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Soluble Urokinase Receptor Levels Correlate with Number of Circulating Tumor Cells in Acute Myeloid Leukemia and Decrease Rapidly during Chemotherapy¹

Haartman Institute, University of Helsinki, FIN-00014 Helsinki, Finland [S. M., A. V.]; Molecular Genetics Unit, Department of Molecular Pathology and Medicine, DIBIT, San Raffaele Scientific Institute, 20132 Milan, Italy [N. S., C. F. M. S., F. B.]; Department of Internal Medicine, Division of Hematology [E. E.] and Department of Clinical Chemistry, Stem Cell Laboratory [R. A.], Helsinki University Central Hospital, FIN-00029 Helsinki, Finland

The importance of plasminogen activation, mediated by urokinase (uPA) and its receptor (uPAR), is well established in many physiological and pathological processes, such as in cell migration and tumor-cell invasion. 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 plasma/serum samples of cancer patients have been shown to correlate with survival prognosis, indicating the relevance of these molecules in malignancy. We previously showed that in acute myeloid leukemia, a high level of plasma soluble uPAR (suPAR) at diagnosis correlates with poor response to chemotherapy. However, in this case, as in other cancers, the origin of suPAR is unknown. Therefore, we have now analyzed uPAR in cells, plasma, and urine of patients with acute leukemia (n = 35) at 0, 5, 14, 28, and 56 days after start of chemotherapy. In response to cytotoxic treatment, suPAR levels decreased rapidly, and the decreasing plasma suPAR (p-suPAR) levels correlated highly with decreasing numbers of circulating tumor cells, suggesting that the elevated p-suPAR was produced by circulating tumor cells. Moreover, the p-suPAR level appeared to correlate with the amount of uPAR in tumor cell lysates at diagnosis. Our results also show for the first time that in lysates of circulating tumor cells, studied by immunoprecipitation and immunoblotting, uPAR was partly in fragmented form, whereas only full-length uPAR was found in normal leukocytes. We also detected fragmented suPAR in peripheral blood plasma, in urine, and especially in the plasma compartment of bone-marrow aspirates of acute myeloid leukemia patients, in a pattern differing considerably from that found in healthy individuals. Because proteolytic cleavage of uPAR induces a potent chemotactic response in vitro, it is possible that these fragments may play a role in the pathophysiology of acute leukemia.

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