Digestive activity evolves as a cascade in which inert proenzymes are successively activated by active enzymes preceding them in the chain. Inhibitors are also elaborated in tandem for control of the process and protease inhibitor balance appears to be abnormally regulated in malignant cells. While excellent correlative evidence has accumulated for a direct role of proteases in metastasis, it remains to be seen whether inhibitors of these enzymes will have a therapeutic impact. Extracellular matrix (ECM) includes basement membranes and stroma. ECM are thin tight membranes that separate immunologically distinct tissues. They surround blood and lymph vessels that tumor cells must pass through to metastasize and consist of type IV collagen, heparin sulfate proteoglycans, laminin, entactin, fibronectin (FN), and other glycoproteins. Type IV collagen polymerizes in a sheet-like lattice connected to adjacent planes by S-S bonds. In addition to forming a structural barrier, ECM also acts as a depot for biologically active molecules where they can be stored and protected. Laminin itself contains a cell binding domain YlGSR sequence that binds to a receptor on metastatic cells and the peptide itself can inhibit metastasis. While not present in normal stroma, the stromal cells surround tumors express tetranectin that can bind the kringle domain of plasminogen (Pg). It is thought to anchor Pg to sulfated polysaccharides in the ECM. It has been known that the ability of human lymphoblastoid cells to invade an artificial matrix, or to grow and spread in a SClD mouse model has also been correlated with the expression of 72kDa type IV collagenase. Human serous ovarian tumors were examined with antibodies to this enzyme. Secretion of a variety of serine proteases is characteristic of many tumor cells. In case of Pg and Pg activators (PAS), the formation of Pn clearly provides a route for activating a cascade of pro-matrix metalloproteinases (MMPs) as well as direct attack on matrix components. Less well studied trypsin-like enzymes may contribute to the understanding of matrix degradation.
ASJC Scopus subject areas
- Organic Chemistry