THE HUMAN MYOEPITHELIAL CELL IS A NATURAL TUMOR-SUPPRESSOR

Myoepithelial cells, which surround ducts and acini of glandular organ s, form a natural border separating proliferating epithelial cells fro m basement membrane and underlying stroma. Myoepithelial cells in situ and in vitro constitutively express high amounts of proteinase inhibi tors that include tissue inhibitor of metalloproteinase 1, protease ne xin-II, alpha-1 antitrypsin, and maspin. Human myoepithelial xenograft s (HMS-X, HMS-3X, and HMS-4X), which our laboratory has established, a ccumulate an abundant extracellular matrix containing sequestered prot einase inhibitors. Humatrix, a gel that we have derived from HMS-X, in hibits tumor cell invasion (down to 25% +/- 10% of Matrigel control; P < 0.01), and our recently established human myoepithelial cell lines, HMS-1, HMS-3, and HMS-4, inhibit tumor cell invasion in cellular inva sion (down to 42% +/- 7% of control; P < 0.05) and in conditioned medi a assays (down to 30% +/- 8% of control; P < 0.01). The anti-invasive effects of HMS-1, HMS-3, and HMS-4 can be enhanced by phorbol 12-myris tate 13-acetate (down to 2% +/- 1% of control) by a maspin-dependent m echanism and abolished by dexamethasone (up to 95% +/- 5% of control) by a maspin-independent mechanism (P < 0.01). HMS-X, HMS-3X, HMS-4X, a nd Humatrix inhibit tumor invasion and metastasis in severe combined i mmunodeficient mice (P < 0.001). The cumulative data suggest that myoe pithelial cells are natural paracrine suppressors of invasion and meta stasis and may specifically inhibit the progression of precancerous di sease states to invasive cancer in vivo.