely resemble normal, finite-life-span fibroblasts by morphology, lack of tumor formation in nude mice, marker expression profile, protein pattern using two-dimensional gel electrophoresis and the ability to undergo myofibroblast conversion. HBFL-1 interacts reciprocally with tumor cells in collagen gel to induce activation of MMP2, leading to tumor-like behavior of epithelial colonies. In vivo, HBFL-1 cells resembled normal-derived myofibroblasts and conferred a significant 3.5- to 7-fold increase in MCF-7 tumor size in nude mice. However, that they were indeed not normal fibroblasts was revealed by residual keratin expression and formation of epithelial microfoci in a reconstituted basement membrane and in nude mice. We conclude that breast cancer can generate its own nonmalignant stroma and that one function for this is that of a reciprocal interaction with epithelial tumor cells to facilitate tumor growth.
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Supported by The Icelandic Research Fund for Graduate Students, Dansk Kræftforskningsfond, The Dagmar Marshallsfond (to T.G.), The Danish Research Council, The Novo Nordisk Foundation, The Thaysen Foundation, Friis Fonden, The Meyer Foundation, The Danish Cancer Society, The Danish Research Council, The Danish Medical Association Research Fund (to O.W.P. and L.R.-J.), Weimanns Legat (to L.R.-J.) and The US National Cancer Institute (grant CA-64786-02 to M.J.B. and O.W.P.) and United States Department of Energy Office of Biological and Environmental Research (contract DE-AC03-76SF00098 to M.J.B.).
