Urokinase Exerts Antimetastatic Effects by Dissociating Clusters of Circulating Tumor Cells

Choi, Jin Woo; Kim, Jun Ki; Yang, Yun; Kim, Pilhan; Yoon, Kwon‐Ha; Yun, Seok Hyun

doi:10.1158/0008-5472.can-15-0684

Cited by 54 publications

(44 citation statements)

References 40 publications

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“…Recently, a Korean group succeeded in prolonging survival in a mouse model of breast cancer by dissociating CTC clusters using urokinase (82), making a first step in CTC cluster-relevant treatment. However, because the dissociated CTCs can still form metastases, the effects of such strategy may be mild and needs further evaluation.…”

Section: Clinical Application Of Ctc Clustersmentioning

confidence: 99%

Circulating tumor cell clusters: What we know and what we expect (Review)

Hong

Fang

Zhang

2016

International Journal of Oncology

192

179

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The major cause of cancer-associated mortality is tumor metastasis, a disease that is far from understood. Many studies have observed circulating tumor cells (CTCs) in patients' circulation systems, and a few latest investigations showed that CTC clusters have a potentially high capacity of metastasis. The capture and analysis of CTC clusters offer new insights into tumor metastasis and can facilitate the development of cancer treatments. We reviewed the research history of the CTC clusters, as well as the technologies used for detecting and isolating CTC clusters. In addition, we discuss the characteristics of CTC clusters and their roles in tumor dissemination. Clinical relevance of CTC clusters was also implicated in currently limited data. Moving forward, the next frontier in this field is to develop more efficient capture methods and decipher conundrums of characterization of CTC clusters. This will ultimately identify the clinical value of CTC clusters as a biomarker and therapeutic target.

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Section: Clinical Application Of Ctc Clustersmentioning

confidence: 99%

Circulating tumor cell clusters: What we know and what we expect (Review)

Hong

Fang

Zhang

2016

International Journal of Oncology

192

179

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“…, Claudine Soria 2, † , Marc Pocard 1 , Massoud Mirshahi 1,2 , and Jeannette Soria 1,2 We were surprised by the results of Choi and colleagues showing that urokinase exerts antimetastatic effects by dissociating clusters of circulating tumor cells (1).…”

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confidence: 99%

Urokinase Antimetastatic Effects—Letter

Mirshahi¹,

Pujade-Lauraine²,

Soria³

et al. 2016

Cancer Research

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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.

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“…We appreciate two commentaries from Dr. Alonso and Dr. Soria’s groups regarding our recent publication on ‘highly metastatic property of clustered circulating tumor cells(CTCs)’ In our research, we suggested the breakdown of CTC cluster slows metastasis pace with preclinical experiments; urokinase plasminogen activator (uPA) utilized to dissociate the CTC cluster showed no effect on primary tumor growth, but the number of metastasized nodules was reduced, expanding survival rate of the animals (1). …”

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confidence: 99%