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See article on page 798
Cell–cell and cell–extracellular matrix (ECM) interactions are essential for cell migration, tissue remodelling, angiogenesis, and tumorigenesis. Pericellular proteolysis of cell surface molecules and ECM provides crucial information in the local environment. Urokinase (uPA) plays an important role through the activation of plasminogen to plasmin, which regulates degradation of elements within the ECM, such as fibrin, fibronectin and lamin, and proteolytic activation of growth factors including hepatocyte growth factor (HGF), basic fibroblast growth factor (FGF-2) and transforming growth factor β (TGF-β). Plasmin also activates the proenzyme forms of the matrix metalloproteinases (MMPs), such as MT1-MMP,1MMP-2 and MMP-9.2 uPA activation is regulated by its specific cell surface receptor, urokinase receptor (uPAR). Binding of uPA to its receptor (uPAR) accelerates uPA activation from an inactive proenzyme (pro-uPA). The activity of plasminogen activators can be regulated by the specific inhibitors, plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2). The urokinase system is implicated in tumour cell invasion on a basis of generally increased uPA activity in metastatic tumours. In particular, uPAR expression on the surface of neoplastic cells is crucial for tumour invasion and metastasis. Overexpression of uPAR has been reported in several types of human carcinoma including gastric cancer, pancreatic cancer and colorectal cancer,3-5 and a high uPAR concentration in resected colorectal tumours is an independent and significant prognostic factor for five year overall survival.6
During cell migration, the expression of the plasminogen activator system is upregulated. uPAR is distributed over the entire cell surface of non-migrating cells, whereas it is polarised towards the leading edge of migrating cells where it increases plasminogen activity to facilitate cell migration. Although uPAR is attached to the cell membrane only by a glycosyl phosphatidyl inositol (GPI) anchor, which is added during post-translational processing, it is also a genuine receptor which induces an intracellular signal. Recent studies have shown that binding of uPA to uPAR activates cellular protein tyrosine kinases,7 the protein kinase C pathway8 and mitogen-activated protein (MAP) kinases.9 Moreover, a direct signalling pathway utilising the Jak/Stat cascade and a second signal transduction mechanism via Src-like protein tyrosine kinases have been implicated in its signalling.10 Interactions of PAI-1 and uPAR with the extracellular matrix protein vitronectin (VN) and integrin receptors have been reported. Excess PAI-1 may promote cell migration by blocking cellular adhesion to VN and/or promoting detachment of uPAR-bearing cells,11 and uPAR changes the adhesive properties of integrins. uPAR forms stable complexes with activated integrins to inhibit their usual adhesive function and promote adhesion to VN mediated by the distinct binding site on uPAR.12 Thus, uPAR is a multifunctional cellular receptor that is involved in activation of proteolytic cascades, altered cell adhesion and intracellular signalling leading to tumour invasion and metastasis.
Various genetic abnormalities, including loss of function of tumour suppressor genes, activation of proto-oncogenes and deficiencies of DNA mismatch repair genes, are thought to contribute to steps in the adenoma–carcinoma sequence in colorectal neoplasia. Cellular transformation often results in a dramatic increase in the activation of the plasminogen activator system, especially urokinase. Kunzet al showed that wild type p53 represses transcription of the uPA and tPA gene through a non-DNA binding mechanism.13 However, the relation between uPAR expression and tumorigenesis has remained elusive. In this issue Suzuki et al (see page 798) show that uPAR expression increases during the transition from adenoma to invasive carcinoma in colorectal epithelium. uPAR expression was detected in 30% of colorectal adenomas and 85% of invasive carcinomas by in situ hybridisation. Importantly, they show that the frequency of uPAR gene expression was significantly increased in severely dysplastic adenomas compared with mildly or moderately dysplastic adenomas, and in Dukes’ stage B or C cancer compared with Dukes’ A cancer. These data implicate uPAR expression in the progression for normal colonic epithelium to an invasive carcinoma. How is the expression of this multifunctional cellular receptor regulated?
uPAR expression is upregulated by a variety of growth factors, including epidermal growth factor (EGF), FGF-2 and HGF, and by phorbol ester. Raised uPAR expression in colon cancer cells is largely a consequence of constitutive activation of the extracellular signal regulated kinases 1 (ERK-1) dependent pathway.14Furthermore, our own data suggest that signalling through the tissue factor (TF)/factor VIIa (FVIIa) pathway results in upregulation of uPAR gene expression and enhanced invasion of pancreatic cancer cells in vitro.15 These data suggest that the expression of the components of the urokinase system depends upon a complicated series of paracrine interactions. Therefore, it is possible that uPA and/or PAI-1, which are expressed by local stromal cells, are assembled at the surface of the uPAR bearing tumour cells and the activated uPA system itself then contributes to paracrine regulation of growth factors and MMPs.
Clearly, the components of the urokinase system, especially uPAR, are attractive targets for cancer therapy. Significant inhibition of cancer growth and neovascularisation by uPAR blockade has been observed for prostate cancer cell lines expressing mutant uPA.16Reduction of uPAR on the cell surface, using an antisense strategy, has also been reported to induce a protracted state of dormancy in human epidermoid carcinoma cells.17 Thus, inhibition of the activated urokinase system may interfere not only with tumour invasion and metastasis but also with malignant progression. No doubt future studies will elucidate how these systems interact with each other, enabling the development of effective strategies for cancer therapy.