Proteolytic pathways: Intersecting cascades in cancer development

Matrix remodeling proteases, including metalloproteinases, serine proteases, and cysteine cathepsins, have emerged as important regulators of cancer development due to the realization that many provide a significant protumor advantage to developing neoplasms through their ability to modulate extracellular matrix metabolism, bioavailability of growth and proangiogenic factors, regulation of bioactive chemokines and cytokines, and processing of cell-cell and cell-matrix adhesion molecules. While some proteases directly regulate these events, others contribute to cancer development by regulating posttranslational activation of other significant protease activities. Thus, understanding the cascade of enzymatic activities contributing to overall proteolysis during carcinogenesis may identify rate-limiting steps or pathways that can be targeted with anticancer therapeutics. This chapter reviews recent insights into the complexity of roles played by extracellular and intracellular proteases that regulate tissue remodeling accompanying cancer development and focuses on the intersecting proteolytic activities that amplify protumor programming of tissues to favor cancer development.