Urokinase Antimetastatic Effects—Letter

Abstract

We were surprised by the results of Choi and colleagues showing that urokinase exerts antimetastatic effects by dissociating clusters of circulating tumor cells (1).It is well known that the role of urokinase (uPA) in cancer is not limited to the vascular compartment, but is also a critical component of the tissue-invasive system used by cancer cells.It is true that, as previously described, polymerized fibrin is a determinant for tumor dissemination by supporting tumor cell migration, through stabilizing tumor cell-associated emboli on the vessel wall. However, plasmin-mediated fibrinolysis was not a critical determinant of the metastatic potential of circulating tumor cells (2).However, several retrospective studies have shown that elevated levels of uPA and its inhibitor (PAI-1) in breast tumor tissue are potent predictors of poor patient outcome (3). High uPA and PAI-1 tumor levels also associated with poor prognosis in ovarian cancer (4).At high concentrations, uPA, when bound to its receptor (uPA-R) on cancer cells cleaves zymogen plasminogen to active plasmin, which degrades extracellular matrix (ECM) components.This degradation induces the release of growth factors sequestered there, resulting in increased cancer cell proliferation, migration, invasion, and metastasis.These results are not in discrepancy with those showing that high levels of PAI-1 in cancer cells also correlate with poor outcome (3, 4). In fact, cellular migration requires coordination between detachment/readhesion cycles. PAI-1, in inhibiting uPA-dependent activation of plasmin, maintains the ECM integrity necessary to facilitate cell migration. PAI-1 also controls interaction of components of the ECM (vitronectin) with their surface-binding elements (integrins). In the absence of uPA, there is a preferential binding of vitronectin to PAI-1, leading to activation of PAI-1, but when PAI-1 reacts with uPA, its affinity for vitronectin drops, inducing the release of PAI-1 from vitronectin, thus exposing binding sites on vitronectin for cell surface uPA-R and for integrins.Therefore, a balanced level of PAI-1 and uPA is required to alternately disrupt and reestablish interactions of vitronectin, with integrin and uPA-R at the leading edge of cell migration.In addition, Duffy and colleagues recently reported that, in a phase II clinical trial, a uPA inhibitor seems to improve patient survival in metastatic cancer (5).In view of these observations, we should not ignore that urokinase treatment may also include the risk of increasing tumor cell invasiveness and metastatic spreading, resulting in an opposite effect to that expected by Choi and colleagues. Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.

Dissecting Breast Cancer Circulating Tumor Cells Competence via Modelling Metastasis in Zebrafish

“…However, preclinical data suggest that urokinase exerts antimetastatic effects by dissociating CTC-clusters [53]. In the light of these findings, our results grant further studies investigating the role of urokinase in CTC clustering and metastatic seeding ability, as urokinase treatment may also increase the risk of tumor cell invasiveness and metastatic spreading [54]. On the other hand, we observed an increased expression of CDK4 and E2F4 in tumor cells isolated from ZF-cluster, genes regulating cell cycle progression.…”

Clusters of circulating tumor cells: A biophysical and technological perspective

“…Choi et al reported the development of such a strategy using urokinase, which they claimed reduced the incidence of metastasis in animal models by lysing fibrin to dissociate CTC clusters[46]. Some have expressed skepticism in the potential use of urokinase for this application however, since urokinase has significant off-target and potentially detrimental effects in many patients[58]. Furthermore, since there is little evidence that fibrin is a significant component of CTC cluster adhesion, the mechanism of action in these studies may not in fact be related to cluster dissociation[58].…”

“…Some have expressed skepticism in the potential use of urokinase for this application however, since urokinase has significant off-target and potentially detrimental effects in many patients[58]. Furthermore, since there is little evidence that fibrin is a significant component of CTC cluster adhesion, the mechanism of action in these studies may not in fact be related to cluster dissociation[58]. These points highlight how important it is that antimetastatic strategies targeting CTC clusters be highly specific and have minimal off-target effects.…”

Agent‐based modelling reveals strategies to reduce the fitness and metastatic potential of circulating tumour cell clusters

“…Based on the proposed and experimentally demonstrated increased metastatic potential of CTC clusters (relative to single CTCs), it has been suggested that their dissociation into single cells might be a valid therapeutic strategy to decrease their aggressivity (Aceto et al, 2014; Hong, Fang, & Zhang, 2016). Studies that directly targeted cell–cell connections and adhesion within clusters by downregulating the expression of plakoglobin (a protein involved in desmosomes and adherens junctions), inhibiting heparanase or administering a thrombolytic agent (Aceto et al, 2014; Choi et al, 2015; Lu, Zeng, Gu, & Ma, 2015; Wei et al, 2018) showed promise, but concerns regarding the side effects of such treatments have been raised (Choi, Yoon, & Yun, 2016; Mirshahi et al, 2016).…”