MESSENGER-RNA FOR UROKINASE PLASMINOGEN-ACTIVATOR IS EXPRESSED IN MYOFIBROBLASTS ADJACENT TO CANCER-CELLS IN HUMAN BREAST-CANCER

Urokinase plasminogen activator (uPA) is a serine proteinase involved in degradation of the extracellular matrix during cancer invasion. uPA is up-regulated in breast cancer, and high levels of uPA in tumor ext racts are strongly associated with poor prognosis. Like several other matrix proteinases, uPA is in some types of cancer, including breast c ancer, expressed by stromal cells. The present study was undertaken to determine the identity of the uPA-expressing stromal cells in breast cancer tissue. By in situ hybridization, a positive signal for uPA mRN A was in 26 of 28 ductal and four of five lobular carcinomas demonstra ted in stromal cells adjacent to nests of cancer cells, whereas only o ne ductal carcinoma showed a positive reaction in the epithelial compo nent itself. The positive stromal cells were found in both the periphe ral and central parts of the tumors. Stromal cells surrounding carcino ma in situ lesions were uPA mRNA positive in a few cases, and no signa l was observed in the neighboring nonmalignant tissue. Cell identifica tion was done by immunostaining with Ab to markers for the following c ell types: myoepithelial cells, myofibroblasts, smooth muscle cells, m acrophages, endothelial cells, and epithelial cells. The only one of t hese cell types that had a distribution similar to the uPA mRNA-expres sing cells was myofibroblasts, recognized as extravascular alpha-smoot h muscle actin-positive and cytokeratin-negative cells. On adjacent se ctions, colocalization was found of cells positive for uPA mRNA and ce lls positive for alpha-smooth muscle actin and negative for cytokerati n. We concluded that the uPA mRNA-expressing cells are myofibroblasts. The myofibroblasts have previously been found to be abundant in breas t cancer tissue. They primarily originate by differentiation of fibrob lasts, probably induced by cytokines released from the cancer cells. T he present findings suggest that the myofibroblasts, through productio n of uPA, play an active role in breast cancer invasion.