Extracellular Proteinases

AND THEIR INHIBITORS IN MOTILITY, INVASION, AND METASTASIS: NOT ONLY A MATTER OF EXTRACELLULAR MATRIX BREAKDOWN

In the three-step hypothesis of Liotta (3), proteolysis is conceived as extracellular matrix (ECM) breakdown which creates a virtual gap to be continuously filled up by the leading edge of the moving cancer cell. Different classes of extracellular proteases have been associated with this phenomenon, of which matrix metalloproteinases (MMPs), the serine proteinases coined plasminogen activators (PAs) and the aspartic protei-nase cathepsine D have been studied in depth in breast cancer. One timely aspect of this type of motility regulation is the recent insight that synthesis and secretion of these proteinases is controlled via different pathways as a response to extracellular stimuli or inhibitors. Known examples of MMP upregulation relevant to metastasis are: MMP-7 (matrilysin-1) upregulation as a result of Wnt pathway stimulation or cyclo-oxygenase-2 (COX-2) overexpression (25), and MMP-9 (gelatinase B) upregulation by integrin a^3 (26) or Src homology phosphatase (Shp-2) (27). Better understanding of these regulatory pathways will help to identify new and old anti-invasive and anti-metastatic agents, such as bisphosphonates, vanillin, and COX-2 inhibitors (28,29). Among PAs, the expression control of u-PA has received major interest, and expression was found to be induced by, for example, hypoxia, osteopontin, and the tyrosine kinase Syk (30,31), while calcitonin was found to inhibit the expression (32). Importantly, these up- and downregulations correlated with stimulated or inhibited motility/invasion and metastasis, respectively (33).

The expression of extracellular proteinases is only one level of regulation of enzymatic activity. Of key importance is also the balance between active enzymes and their natural inhibitors: tissue inhibitors of metallo-proteinase (TIMPs) for MMPs and plasminogen activator inhibitors (PAIs) for PAs (34). Here, the interpretation becomes tricky when PAI-1 and PAI-3 inhibit u-PA, but finally stimulate motility of breast cancer cells as a result of an intrinsic motogenic activity (35). TIMP-2, however, appears to be a bona fide inhibitor of motility (36). A third level of regulation relates to the localisation of the proteinases with respect to the surface of the invading cancer cell. Some MMP's are anchored to the plasma membrane (the so-called membrane-type MMP's and the "a disintegrin and metalloproteinase" (ADAMs)) (37), while for u-PA a typical surface receptor (u-PAR) can be expressed. A fourth level of regulation is brought in by factors from other cell types (e.g., fibroblasts and myofibroblasts) present in the tumour's microenvironment. Taken together, the role of extracellular proteinases in cancer progression can hardly be inferred from their simple presence as such, but needs confirmation by signs of their in situ activity. We are convinced that ultrastructural visualisation of typical ECM breakdown products (like collagen type I fragments) at the invading edge of cancer cells is the most relevant technique to identify proteolysis in situ.

Breakdown of ECM is probably only one important aspect of extracellular proteinase activity. Cleavage of ectodomains of surface receptors and cell-cell adhesion molecules can also influence motility, invasion, and metastasis, described in more detail in section 4.

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