Urokinase-Type Plasminogen Activator System in Breast Cancer

Gelder, Marion E. Meijer–van; Look, Maxime P.; Peters, H. A.; Brünner, Nils; Harbeck, Nadia; Klijn, Jan G.M.; Foekens, John A.

doi:10.1158/0008-5472.can-03-3848

Cited by 58 publications

(28 citation statements)

References 49 publications

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“…We also showed co-expression of uPAR with CD44 and MDR1, which may explain the association between advanced malignancy and drug resistance. Several studies have investigated individually the role of uPAR, CD44 and MDR1 in various malignancies [5], [13], [14], [17], [19], 24,27,28,29,30,31,32, however, to our knowledge this is the first study that provides evidence for expression of CD44 and MDR1 on uPAR-positive cells in SCLC. We also detected CD44 and MDR1 expression on uPAR-negative cells, the functional implications of which remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…In several types of tumors increased levels of urokinase plasminogen activator (uPA) and its receptor uPAR (CD87) strongly correlate with poor prognosis and unfavorable clinical outcome [2], [3], [4], [5], [6]. uPA and uPAR are instrumental in controlling membrane-associated extracellular proteolysis and transmembrane signaling, thus affecting cell migration and invasion under physiological and pathological conditions [2], [7], [8], [9], [10].…”

Section: Introductionmentioning

confidence: 99%

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Identification of uPAR-positive Chemoresistant Cells in Small Cell Lung Cancer

et al. 2007

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BackgroundThe urokinase plasminogen activator (uPA) and its receptor (uPAR/CD87) are major regulators of extracellular matrix degradation and are involved in cell migration and invasion under physiological and pathological conditions. The uPA/uPAR system has been of great interest in cancer research because it is involved in the development of most invasive cancer phenotypes and is a strong predictor of poor patient survival. However, little is known about the role of uPA/uPAR in small cell lung cancer (SCLC), the most aggressive type of lung cancer. We therefore determined whether uPA and uPAR are involved in generation of drug resistant SCLC cell phenotype.Methods and FindingsWe screened six human SCLC cell lines for surface markers for putative stem and cancer cells. We used fluorescence-activated cell sorting (FACS), fluorescence microscopy and clonogenic assays to demonstrate uPAR expression in a subpopulation of cells derived from primary and metastatic SCLC cell lines. Cytotoxic assays were used to determine the sensitivity of uPAR-positive and uPAR-negative cells to chemotherapeutic agents. The uPAR-positive cells in all SCLC lines demonstrated multi-drug resistance, high clonogenic activity and co-expression of CD44 and MDR1, putative cancer stem cell markers.ConclusionsThese data suggest that uPAR-positive cells may define a functionally important population of cancer cells in SCLC, which are resistant to traditional chemotherapies, and could serve as critical targets for more effective therapeutic interventions in SCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of uPAR-positive Chemoresistant Cells in Small Cell Lung Cancer

et al. 2007

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“…The presence of uPAR in breast cancer tissue is also a strong indicator of drug resistance. Increased levels of uPAR directly correlated with resistance to tamoxifen and low progression free survival for patients who developed tamoxifen resistance 18.…”

Section: Introductionmentioning

confidence: 98%

Imaging the Urokinase Plasminongen Activator Receptor in Preclinical Breast Cancer Models of Acquired Drug Resistance

