During tumor progression, there are several key stages that require the action of proteases (Figure 15.1). First, the induction of angiogenesis, or new blood vessel growth, involves degradation of the vascular basement membrane and the release and/or activation of matrix-bound proangiogenic growth factors. Second, invasion of cancer cells into the surrounding tissue requires the dissolution of cell–cell junctions and degradation of the epithelial basement membrane/extracellular matrix (BM/ECM) for cancer cells to spread from the primary tumor. Third, at least two key steps in metastasis require proteolysis: intravasation of cancer cells into the blood or lymphatic circulation at the primary site, and extravasation at the secondary site, where proteases can again play a role in promoting the colonization and growth of cancer cells as they do in the primary tumor.

Proteases not only are essential for the degradation of BM/ECM proteins, however; they also have more specialized processing roles that are important for cell signaling, such as in the restricted cleavage of pro-domains and subsequent activation of growth factors and cytokines. These functions are tightly regulated in a cascade of proteolytic interactions, allowing for control and amplification of proteolysis in metastasis.

The realization that proteolysis is necessary for multiple stages in metastasis emphasizes the importance of identifying the key tumor-promoting proteases, determining how individual proteases interact with each other, and developing therapeutic strategies to inhibit their actions.