Local proteolytic activity in tumor cell invasion and metastasis

Abstract

Proteolytic cleavage of extracellular matrix (ECM) is a critical regulator of many physiological and pathological events. It affects fundamental processes such as cell growth, differentiation, apoptosis and migration. Most proteases are produced as inactive proenzymes that undergo proteolytic cleavage for activation. Proteolytic activity is additionally modified by endogenous inhibitors. Mechanisms that localize and concentrate protease activity in the pericellular microenvironment of cells are prerequisites for processes like angiogenesis, bone development, inflammation and tumor cell invasion. Methods that enable real-time, high-resolution imaging and precise quantification of local proteolytic activity in vitro and in vivo remain major challenges. These methods will play an important role in the understanding of basic principles e.g. in cancer cell invasion, the identification of new therapeutical targets and hence drug design. This review highlights mechanisms and functions of local proteolytic activity with special emphasis on tumor cell invasion and metastasis, and focuses on techniques for the investigation of this process.

Interdependency of cell adhesion, force generation and extracellular proteolysis in matrix remodeling

“…The functionally relevant proteolytic net activity in the cell microenvironment results from the fragile and complex local balance of distinct proteases, their substrates and inhibitors (Ludwig, 2005). However, it is becoming increasingly evident that the micromechanics of cells and their environment determine cell fate and function as much as soluble molecular factors do (Chen et al, 1997;Discher et al, 2005;Ludwig et al, 2008a;Vogel and Sheetz, 2006).…”

Probing cellular microenvironments and tissue remodeling by atomic force microscopy

“…This methodological gap is pinpointed by the disastrous failure of synthetic MMP inhibitors in cancer therapy [5,15,16,85,114]. Although criticism regarding the general setting of these trials is reasonable, they questioned the actual knowledge regarding the regulation of proteolytic activity [26].…”

“…The quantification of proteolytic activity in vitro and even more in situ is hampered by two major obstacles: excessive posttranslational regulation and spatial restriction (Fig. 12b), both of which are major topics of ongoing research themselves [85,88,89,136].…”

Activity-based Protein Profiling Implicates Urokinase Activation as a Key Step in Human Fibrosarcoma Intravasation

“…Proteolytic enzymes play a critical role in tumor cell dissemination (1)(2)(3). They are responsible in part for remodeling of the extracellular matrix (ECM), 2 thus allowing tumor cells to invade the surrounding tissue, enter the vasculature, and establish metastatic foci at distant sites.…”