Figure 3: Model of TGF-β1 + EGF-enhanced plasmin-dependent collagen matrix remodeling and development of an invasive phenotype. In the presence of plasmin, increased MMP-10 levels promote MMP activation creating a proteolytic axis that accelerates collagen degradation through “superactivation” of MMP-1. STAT3 may act as a positive switch in this process, via promotion of EGF-stimulated proMMP-10 expression [23]. Upregulation of PAI-1 in response to TGF-β1 + EGF may subsequently shift this proteolytic balance, enabling PAI-1 to “titrate” the extent and locale of collagen matrix remodeling to facilitate stromal invasion. Indeed, PAI-1 induction occurs early in this transition and required for stimulated migration and collagen invasion since PAI-1 knockdown (with siRNA constructs) effectively inhibited both events [22].