Mustjoki S, Sidenius N, Sier C F, Blasi F, Elonen E, Alitalo R, Vaheri A
Haartman Institute, University of Helsinki, Finland.
Cancer Res. 2000 Dec 15;60(24):7126-32.
The importance of plasminogen activation, mediated by urokinase (uPA) and its receptor (uPAR), is well established in many physiologica 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.
由尿激酶（uPA）及其受体（uPAR）介导的纤溶酶原激活在许多生理和病理过程中，如细胞迁移和肿瘤细胞侵袭，其重要性已得到充分证实。最近，uPA和uPAR还被发现具有其他功能，特别是在细胞黏附和趋化作用方面。已表明，各种肿瘤类型以及癌症患者血浆/血清样本中的uPA和uPAR含量与生存预后相关，这表明这些分子在恶性肿瘤中具有相关性。我们之前发现，在急性髓系白血病中，诊断时血浆中高水平的可溶性uPAR（suPAR）与化疗反应不佳相关。然而，在这种情况下，与其他癌症一样，suPAR的来源尚不清楚。因此，我们现在分析了35例急性白血病患者在化疗开始后0、5、14、28和56天的细胞、血浆和尿液中的uPAR。在细胞毒性治疗反应中，suPAR水平迅速下降，血浆suPAR（p-suPAR）水平的下降与循环肿瘤细胞数量的减少高度相关，这表明升高的p-suPAR是由循环肿瘤细胞产生的。此外，p-suPAR水平似乎与诊断时肿瘤细胞裂解物中uPAR的含量相关。我们的结果还首次表明，通过免疫沉淀和免疫印迹研究发现，循环肿瘤细胞裂解物中的uPAR部分呈片段化形式，而在正常白细胞中仅发现全长uPAR。我们还在外周血浆、尿液中，特别是在急性髓系白血病患者骨髓抽吸物的血浆部分中检测到片段化的suPAR，其模式与健康个体有很大不同。由于uPAR的蛋白水解切割在体外可诱导强烈的趋化反应，因此这些片段可能在急性白血病的病理生理学中发挥作用。
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