Figure 4.

Schematic view of the region represented with an asterisk in Fig. 3, showing a distinct network of proteolytic relationships during cancer cell migration within the stroma. Kallikrein‐related peptidases, many of which are secreted by cancer cells, have been found capable of activating pro‐uPA (produced abundantly by stromal cells) and generate active uPA. In turn, uPA binds to its receptor, uPAR, present in the plasma membrane of the cancer cells, and converts plasminogen into active plasmin. Once plasmin is activated, it may, in turn, proceed to activate several inactive pro‐MMPs and generate active enzymes (MMPs). The latter are mainly responsible for ECM degradation. In addition, KLKs (e.g. KLK1) may be able to directly activate MMPs and also cleave constituents of the ECM themselves. uPA, urokinase‐type plasminogen activator; pro‐uPA, proform of uPA; uPAR, uPA receptor; MMPs, matrix metalloproteinases; pro‐MMPs, proform of MMPs; KLKs, kallikreins; ECM, extracellular matrix. Arrows between two molecules represent activation; arrows initiating from a molecule and pointing out in arrows represent enzymatic interaction; arrows initiating from cell interior and pointing in molecules represent secretion.