Urokinase-type plasminogen activator in carcinomatous pleural fluid

Ishikawa, Hiroichi; Satoh, Hiroaki; Hasegawa, Shizuo; Yazawa, Takuya; Naito, Takashi; Yt, Yamashita; Ohtsuka, Morio; Ogata, Tsutomu; Kamma, Hiroshi

doi:10.1183/09031936.97.10071566

Cited by 11 publications

(8 citation statements)

References 20 publications

(24 reference statements)

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“…The differences in uPA expression correlated with the biological behavior of the tumor cells. Consistent with a previous report showing that malignant PE contains high levels of uPA, 39 the PC14PE6 cells expressed a high level of uPA, whereas the H226 cells did not (Figure 3). Further determination of the role of uPA in invasion of lung cancer cells and formation of PE is underway.…”

Section: Discussionsupporting

confidence: 93%

Production of Experimental Malignant Pleural Effusions Is Dependent on Invasion of the Pleura and Expression of Vascular Endothelial Growth Factor/Vascular Permeability Factor by Human Lung Cancer Cells

Yano

Shinohara

Herbst

et al. 2000

The American Journal of Pathology

137

119

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We determined the molecular mechanisms that regulate the pathogenesis of malignant pleural effusion (PE) associated with advanced stage of human, non-small-cell lung cancer. Intravenous injection of human PC14 and PC14PE6 (adenocarcinoma) or H226 (squamous cell carcinoma) cells into nude mice yielded numerous lung lesions. PC14 and PC14PE6 lung lesions invaded the pleura and produced PE containing a high level of vascular endothelial growth factor (VEGF)-localized vascular hyperpermeability. Lung lesions produced by H226 cells were confined to the lung parenchyma with no PE. The level of expression of VEGF mRNA and protein by the cell lines directly correlated with extent of PE formation. Transfection of PC14PE6 cells with antisense VEGF165 gene did not inhibit invasion into the pleural space but reduced PE formation. H226 cells transfected with either sense VEGF 165 or sense VEGF 121 genes induced localized vascular hyperpermeability and produced PE only after direct implantation into the thoracic cavity. The production of PE was thus associated with the ability of tumor cells to invade the pleura, a property associated with expression of high levels of urokinase-type plasminogen activator and low levels of TIMP-2. Collectively, the data demonstrate that the production of malignant PE requires tumor cells to invade the pleura and express high levels of VEGF/VPF.

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Section: Discussionsupporting

confidence: 93%

Production of Experimental Malignant Pleural Effusions Is Dependent on Invasion of the Pleura and Expression of Vascular Endothelial Growth Factor/Vascular Permeability Factor by Human Lung Cancer Cells

Yano

Shinohara

Herbst

et al. 2000

The American Journal of Pathology

137

119

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“…Vascular endothelial growth factor (VEGF) can increase vascular permeability and the proliferation and migration of endothelial cells. Both OPN and VEGF are involved in the production of urokinase-type plasminogen activator (uPA) and the formation of MPE [ 7 – 10 ].…”

Section: Introductionmentioning

confidence: 99%

Pleural fluid osteopontin, vascular endothelial growth factor, and urokinase-type plasminogen activator levels as predictors of pleurodesis outcome and prognosticators in patients with malignant pleural effusion: a prospective cohort study

Hsu

Liao

et al. 2016

BMC Cancer

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BackgroundRapidly growing cancer cells secrete growth-promoting polypeptides and have increased proteolytic activity, contributing to tumor progression and metastasis. Their presentation in malignant pleural effusion (MPE) and their predictive value for the outcome of pleurodesis and survival were studied.MethodsBetween February 2011 and March 2012, MPE samples were prospectively collected from 61 patients. Twenty-five patients with non-malignant pleural effusion in the same period were included as controls. Pleural fluid osteopontin (OPN), vascular endothelial growth factor (VEGF), and urokinase-type plasminogen activator (uPA) concentrations were measured.ResultsPatients with MPE had higher pleural fluid OPN, VEGF, and uPA concentrations than those with non-malignant pleural effusion, but only differences in VEGF were statistically significant (p = 0.045). Patients with distant metastases had significantly elevated pleural fluid VEGF concentrations than those without (p = 0.004). Pleural fluid OPN, VEGF, and uPA concentrations were positively correlated in most patients. However, there was no significant difference in pleural fluid OPN, VEGF, and uPA concentrations between patients with successful pleurodesis and those without. There was also no significant difference in cancer-specific survival between sub-groups with higher and lower pleural fluid OPN, VEGF, or uPA concentrations. Patients with successful pleurodesis had significantly longer cancer-specific survival than those without (p = 0.015).ConclusionsPleural fluid OPN, VEGF, and uPA concentrations are elevated in MPE but are not satisfactory predictors of pleurodesis outcome or survival. Patients with higher pleural fluid VEGF concentration have higher risk of distant metastasis. Evaluating the benefits of therapy targeting the VEGF pathway in these patients warrants further studies.

