Osteopontin is an autocrine mediator of hepatocyte growth factor-induced invasive growth

In epithelial cells, hepatocyte growth factor (HGF) activates a genetic pro gram involving cell-cell dissociation ("scattering"), growth and invasivene ss. The full program is not elicited by other growth factors like epidermal growth factor, and is aberrantly activated during cancer progression to th e invasive-metastatic phenotype. To identify genes involved in the onset of invasive growth, we explored by cDNA microarrays the in vitro transcriptio nal response to HGF of mouse embryo liver cells. We identified osteopontin (OPN), a secreted matrix protein, as a major HGF transcriptional target. Th e wave of OPN induction is maximal at 6 h, in concomitance with the initiat ion of scattering, and is specific, because no other matrix protein among t hose explored by the microarray is affected. Interestingly, HGF, but not ep idermal growth factor, promotes cell adhesion to OPN via the CD44 receptor. Scattering is significantly impaired by antibodies against OPN and CD44; c onversely, constitutive OPN overexpression dramatically increases the motil e and invasive responses to HGF, leading to disruption of the ordered morph ogenetic program triggered by this ligand.