Title:Plasminogen Receptors in Human Malignancies: Effects on Prognosis and Feasibility as Targets for Drug Development
Volume: 21
Issue: 7
Author(s): Steven L. Gonias*Carlotta Zampieri
Affiliation:
- Department of Pathology, University of California San Diego, La Jolla, CA, 92093,United States
Keywords:
Plasminogen, tissue-type plasminogen activator, urokinase-type plasminogen activator, α-enolase, annexin-A2,
cytokeratin 8, Plg-RKT, uPAR, LDL receptor-related protein-1, NMDA receptor.
Abstract: The major proteases that constitute the fibrinolysis system are tightly regulated. Protease
inhibitors target plasmin, the protease responsible for fibrin degradation, and the proteases that convert
plasminogen into plasmin, including tissue-type plasminogen activator (tPA) and urokinase-type
plasminogen activator (uPA). A second mechanism by which fibrinolysis is regulated involves exosite
interactions, which localize plasminogen and its activators to fibrin, extracellular matrix (ECM) proteins,
and cell surfaces. Once plasmin is generated in association with cell surfaces, it may cleave
transmembrane proteins, activate growth factors, release growth factors from ECM proteins, remodel
ECM, activate metalloproteases, and trigger cell-signaling by cleaving receptors in the Proteaseactivated
Receptor (PAR) family. These processes are all implicated in cancer. It is thus not surprising
that a family of structurally diverse but functionally similar cell-surface proteins, called Plasminogen
Receptors (PlgRs), which increase the catalytic efficiency of plasminogen activation, have received
attention for their possible function in cancer and as targets for anticancer drug development. In this
review, we consider four previously described PlgRs, including: α-enolase, annexin-A2, Plg-RKT, and
cytokeratin-8, in human cancer. To compare the PlgRs, we mined transcriptome profiling data from
The Cancer Genome Atlas (TCGA) and searched for correlations between PlgR expression and patient
survival. In glioma, the expression of specific PlgRs correlates with tumor grade. In a number of malignancies,
including glioblastoma and liver cancer, increased expression of α-enolase or annexin-A2
is associated with an unfavorable prognosis. Whether these correlations reflect the function of PlgRs
as receptors for plasminogen or other activities is discussed.
