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ISSN: 2329-8790
Journal of Hematology & Thromboembolic Diseases
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Urokinase Plasminogen Activator System and Hematologic Malignancies: Potential Role in Diagnosis and Therapy

Adel Gouri1*, Aoulia Dekaken2, Aleksandra Klisic3, Arifa Aissaoui1, Mohamed Chefrour4, Régis Guieu3 and Sadek Benharkat1
1Laboratory of Medical Biochemistry, IBN ROCHD University Hospital, Annaba, Algeria
2Department of Internal Medicine, Pr EL OKBI Public Hospital, Guelma, Algeria
3Center of Laboratory Diagnostics, Primary Health Care Center, Podgorica, Montenegro
4Laboratory of Biochemistry, La TIMONE Hospital University of Marseille, AP-HM, France
Corresponding Author : Adel Gouri
Laboratory of Medical Biochemistry
IBN ROCHD University Hospital, Annaba, Algeria
Tel: 00213 666 088
E-mail: [email protected]
Received: July 27, 2015 Accepted: July 28, 2015 Published: July 30, 2015
Citation: Gouri A, Dekaken A, Klisic A, Aissaoui A, Chefrour M, et al. (2015) Urokinase Plasminogen Activator System and Hematologic Malignancies: Potential Role in Diagnosis and Therapy. J Hematol Thrombo Dis S1:e101. doi:10.4172/2329-8790.1000S1e101
Copyright: © 2015 Gouri A et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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The urokinase plasminogen activating system (uPAS) consists of the urokinase plasminogen activator (uPA), its cognate cell membrane receptor (uPAR or CD87) and two main inhibitors belonging to the serine proteinase inhibitors (serpin) superfamily, the plasminogen activator inhibitor-1 (PAI-1) and -2 (PAI-2) [1,2].

For over a decade, the uPA system has been implicated in cancer invasion and metastasis. uPA was originally believed to mediate these processes by catalysing degradation of the extracellular matrix (ECM) thus allowing malignant cells to invade locally and eventually spread to distant sites. Recently, additional functions have been described for uPA and uPAR, particularly in cell adhesion and chemotaxis, the amounts of uPA and uPAR in various tumor types and in the tissue/serum samples of cancer patients have been shown to correlate with survival prognosis, indicating the relevance of these molecules in malignancy [3].

The distribution and expression of uPAS in different hematological disorders was reported in several studies, a high level of plasma soluble uPAR (suPAR) at diagnosis was correlated with poor response to chemotherapy in acute leukemia [4].

Literature data show that uPAR (CD87) expression has a potential role in the diagnostic or prognostic work-up of several hematologic malignancies, particularly acute leukemia and multiple myeloma (MM) [5].

Wada H et al. found that the level of the tissue type PA (t-PA) antigen was highest in acute myeloblastic leukemia (AML) and that of the urokinase type PA (u-PA) was highest in acute promyelocytic leukemia (APL). The PAI-I antigen showed no marked cell specificity, but the PAI-II antigen was markedly increased in myelomonocytic leukemia and acute monocytic leukemia (AMOL). From these findings, various PAs and PAIs are considered to be present in leukemia cells and to be involved in hemostatic disorders, thus they are of diagnostic value in leukemia. CD87 expression has also been correlated in AML patients with higher frequency of bleeding complications, mucocutaneous infiltration, hepatosplenomegaly and lymphadenopathy. These observations suggest that uPAS activity is associated with clinical features predicting a more aggressive course of the disease [5,6].

In addition, high levels of soluble uPAR appear to represent an independent factor predicting worse prognosis and extramedullary involvement in multiple myeloma (MM) [7].

Hjertner et al. showed that uPA and uPAR are expressed by myeloma cells and that this proteolytic system is functionally active in both primary myeloma cells and in myeloma cell lines. Therefore, the uPAS can also potentially influence important biological events in MM such as bone matrix degradation, tumour invasion and homing of plasma cells to the bone marrow [8]. Moreover, positive correlation was observed between number of leukocytes and of granulocytes and u-PA concentration in the blood of patients with myeloproliferative syndromes which could confirm the above hypothesis and explain fibrinolysis system activation reported in these patients [4].

Finally, recent results from preclinical studies show that inhibition of uPA protease activity or blockage of uPA from binding to its receptor prevents tumor progression. Several therapeutical approaches have been shown to possess anti-tumor effects in preclinical assays, including selective inhibitors of uPA activity, antagonist peptides, monoclonal antibodies able to prevent uPA binding to uPAR and gene therapy techniques silencing uPA/uPAR expression. The recent development of anti-urokinase receptor antibodies, may further underline the possibility that the uPAR molecule could represent a suitable target for new therapeutic options. [9,10].

The most interesting approach, as far as hematological disorders are concerned, is represented by the development of such fusion proteins as the diphtheria toxin/urokinase fusion protein, which has been demonstrated, in vitro, to be toxic to CD87‏ AML blasts. Overall, these preliminary observations suggest that the uPAR molecule could represent a suitable target for new therapeutic strategies in hematological malignancies [11].

In conclusion, further studies are needed to increase the comprehension of the molecular mechanisms implicating the uPAS system in tumorigenesis, along with more exhaustive clinical investigations to prove the efficacy of uPAS inhibitors, in monotherapy or in combination with conventional or novel anti-cancer therapies.

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