Osteopontin-induced, integrin-dependent migration of human mammary epithelial cells involves activation of the hepatocyte growth factor receptor (Met)

Osteopontin (OPN) is a secreted glycophosphoprotein which induces migration of mammary carcinoma cells, and has been implicated in the malignancy of b reast carcinoma. Hepatocyte growth factor (HCF) induces cell migration of s everal mammary epithelial cell (MEC) lines, via activation of its cognate r eceptor (Met). This study examines the mechanism of OPN-induced MEC migrati on, in terms of the cell surface integrins involved and induction of the HG F/Met pathway. Three different MEC cell lines were used, representing diffe rent stages of tumor progression: 21PT, non-tumorigenic; 21NT, tumorigenic; non-metastatic; and MDA-MB-435, tumorigenic, highly metastatic. Human reco mbinant OPN was found to induce the migration of all three lines. OPN-induc ed migration of 21 PT and 21 NT cells was alpha v beta 5 and pl-integrin de pendent, and alpha v beta 3-independent, while that of MDA-MB-435 cells was alpha v beta 3-dependent. HGF also induced migration of all three cell lin es, and a synergistic response was seen to HCF and OPN together. The increa sed migration response to OPN was found to be associated with an initial in crease in Met kinase activity (within 30 min), followed by an increase in M et mRNA and protein expression. OPN-induced cell migration is thus mediated by different cell surface integrins in MEC lines representing different st ages of progression, and involves activation of the HCF receptor. (C) 2000 Wiley-Liss, Inc.