Much progress has been made in understanding how matrix remodeling
proteases, including
metalloproteinases,
serine proteases, and
cysteine cathepsins, functionally contribute to
cancer development. In addition to modulating extracellular matrix metabolism,
proteases provide a significant protumor advantage to developing
neoplasms through their ability to modulate bioavailability of growth and proangiogenic factors, regulation of bioactive
chemokines and
cytokines, and processing of cell-cell and cell-matrix adhesion molecules. Although some
proteases directly regulate these events, it is now evident that some
proteases indirectly contribute to
cancer development by regulating posttranslational activation of latent
zymogens that then directly impart regulatory information. Thus, many
proteases act in a cascade-like manner and exert their functionality as part of a proteolytic pathway rather than simply functioning individually. Delineating the cascade of enzymatic activities contributing to overall proteolysis during
carcinogenesis may identify rate-limiting steps or pathways that can be targeted with anti-
cancer therapeutics. This chapter highlights recent insights into the complexity of roles played by pericellular and intracellular
proteases by examining mechanistic studies as well as the roles of individual
protease gene functions in various organ-specific mouse models of
cancer development, with an emphasis on intersecting proteolytic activities that amplify programming of tissues to foster neoplastic development.