The Urokinase Plasminogen Activator Receptor as a Target for Cancer Therapy

Abstract

Proteolytic processes are necessary for normal physiological functions in the body, including normal blood vessel maintenance, clot formation and dissolution, bone remodeling, and ovulation. The same enzyme system for the above roles is also used by the cancer cells for their growth and spread. These enzymes are produced by the tumor cells or cells surrounding them and can degrade the basement membrane and extracellular matrix (ECM) which consist of several components including collagens, glycoproteins, proteoglycans, and glycosaminoglycans. A major protease system responsible for ECM degradation is the plasminogen activation system, which generates the potent serine protease plasmin. The subject of this chapter, the urokinase plasminogen activator (uPA) receptor, plays an impressive range of distinct but overlapping functions in the process of cancer invasion and metastasis. Indeed, overexpression of this molecule is strongly correlated with poor prognosis in a variety of malignant tumors. Impairment of uPAR function, or inhibition of its expression, impedes the metastatic potential of many tumors. Several approaches have been employed to target uPAR with the aim of disrupting its ligand-independent action or interaction with uPA, Vn, or integrins, including the more recent antisense technology. This chapter also discusses the in vivo and in vitro use of antisense approaches and other similar techniques for downregulating uPAR as a potential therapy for cancer.