Proteases in Oncology

Of all proteins expressed by living organisms, proteases are among the most critical in mediating pathways of cell life en death. In fact, the initial interactions between protease and substrate and the subsequent cleavage lie at the base of a vast spectrum of essential biological events including thrombosis, coagulation and apoptosis. Dysregulated proteolysis, or imbalance between proteases and antiproteases, has been searched intensively based on the suspicion that it could be a key factor in many pathologies where proteases have been involved such as cancer, autoimmune diseases, inflammation and infectious diseases.

In cancer progression, the invasive cells are able to hydrolyze the extracellular matrix proteins (vitronectin, fibronectin, laminin and collagens), which form a non-cellular compartment to the tumor microenvironment, using a proteolytic cascade involving several proteases. Three main families of proteases seem to be involved in hydrolysis of the basement membrane and invasion of the adjacent stroma: the serine proteases, including u-PA, elastase, plasmin and kallikreins, the matrix metalloproteinases, which include gelatinases, collagenases and matrilysin and the cysteine proteases such as cathepsins B and L. (Figure 1)

Proteases in Oncology

Because proteases produced by cancer cells have been shown to mediate invasive procedures such as pericellular ECM breakdown and growth-factor activation, pharmacological protease inhibitors have been developed as cancer therapeutics.