Tumor cell-mediated proteolysis: regulatory mechanisms and functional consequences

The mammalian organism is composed of an inter-dependent series of tissue compartments separated from each other by an extracellular matrix (ECM). This ECM functions as both a determinant of tissue architecture and a mechanical barrier to cellular invasion. ECM proteolysis facilitates tissue penetration, and a distinctive property of many malignant tumor cells is the capacity to invade host tissues and establish metastatic foci. Malignant cells produce a spectrum of matrix-degrading proteinases with activities directed against the major ECM proteins. These enzymes are identical to those normally involved in physiologic processes; however, proteinase regulation is altered such that enzyme expression and/or activity are inappropriately controlled. The purpose of this review is to highlight biochemical mechanisms commonly utilized by tumor cells to regulate proteinase activity and to discuss the potential functional consequences with respect to tumor cell behavior. Specific examples will be provided to illustrate the concepts of regulation via limited proteolysis, enzyme-inhibitor binding, compartmentalization, and alteration of proteinase expression.