IN-VIVO EVIDENCE THAT THE STROMELYSIN-3 METALLOPROTEINASE CONTRIBUTESIN A PARACRINE MANNER TO EPITHELIAL-CELL MALIGNANCY

Stromelysin-3 (ST3; Basset, P., J.P. Bellocq, C. Wolf, I. Stoll, P. Hu tin, J.M. Limacher, O.L. Podhajcer. M.P. Chenard, M.C. Rio, P. Chambon . 1990. Nature. 348:699-704) is a matrix metalloproteinase (MMP) expre ssed in mesenchymal cells located close to epithelial cells, during ph ysiological and pathological tissue remodeling processes. In human car cinomas, high ST3 levels are associated with a poor clinical outcome, suggesting that ST3 plays a role during malignant processes. In this s tudy we report the ST3 gene inactivation by homologous recombination. Although ST3 null mice (ST3(-/-)) were fertile and did not exhibit obv ious alterations in appearance and behavior. the lack of ST3 altered m alignant processes. Thus, the suppression of ST3 results in a decrease d 7,12-dimethylbenzanthracene-induced tumorigenesis in ST3(-/-) mice. Moreover, ST3(-/-) fibroblasts have lost the capacity to promote impla ntation of MCF7 human malignant epithelial cells in nude mice (P < 0.0 08). Finally, we show that this ST3 paracrine function requires extrac ellular matrix (ECM)-associated growth factors. Altogether, these find ings give evidence that ST3 promotes. in a paracrine manner, homing of malignant epithelial cells, a key process for both primary tumors and metastases. Therefore, ST3 represents an appropriate target for speci fic MMP inhibitor(s) in future therapeutical approaches directed again st the stromal compartment of human carcinomas.