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Although the underlying biochemical processes for metastasis are still not fully understood, a large body of research has shown that the urokinase type Plasminogen Activator (uPA), a member of the serine protease family, and its receptor (uPAR) play a major role in this process. Both micro-biological findings and epidemiological studies conducted with several thousand cancer patients worldwide strongly suggest that the uPA system is an attractive target for the development of cancer drugs, which attack cancer by acting at multiple points of the metastatic process. uPA System: Components The uPA system is an extra-cellular enzyme system over-expressed on certain aggressive metastasizing solid tumours. The uPA system (see figure) consists of:
 Figure: Components and mode of action of the uPA system |
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uPA System: Mode of Action The uPA system triggers off proteolytic processes through which tumour cells are enabled to degrade their surrounding tissue (the extracellular matrix), to invade into healthy tissue and blood vessels and thus to migrate and form new tumours at distant sites. In addition, the uPA-system interacts with other molecular-biological systems, and thus can promote primary tumour growth. uPA mode action in detail |
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Through the binding of uPA to the uPA receptor (uPAR) plasminogen is converted to plasmin, which in turn degrades the extracellular matrix (ECM). The ECM is the protein network, which the tumour cells are embedded in. Degradation of ECM helps tumour cells to invade into adjacent tissue and, eventually, into the blood stream. It also promotes the release of various growth factors that are otherwise sequestrated by intact ECM. Furthermore, uPA and plasminogen may activate other families of protein-cleaving enzymes such as metalloproteinases, or MMPs, which, along with the uPA system, promote tumour cell invasion and angiogenesis. The binding of uPA to uPAR induces growth promoting signals in tumour cells, events which are separate from its enzymatic activity. In addition, uPAR interacts with vitronectin and integrins, which are involved in cell adhesion and signal transduction. Thus, tumour cells acquire growth and survival advantages by overexpressing the uPA system, which promotes the growth, invasion, and metastatic spread of tumour cells via multiple mechanisms. In the opinion of the Company this makes the uPA system an attractive target for the development of cancer drugs, which attack cancer by acting at multiple points of the metastatic process. |
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uPA System: Clinical Relevance Over the last decade, substantial scientific and clinical evidence has been established that components of the uPA system play a key role in metastasis. Examination of human cancers led to the discovery of uPA over-expression in a wide range of tumour types including breast, gastric and ovarian cancer. In a number of different cancers, high levels of uPA and PAI-1 have been shown to be associated with unfavorable disease progression, whereas low levels of uPA and PAI-1 are associated with a more favorable prognosis. Patients with high levels of uPA expressions have a significantly shorter disease-free survival and overall survival than those with low levels. uPA and PAI-1 have been qualified as new prognostic markers of breast cancer with the highest level of evidence, or LOE-1, by the European Organization for Research and Treatment of Cancer, or EORTC.  Figure: High tumour antigen levels of uPA and PAI-1 correlate with shorter overall survival compared to low tumours antigen levels. Source: Longterm study of over 6,400 breast cancer patients. Look et. al., JNCI, 2002. |
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| © 2006 WILEX AG |
Overview
Therapeutic Target