Spontaneous lung and lymph node metastasis in transgenic breast cancer is independent of the urokinase receptor uPAR

Almholt, Kasper; Lærum, Ole Didrik; Nielsen, Boye Schnack; Lund, Ida Katrine; Lund, Leif R.; Rømer, John; Jögi, Annika

doi:10.1007/s10585-015-9726-1

Cited by 6 publications

(5 citation statements)

References 59 publications

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“…uPAR overexpression is associated with an increased propensity for cancer progression and metastasis, and thus it has emerged as a promising novel target for the treatment of cancer (17). Previous studies indicated that intact uPAR and its cleaved forms are associated with the process of tumor initiation (18) and metastasis (19). Results of the study by Margheri et al (20) indicated that silencing of uPAR altered the metastatic characteristics of advanced cancer; however, to the best of our knowledge, the mechanism underlying the role of uPAR in OTSCC invasion and migration has not been previously studied.…”

Section: Discussionmentioning

confidence: 99%

Silencing of uPAR via RNA interference inhibits invasion and migration of oral tongue squamous cell carcinoma

et al. 2018

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Overexpression of urokinase-type plasminogen activator receptor (uPAR) has been implicated in promoting tumor invasion in various cancer types, including oral tongue squamous cell carcinoma (OTSCC); therefore, the effect of suppressing uPAR expression on the invasive and metastatic potential of OTSCC was investigated. A total of 65 paraffin-embedded tissues were obtained from patients with OTSCC. Immunohistochemistry was used to determine the expression level of uPAR. The Ts cells transfected with short hairpin RNA targeting uPAR were constructed and validated. The cells were used in a number of analyses, including migration, invasion and western blot analysis assays. Furthermore, a mouse lung metastatic model was used to detect the metastatic ability of OTSCC cells in the lungs. OTSCC cell metastasis and relapse were determined to be associated with uPAR immunopositivity. Inhibition of uPAR expression in Ts cells demonstrated a 40% decrease in migration and a 60% decrease in invasion, with an associated downregulation of matrix metalloprotease (MMP)-2, MMP-9 and phosphorylated extracellular signal-regulated kinase. analysis indicated a 90% decrease in the number of mice bearing macroscopic lung metastases. In conclusion, the present study demonstrated that the targeting of uPAR-inhibited cellular proliferation and invasion would provide a potential treatment for OTSCC in the future.

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Section: Discussionmentioning

confidence: 99%

Silencing of uPAR via RNA interference inhibits invasion and migration of oral tongue squamous cell carcinoma

et al. 2018

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“…In general, pathologies associated with chronic inflammation, such as rheumatoid arthritis, cancer, and Crohn’s disease, display elevated uPAR expression levels at their lesion sites primarily due to infiltrating immune cells. While evidence for a direct causal effect of uPAR-expression on disease progression often remains uncertain ( Almholt et al, 2015 ), elevated uPAR levels in resected lesions or shed into the circulation are strong and robust surrogate biomarkers of disease severity. Most observational studies find an inverse correlation between elevated plasma levels of soluble uPAR and patient performance and survival ( Lund et al, 2011 ; Madunic, 2018 ).…”

Section: Upar Biologymentioning

confidence: 99%

Targeting the Urokinase-Type Plasminogen Activator Receptor (uPAR) in Human Diseases With a View to Non-invasive Imaging and Therapeutic Intervention

Leth

Ploug

2021

Front. Cell Dev. Biol.

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The interaction between the serine protease urokinase-type plasminogen activator (uPA) and its glycolipid-anchored receptor (uPAR) focalizes plasminogen activation to cell surfaces, thereby regulating extravascular fibrinolysis, cell adhesion, and migration. uPAR belongs to the Ly6/uPAR (LU) gene superfamily and the high-affinity binding site for uPA is assembled by a dynamic association of its three consecutive LU domains. In most human solid cancers, uPAR is expressed at the invasive areas of the tumor-stromal microenvironment. High levels of uPAR in resected tumors or shed to the plasma of cancer patients are robustly associated with poor prognosis and increased risk of relapse and metastasis. Over the years, a plethora of different strategies to inhibit uPA and uPAR function have been designed and investigated in vitro and in vivo in mouse models, but so far none have been implemented in the clinics. In recent years, uPAR-targeting with the intent of cytotoxic eradication of uPAR-expressing cells have nonetheless gained increasing momentum. Another avenue that is currently being explored is non-invasive imaging with specific uPAR-targeted reporter-molecules containing positron emitting radionuclides or near-infrared (NIR) florescence probes with the overarching aim of being able to: (i) localize disease dissemination using positron emission tomography (PET) and (ii) assist fluorescence guided surgery using optical imaging. In this review, we will discuss these advancements with special emphasis on applications using a small 9-mer peptide antagonist that targets uPAR with high affinity.

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“…Although impairment of uPAR function or inhibition of its expression was associated with impaired invasive, metastatic, and tumorigenic potential of many tumor models in vitro and in vivo [ 4 , 11 , 12 , 14 , 16 , 17 , 20 , 52 , 57 , 79 , 84 , 85 ], one study in transgenic mice with uPAR gene ablation showed no pronounced causal effects on disease dissemination by metastasis [ 86 ].…”

Section: Biology Of the Urokinase Receptormentioning

confidence: 99%

The Urokinase Receptor (uPAR) as a “Trojan Horse” in Targeted Cancer Therapy: Challenges and Opportunities

Metrangolo

Ploug

Engelholm

2021

Cancers

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One of the largest challenges to the implementation of precision oncology is identifying and validating selective tumor-driving targets to enhance the therapeutic efficacy while limiting off-target toxicity. In this context, the urokinase-type plasminogen activator receptor (uPAR) has progressively emerged as a promising therapeutic target in the management of aggressive malignancies. By focalizing the plasminogen activation cascade and subsequent extracellular proteolysis on the cell surface of migrating cells, uPAR endows malignant cells with a high proteolytic and migratory potential to dissolve the restraining extracellular matrix (ECM) barriers and metastasize to distant sites. uPAR is also assumed to choreograph multiple other neoplastic stages via a complex molecular interplay with distinct cancer-associated signaling pathways. Accordingly, high uPAR expression is observed in virtually all human cancers and is frequently associated with poor patient prognosis and survival. The promising therapeutic potential unveiled by the pleiotropic nature of this receptor has prompted the development of distinct targeted intervention strategies. The present review will focus on recently emerged cytotoxic approaches emphasizing the novel technologies and related limits hindering their application in the clinical setting. Finally, future research directions and emerging opportunities in the field of uPAR targeting are also discussed.

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Spontaneous lung and lymph node metastasis in transgenic breast cancer is independent of the urokinase receptor uPAR

Cited by 6 publications

References 59 publications

Silencing of uPAR via RNA interference inhibits invasion and migration of oral tongue squamous cell carcinoma

Silencing of uPAR via RNA interference inhibits invasion and migration of oral tongue squamous cell carcinoma

Targeting the Urokinase-Type Plasminogen Activator Receptor (uPAR) in Human Diseases With a View to Non-invasive Imaging and Therapeutic Intervention

The Urokinase Receptor (uPAR) as a “Trojan Horse” in Targeted Cancer Therapy: Challenges and Opportunities

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