Trends in Biotechnology
ReviewThe urokinase plasminogen activator receptor as a gene therapy target for cancer
Introduction
The predominant cause of death in patients with malignant solid tumours such as carcinomas is the ability of cancer cells to invade surrounding tissues and form distant metastases. The spread of cancer cells from the primary site to a distant location is known to follow a sequence that requires their detachment from the primary site, migration through the local stroma, invasion into and then extravasation from the vascular tree, before finally migrating toward, adhering to and proliferating at a distant site to form a metastatic tumour.
A major determinant for the invasive and metastatic potential of tumour cells is their ability to proteolytically degrade extracellular matrix (ECM) and the basement membrane surrounding the primary tumour, which facilitates local invasion and intravasation, leading to distant dissemination of the disease 1, 2. Although several extracellular protease systems have been implicated in the tissue degradation and remodelling that often accompanies cancer invasion, several studies show that the urokinase plasminogen activator (uPA) system is central to these processes, as reviewed previously 1, 3, 4, 5, 6. Components of the uPA system thus represent promising candidates for targeted cancer therapies.
Section snippets
The uPA system
The uPA system is involved in a variety of cell functions, including extracellular proteolysis, adhesion, proliferation, chemotaxis, neutrophil priming for oxidant production and cytokine release, all of which variously contribute to the development, implantation, angiogenesis, inflammation and metastasis of tumours [7].
The uPA system consists mainly of the serine protease uPA, its cell membrane-associated receptor (uPAR), a substrate (plasminogen) and plasminogen activator inhibitors (PAI-1
The uPA receptor
The uPAR protein is a heavily glycosylated extracellular receptor that is covalently linked to the outer layer of the cell membrane through a C-terminal glycosyl phosphatidylinositol (GPI) anchor and does not possess a transmembrane domain 5, 9. It is a 50–60 kDa glycoprotein, with protein contributing to 31.5 kDa of the mass 5, 10, with three cysteine-rich domains (D1, D2 and D3), connected by short linker regions [10]. The N-terminus of the uPAR domain 1 is the primary site for the binding of
Clinical relevance of uPAR overexpression
uPAR is overexpressed across a variety of tumour cell lines and tissues, including those of the colon, breast, ovary, lung, kidney, liver, stomach, bladder, endometrium and bone 3, 6, 7. uPAR expression is not confined to the tumour cells themselves: several tumour-associated cell types, including macrophages, mast cells, endothelial cells, NK cells and fibroblasts, are all capable of uPAR expression in various tumour types 5, 8.
uPAR levels have been strongly correlated with metastatic
Antigene therapeutic strategies for downregulation of uPAR in vivo
Kook and co-workers were the first to evaluate the effect of antisense inhibition of uPAR on invasion and metastasis in human squamous cell carcinoma. Using a vector that is capable of expressing an antisense transcript against uPAR, Kook et al. [15] demonstrated that highly malignant human squamous carcinoma cells that express antisense uPAR had reduced invasive potential. Furthermore, the tumours that developed from antisense clones were less invasive and non-tumorigenic in chick embryos 7
Impact of uPAR downregulation on cellular function and molecular signaling
Researchers that have used either antisense or siRNA technologies for the successful in vivo downregulation of uPAR in various cancers have concurrently tested these same technologies in relevant in vitro biological assays. Evaluation of the results of these in vitro assays reveals that downregulation of uPAR has lead, in most cases, to inhibition of invasion 16, 17, 19, 23, 24, 28, migration 19, 23, adhesion [19] and proliferation 16, 17, 28. In addition, reduced uPAR levels lead to inhibition
Combining uPAR downregulation with gene modulation of other molecular targets
Downregulation of more than one component involved in tumour invasion and metastasis might possibly have a synergistic or additive effect in impeding tumour dissemination. Lakka et al.[29] reported that intracranial injection of human glioma cells infected with an adenovirus bicistronic construct capable of simultaneously expressing antisense uPAR and antisense matrix metalloproteinase-9 (MMP-9) showed decreased invasiveness and tumorigenicity in mice. Subcutaneous injections of the bicistronic
Future directions – towards clinical evaluation
Delivery of uPAR downregulation constructs, whether plasmid vectors, adenoviral vectors, or synthetic strands, remains to be tested appropriately. With the current state of cancer gene therapy, delivery is a major stumbling block, and various carriers such as liposomes [35], polymers [36] and microparticles [37] are being evaluated to address this issue. The closest to clinical relevancy in terms of delivery (administration) that all the studies listed above came to was the use of mini-osmotic
References (40)
Inhibition of invasion and metastasis in oral cancer by targeting urokinase-type plasminogen activator receptor
Oral Oncol.
(2005)RNA interference-directed knockdown of urokinase plasminogen activator and urokinase plasminogen activator receptor inhibits prostate cancer cell invasion, survival, and tumorigenicity in vivo
J. Biol. Chem.
(2005)Specific interference of urokinase-type plasminogen activator receptor and matrix metalloproteinase-9 gene expression induced by double-stranded RNA results in decreased invasion, tumor growth, and angiogenesis in gliomas
J. Biol. Chem.
(2005)The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia
Crit. Rev. Oncol. Hematol.
(2004)Cathepsin B and tumor proteolysis: contribution of the tumor microenvironment
Semin. Cancer Biol.
(2005)The receptor for urokinase-type plasminogen activator is not essential for mouse development or fertility
J. Biol. Chem.
(1995)The urokinase receptor as a potential target in cancer therapy
Curr. Pharm. Des.
(2004)Interference with the urokinase plasminogen activator system: a promising therapy concept for solid tumours
Expert Opin. Biol. Ther.
(2001)- et al.
The urokinase receptor and the regulation of cell proliferation
Thromb. Haemost.
(2005) - et al.
uPAR: a versatile signalling orchestrator
Nat. Rev. Mol. Cell Biol.
(2002)
The urokinase plasminogen activator receptor (uPAR) as a target for the diagnosis and therapy of cancer
Anticancer Drugs
The role and regulation of urokinase-type plasminogen activator receptor gene expression in cancer invasion and metastasis
Med. Res. Rev.
Urokinase plasminogen activator receptor (CD87): something old, something new
Lab. Hematol.
The urokinase plasminogen activator system in cancer: implications for tumor angiogenesis and metastasis
Angiogenesis
Structure of human urokinase plasminogen activator in complex with its receptor
Science
Structure–function relationships in the interaction between the urokinase-type plasminogen activator and its receptor
Curr. Pharm. Des.
Urokinase receptor and integrin interactions
Curr. Pharm. Des.
The urokinase activator receptor in the regulation of the actin cytoskeleton and cell mobility
Biol. Chem.
Expression and localization of urokinase-type plasminogen activator receptor in human gliomas
Cancer Res.
Immunocytochemical localization of urokinase-type plasminogen activator in Lewis lung carcinoma
J. Cell Biol.
Cited by (104)
Regulation of cancer cell signaling pathways as key events for therapeutic relevance of edible and medicinal mushrooms
2022, Seminars in Cancer BiologyAtorvastatin from target screening attenuates endothelial cell tube formation and migration by regulating urokinase receptor-related signaling pathway and F/G actin
2017, Journal of the Chinese Medical AssociationGenetic Modifications That Expand Oncolytic Virus Potency
2022, Frontiers in Molecular Biosciences