The Urokinase Receptor and its Structural Homologue C4.4A in Human Cancer: Expression, Prognosis and Pharmacological Inhibition

Authors: Jacobsen, B.; Ploug, M.

Source: Current Medicinal Chemistry, Volume 15, Number 25, October 2008 , pp. 2559-2573(15)

Publisher: Bentham Science Publishers

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Abstract:

The urokinase-type plasminogen activator receptor (uPAR) and its structural homologue C4.4A are multidomain members of the Ly6/uPAR/α-neurotoxin protein domain family. Both are glycosylphosphatidylinositol-anchored membrane glycoproteins encoded by neighbouring genes located on chromosome 19q13 in the human genome. The structural relationship between the two proteins is, however, not reflected at the functional level. Whereas uPAR has a wellestablished role in regulating and focalizing uPA-mediated plasminogen activation to the surface of those cells expressing the receptor, the biological function of C4.4A remains elusive. Nonetheless, both uPAR and C4.4A have been implicated in human pathologies such as wound healing and cancer. A large body of experimental evidence thus demonstrates that high levels of uPAR in resected tumour tissue as well as in plasma are associated with poor prognosis in a number of human cancers including colon adenocarcinoma and pulmonary squamous cell carcinoma. Targeting uPAR in experimental animal models has also provided promising results regarding the interference with pathogenic plasminogen activation. In the case of C4.4A, very recent data have demonstrated that high protein expression in tumour cells of non-small cell pulmonary adenocarcinomas is associated with a particularly severe disease progression. This review will evaluate structuralfunctional and disease-related aspects of uPAR and C4.4A with a view to possible pharmacological targeting strategies for therapy and for non-invasive bioimaging.

Keywords: CD87; LU protein domain family; PET; non-small cell lung cancer; peptide antagonists; pharmacological targeting; prognosis; uPAR

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986708785909012

Affiliations: Finsen Laboratory, Section 3735, Copenhagen Biocenter, Rigshospitalet, Ole Maaloes Vej 5, Room 3.3.31, DK-2200 Copenhagen N, Denmark.

Publication date: October 1, 2008

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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