The plasminogen activation system in tumor growth, invasion, and metastasis

Abstract

Generation of the serine proteinase plasmin from the extracellular zymogen plasminogen can be catalyzed by either of two other serine proteinases, the urokinase- and tissue-type plasminogen activators (uPA and tPA). The plasminogen activation system also includes the serpins PAI-1 and PAI-2, and the uPA receptor (uPAR). Many findings, gathered over several decades, strongly suggest an important and causal role for uPA-catalyzed plasmin generation in cancer cell invasion through the extracellular matrix. Recent evidence suggests that the uPA system is also involved in cancer cell-directed tissue remodeling. Moreover, the system also supports cell migration and invasion by plasmin-independent mechanisms, including multiple interactions between uPA, uPAR, PAI-1, extracellular matrix proteins, integrins, endocytosis receptors, and growth factors. These interactions seem to allow temporal and spatial reorganizations of the system during cell migration and a selective degradation of extracellular matrix proteins during invasion. The increased knowledge about the plasminogen activation system may allow utilization of its components as targets for anti-invasive therapy.

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

“…SERPINE2 is a secreted ECM protease inhibitor that enhances the local invasiveness of cancers and is overexpressed (54-fold) in GIST-R cells (Buchholz et al, 2003). Accumulating evidence suggests that the interplay of extracellular proteases and their inhibitors in invasion and metastasis is complex and extends beyond their roles as protease inhibitors (Andreasen et al, 2000). The Wnt signaling pathway modulates the ECM in some human tumors.…”

Anthocyanidins inhibit migration of glioblastoma cells: Structure‐activity relationship and involvement of the plasminolytic system

“…Recent evidence suggests that the uPA/uPAR system plays a role in the regulation of cell-matrix interactions such as cell adhesion and migration [Irigoyen et al, 1999]. Furthermore, uPAR seems to control a promigratory signaling system, and high expression of this receptor is associated with invasiveness of various tumors including glioblastoma [Andreasen et al, 2000;Mori et al, 2000]. The present study characterizes the effects of the six representative kinds of anthocyanidins (Cy, Dp, Mv, Pg, Pn, and Pt), and a Dp glycosylated form, delphinidin 3-O-beta-glucopyranoside (Dp 3-glu), on the migration of human glioblastoma cells (U-87).…”

Farnesyltransferase inhibitor SCH‐66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration

“…6,7,12 MMPs, TIMPs and serine proteases of the plasminogen activation system, including uPA, uPAR, PAI-1 and plasmin, play pivotal roles in ECM remodeling during cancer invasion, metastasis and angiogenesis. [13][14][15][16][17] Components of the plasminogen activation system are regulated by Ras isoforms. For example, transfection of NIH-3T3 fibroblast cells with constitutively active H-Ras stimulates uPAR transcription about 4-fold, 18 while disruption of mutated K-ras by homologous recombination downregulates uPAR expression.…”

“…22 In addition, cell transfection with an activated H-ras increases MMP-9 gelatinolytic activity. 23,24 Since MMP activity is stimulated by uPA and plasmin, 13,14,16,17 plasmin, uPA, uPAR and MMPs could be regulated by FTIs through inhibition of Ras prenylation and activity.…”