ABSTRACT
Cathepsins and other proteases play a role in tumor angiogenesis mainly through degradation and remodeling of the extracellular matrix proteins, which promotes vessel ingrowth. Cathepsins are cysteine proteases usually resident in lysosomal compartments, but are released to the extracellular environment by diseased cells. Tight regulation of cathepsin activity prevents aberrant cathepsins from functioning extracellularly, but microenvironmental changes in pH, oxidation state, and overexpression of enzymes overcome these regulatory mechanisms to degrade the collagens, laminins, fibronectins, and other extracellular matrix proteins between the
growing tumor and the vasculature. These enzymes are the most potent collagenases and elastases and are therefore able to greatly assist in carving a way for the tumor to metastasize as well as for vessels to penetrate. Endothelial cells, tumor cells, tumor associated macrophages and other cell types have been shown to upregulate these enzymes and play different roles in the angiogenic process. This chapter will discuss cathepsin structure and function, and the regulation of their activity in normal and tumor environments by cells, extracellular matrix, glycosaminoglycans, and other biological molecules. A particular focus will be on cathepsins B, K, L, S, and V as well as cystatin C, their endogenous protein inhibitor as these are most implicated in this disease, particularly breast, lung, and prostate cancer as well as their metastasis to bone. Traditional and novel methods to detect cathepsin activity and the benefits or trade-offs of each will be discussed. Finally, therapeutic strategies that target inhibition of proteases will be presented with a discussion of their controversy and difficulty passing clinical trials due to severe side effects.
