Conclusions and Perspectives

uPAR is a multifunctional molecule, present in intact and cleaved forms and involved in extracellular proteolysis, cell adhesion, mobility, and cell signaling events [5-8, 155-157]. It is located mainly on stromal cells at the invasive front in breast and colorectal cancer and present in elevated levels in tumor tissue and blood from cancer patients as well as patients with infectious diseases. High levels of uPAR correlate with short survival in breast, colorectal, and lung cancer as well as in patients with HIV. Cleavage of uPAR could be an indication of an active plasminogen activation system. With the design of immunoassays that can quantify the individual uPAR variants, domain I was found to be a stronger prognostic marker than the total uPAR amount in tumor extracts of NSCLC patients [35]. It is possible that domain I or one of the other uPAR forms would have a stronger prognostic potential than the combined uPAR forms both in tumor tissue and blood from cancer patients. The use of either the total amount or the individual forms of uPAR for monitoring therapy response should be investigated. In AML, it has already been shown that the levels of suPAR(II-III) in plasma decrease following chemotherapy and this correlates with a decrease in the number of circulating tumor cells [18].

In a mouse cancer model for breast cancer, the volume of the lung metastases was demonstrated to be significantly reduced in mice deficient in uPA [158]. The therapeutic potential of blocking the interaction between uPAR (I-III) and uPA has been proven in several model systems and reviewed [157]. In vivo studies in mice using xenotransplanted human tumors and syngeneic tumors have demonstrated reduction of primary tumor growth, metastasis, and angiogenesis, by blockage of cellular binding of uPA by various antagonists including pAbs [25, 29, 159, 160]. mAbs raised against uPAR, blocking uPA binding, might thus be potential therapeutic agents [1,26]. The presently available mAbs against uPAR, which prevent uPA binding, are directed against the human form of uPAR (Section 4). Due to species specificity, these will have no effect in mouse on the muPA-muPAR interaction. For therapy experiments in genetically induced mouse cancer models, murine mAbs specific for mouse uPAR are required. Mice deficient in uPAR have no defects in their humoral immune response [161]. Anti-muPAR mouse mAbs that inhibit the muPA-muPAR interaction have recently been obtained by immunizing uPAR mice [162]. These mAbs have in vivo efficacy and will be important tools in therapeutic studies in murine cancer models. The results of such experiments could serve as proof of principle for further development of anti-uPAR mAbs for clinical use.


We thank Professor Keld Dan0 and Dr. Ross W. Stephens for critical reading of the chapter and Dr. Kirsty Green for correcting the language. The excellent technical assistance from Annegrethe Poulsen, Ruth Pettersson, and Anne Moller is gratefully acknowledged as is the excellent graphic assistance provided by John Post. This work was supported by EU contracts QLK3-CT-2002-02136 and LSHC-CT-2003-503297 as well as the Danish Cancer Society.


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