et al. 2014

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Subtype-targeted therapies can have a dramatic impact on improving the quality and quantity of life for women suffering from breast cancer. Despite an initial therapeutic response, cancer recurrence and acquired drug-resistance are commonplace. Non-invasive imaging probes that identify drug-resistant lesions are urgently needed to aid in the development of novel drugs and the effective utilization of established therapies for breast cancer. The protease receptor urokinase plasminogen activator receptor (uPAR) is a target that can be exploited for non-invasive imaging. The expression of uPAR has been associated with phenotypically aggressive breast cancer and acquired drug-resistance. Acquired drug-resistance was modeled in cell lines from two different breast cancer subtypes, the uPAR negative luminal A subtype and the uPAR positive triple negative subtype cell line MDA-MB-231. MCF-7 cells, cultured to be resistant to tamoxifen (MCF-7 TamR), were found to significantly over-express uPAR compared to the parental cell line. uPAR expression was maintained when resistance was modeled in triple-negative breast cancer by generating doxorubicin and paclitaxel resistant MDA-MB-231 cells (MDA-MB-231 DoxR and MDA-MB-231 TaxR). Using the antagonistic uPAR antibody 2G10, uPAR was imaged in vivo by near-infrared (NIR) optical imaging and 111In-single photon emission computed tomography (SPECT). Tumor uptake of the 111In-SPECT probe was high in the three drug-resistant xenografts (> 46 %ID/g) and minimal in uPAR negative xenografts at 72 hours post-injection. This preclinical study demonstrates that uPAR can be targeted for imaging breast cancer models of acquired resistance leading to potential clinical applications.

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“…Therefore, there is a strong need for more sensitive and predictive biomarkers for response to endocrine therapy. In a recent study by Meijer-van Gelder et al, uPA, uPAR, and PAI-1 were all predictive for improved efficacy of tamoxifen therapy in patients treated for recurrent breast cancer 39. Therefore, the status of uPA system proteins in patient tumor specimens may be useful in developing individualized therapy protocols.…”

Section: The Urokinase Plasminogen Activator (Upa) Systemmentioning

confidence: 98%

Candidate prognostic markers in breast cancer: focus on extracellular proteases and their inhibitors

Roy

Walsh

2014

BCTT

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The extracellular matrix (ECM) is the complex network of proteins that surrounds cells in multicellular organisms. Due to its diverse nature and composition, the ECM has a multifaceted role in both normal tissue homeostasis and pathophysiology. It provides structural support, segregates tissues from one another, and regulates intercellular communication. Furthermore, the ECM sequesters a wide range of growth factors and cytokines that may be released upon specific and well-coordinated cues. Regulation of the ECM is performed by the extracellular proteases, which are tasked with cleaving and remodeling this intricate and diverse protein matrix. Accordingly, extracellular proteases are differentially expressed in various tissue types and in many diseases such as cancer. In fact, metastatic dissemination of tumor cells requires degradation of extracellular matrices by several families of proteases, including metalloproteinases and serine proteases, among others. Extracellular proteases are emerging as strong candidate cancer biomarkers for aiding and predicting patient outcome. Not surprisingly, inhibition of these protumorigenic enzymes in animal models of metastasis has shown impressive therapeutic effects. As such, many of these proteolytic inhibitors are currently in various phases of clinical investigation. In addition to direct approaches, aberrant expression of extracellular proteases in disease states may also facilitate the selective delivery of other therapeutic or imaging agents. Herein, we outline extracellular proteases that are either bona fide or probable prognostic markers in breast cancer. Furthermore, using existing patient data and multiple robust statistical analyses, we highlight several extracellular proteases and associated inhibitors (eg, uPA, ADAMs, MMPs, TIMPs, RECK) that hold the greatest potential as clinical biomarkers. With the recent advances in high-throughput technology and targeted therapies, the incorporation of extracellular protease status in breast cancer patient management may have a profound effect on improving outcomes in this deadly disease.

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Urokinase-Type Plasminogen Activator System in Breast Cancer

Cited by 58 publications

References 49 publications

Identification of uPAR-positive Chemoresistant Cells in Small Cell Lung Cancer

Identification of uPAR-positive Chemoresistant Cells in Small Cell Lung Cancer

Imaging the Urokinase Plasminongen Activator Receptor in Preclinical Breast Cancer Models of Acquired Drug Resistance

Candidate prognostic markers in breast cancer: focus on extracellular proteases and their inhibitors

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