TY - JOUR
T1 - The urokinase receptor and its structural homologue C4.4A in human cancer
T2 - expression, prognosis and pharmacological inhibition
AU - Jacobsen, B
AU - Ploug, M
PY - 2008
Y1 - 2008
N2 - The urokinase-type plasminogen activator receptor (uPAR) and its structural homologue C4.4A are multidomain members of the Ly6/uPAR/alpha-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 well-established 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 structural-functional and disease-related aspects of uPAR and C4.4A with a view to possible pharmacological targeting strategies for therapy and for non-invasive bioimaging.
AB - The urokinase-type plasminogen activator receptor (uPAR) and its structural homologue C4.4A are multidomain members of the Ly6/uPAR/alpha-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 well-established 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 structural-functional and disease-related aspects of uPAR and C4.4A with a view to possible pharmacological targeting strategies for therapy and for non-invasive bioimaging.
KW - Adenocarcinoma
KW - Animals
KW - Antibodies, Monoclonal
KW - Carcinoma, Squamous Cell
KW - Cell Membrane
KW - Colorectal Neoplasms
KW - Gene Expression Regulation, Neoplastic
KW - Glycoproteins
KW - Glycosylphosphatidylinositols
KW - Humans
KW - Lung Neoplasms
KW - Molecular Sequence Data
KW - Neoplasms
KW - Plasminogen Inactivators
KW - Prognosis
KW - Receptors, Urokinase Plasminogen Activator
KW - Sequence Homology, Amino Acid
KW - Serine Proteinase Inhibitors
KW - Structure-Activity Relationship
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
KW - Review
M3 - Review
C2 - 18855679
SN - 0929-8673
VL - 15
SP - 2559
EP - 2573
JO - Current Medicinal Chemistry
JF - Current Medicinal Chemistry
IS - 25
ER -