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“…Single-chain urokinase induces sustained local fibrinolysis and reversibly prevents pleural loculation for up to 48 h after intrapleural administration after tetracycline-induced injury. pleurodesis; pleuritis; loculation; fibrinolysis ABERRANT FIBRIN TURNOVER and intrapleural fibrin deposition are strongly implicated in the pathogenesis of pleural loculation and fibrosis (1,7,14,16). Adhesions between the visceral and parietal pleural surfaces begin to form after 24 h following acute pleural injury induced by intrapleural administration of tetracycline (TCN) in rabbits and are primarily composed of fibrin (14).…”

mentioning

confidence: 99%

Intrapleural activation, processing, efficacy, and duration of protection of single-chain urokinase in evolving tetracycline-induced pleural injury in rabbits

Idell¹,

Allen²,

Chen³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Intrapleural fibrinolysins have been used to treat pleural loculations. However, the efficacy of clinically available agents has recently been questioned, providing a rationale for investigation of new interventions. Single-chain urokinase plasminogen activator resists inhibition by serpins, and repeated, daily intrapleural administration of this agent prevents intrapleural loculation more effectively than complexes of this proenzyme with its receptor (Idell S, Mazar A, Cines D, Kuo A, Parry G, Gawlak S, Juarez J, Koenig K, Azghani A, Hadden W, McLarty J, Miller E. Am J Respir Crit Care Med 166: 920-926, 2002). Understanding of the protective mechanism and intrapleural processing remains unclear. We speculated that single-chain urokinase could induce sustained local fibrinolysis and protection by selective administration either before, during, or following loculation after pleural injury induced by tetracycline in rabbits. Enzymography, immunoassays, histology, immunohistochemistry, morphology, and morphometry were used to test the efficacy, duration of protective effect, and processing of single-chain urokinase. Intrapleural single chain urokinase prevented loculation at 72 h after injury (P < 0.01) if given either before or during adhesion formation and was converted to two-chain high-molecular-weight urokinase, which remained active for at least 24 h within pleural fluids. The effect was dose dependent, and established loculations at 72 h after tetracycline-induced injury were reversed at 96 h by single-dose treatment. Single-chain urokinase bound and saturated intrapleural plasminogen activator inhibitory (PAI)-1-like activity and urokinase-related immunoreactivity of the mesothelium was comparable in treatment or vehicle-control groups. Adhesions recurred by 2 wk after treatment with recurrence of excess local PAI activity. Single-chain urokinase induces sustained local fibrinolysis and reversibly prevents pleural loculation for up to 48 h after intrapleural administration after tetracycline-induced injury.

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Urokinase-type plasminogen activator in carcinomatous pleural fluid

Cited by 11 publications

References 20 publications

Production of Experimental Malignant Pleural Effusions Is Dependent on Invasion of the Pleura and Expression of Vascular Endothelial Growth Factor/Vascular Permeability Factor by Human Lung Cancer Cells

Production of Experimental Malignant Pleural Effusions Is Dependent on Invasion of the Pleura and Expression of Vascular Endothelial Growth Factor/Vascular Permeability Factor by Human Lung Cancer Cells

Pleural fluid osteopontin, vascular endothelial growth factor, and urokinase-type plasminogen activator levels as predictors of pleurodesis outcome and prognosticators in patients with malignant pleural effusion: a prospective cohort study

Intrapleural activation, processing, efficacy, and duration of protection of single-chain urokinase in evolving tetracycline-induced pleural injury in rabbits

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