Abstract
Proteolytic enzymes constitute 2-3 % of all known human genes and represent an important tool for the control of the biological functions of proteins. During gliomagenesis, the complex regulation of proteases in transformed and stromal cells is impaired as a result of several factors, and proteases critically contribute to the hallmarks of gliomas.
Proteins regulated by proteases include components of the extracellular matrix, local mediators, cell surface receptors, ion channels and adhesion molecules, cytoskeletal proteins, components of the intracellular sig- naling cascades, and regulators of the cell cycle. Via the proteolytic modifications of these substrates and/or by non-proteolytic mechanisms, the extracellular as well as intracellular proteases contribute to the increased invasiveness of glioma cells, promote the self-renewal and proliferation of glioma stem-like cells, and facilitate tumor neovascularization.
The role of proteases in glioma progression is therefore multifaceted and complex. Glioma-associated proteases represent attractive therapeutic targets and several approaches were proposed including the inhibition of the extracellular proteases involved in glioma invasiveness as well as the inhibition of the proteasome and γ-secretase.
However, a more precise understanding of the pathogenetic role of proteases in individual glioma patients at different stages of the disease is necessary as indicated by the relatively low therapeutic efficacy of the protease inhibitors in the initial clinical trials. Identifi- cation of the key protease-dependent processes in individual glioma patients, the most effective modes of protease targeting, and optimal delivery schedules and routes seem to be crucial to improve the therapeutic outcomes.