Elevated expression of polymorphonuclear leukocyte elastase in breast cancer tissue is associated with tamoxifen failure in patients with advanced disease

Besides a variety of other proteases, polymorphonuclear leukocyte elastase (PMN-E) is also suggested to play a role in the processes of tumour cell invasion and metastasis. Yet, there is only limited data available on the relation between the tumour level of PMN-E and prognosis in patients with primary breast cancer, and no published information exists on its relation with the efficacy of response to systemic therapy in patients with advanced breast cancer. In the present study, we have measured with enzyme-linked immunosorbent assay the levels of total PMN-E in cytosolic extracts of 463 primary breast tumours, and have correlated their levels with the rate and duration of response on first-line tamoxifen therapy (387 patients) or chemotherapy (76 patients) in patients with locally advanced and/or distant metastatic breast cancer. Furthermore, the probabilities of progression-free survival and postrelapse survival were studied in relation to the tumour levels of PMN-E. Our results show that in logistic regression analysis for response to tamoxifen treatment in patients with advanced disease, high PMN-E tumour levels were associated with a poor rate of response compared with those with low PMN-E levels (odds ratio: OR, 0.40; 95% CI, 0.22-0.73; P = 0.003). After correction for the contribution of the traditional predictive factors in multivariate analysis, the tumour PMN-E status was an independent predictor of response (P = 0.01). Furthermore, a high tumour PMN-E level was related with a poor progression-free survival (P<0.001) and postrelapse survival (P = 0.002) in a time-dependent analysis. In contrast, the tumour level of PMN-E was not significantly related with the efficacy of response to first-line chemotherapy in patients with advanced breast cancer. Our present results suggest that PMN-E is an independent predictive marker for the efficacy of tamoxifen treatment in patients with advanced breast cancer

Elevated serum neutrophil elastase is related to prehypertension and airflow limitation in obese women

<p>Abstract</p> <p>Background</p> <p>Neutrophil elastase level/activity is elevated in a variety of diseases such as atherosclerosis, systolic hypertension and obstructive pulmonary disease. It is unknown whether obese individuals with prehypertension also have elevated neutrophil elastase, and if so, whether it has a deleterious effect on pulmonary function. Objectives: To determine neutrophil elastase levels in obese prehypertensive women and investigate correlations with pulmonary function tests.</p> <p>Methods</p> <p>Thirty obese prehypertensive women were compared with 30 obese normotensive subjects and 30 healthy controls. The study groups were matched for age. Measurements: The following were determined: body mass index, waist circumference, blood pressure, lipid profile, high sensitivity C-reactive protein, serum neutrophil elastase, and pulmonary function tests including forced expiratory volume in one second (FEV₁), forced vital capacity (FVC) and FEV₁/FVC ratio.</p> <p>Results</p> <p>Serum neutrophil elastase concentration was significantly higher in both prehypertensive (405.8 ± 111.6 ng/ml) and normotensive (336.5 ± 81.5 ng/ml) obese women than in control non-obese women (243.9 ± 23.9 ng/ml); the level was significantly higher in the prehypertensive than the normotensive obese women. FEV1, FVC and FEV1/FVC ratio in both prehypertensive and normotensive obese women were significantly lower than in normal controls, but there was no statistically significant difference between the prehypertensive and normotensive obese women. In prehypertensive obese women, there were significant positive correlations between neutrophil elastase and body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, low density lipoprotein cholesterol, high sensitivity C-reactive protein and negative correlations with high density lipoprotein cholesterol, FEV1, FVC and FEV1/FVC.</p> <p>Conclusion</p> <p>Neutrophil elastase concentration is elevated in obese prehypertensive women along with an increase in high sensitivity C-reactive protein which may account for dyslipidemia and airflow dysfunction in the present study population.</p

Quantifying the Proteolytic Release of Extracellular Matrix-Sequestered VEGF with a Computational Model

BACKGROUND: VEGF proteolysis by plasmin or matrix metalloproteinases (MMPs) is believed to play an important role in regulating vascular patterning in vivo by releasing VEGF from the extracellular matrix (ECM). However, a quantitative understanding of the kinetics of VEGF cleavage and the efficiency of cell-mediated VEGF release is currently lacking. To address these uncertainties, we develop a molecular-detailed quantitative model of VEGF proteolysis, used here in the context of an endothelial sprout. METHODOLOGY AND FINDINGS: To study a cell's ability to cleave VEGF, the model captures MMP secretion, VEGF-ECM binding, VEGF proteolysis from VEGF165 to VEGF114 (the expected MMP cleavage product of VEGF165) and VEGF receptor-mediated recapture. Using experimental data, we estimated the effective bimolecular rate constant of VEGF165 cleavage by plasmin to be 328 M(-1) s(-1) at 25 degrees C, which is relatively slow compared to typical MMP-ECM proteolysis reactions. While previous studies have implicated cellular proteolysis in growth factor processing, we show that single cells do not individually have the capacity to cleave VEGF to any appreciable extent (less than 0.1% conversion). In addition, we find that a tip cell's receptor system will not efficiently recapture the cleaved VEGF due to an inability of cleaved VEGF to associate with Neuropilin-1. CONCLUSIONS: Overall, VEGF165 cleavage in vivo is likely to be mediated by the combined effect of numerous cells, instead of behaving in a single-cell-directed, autocrine manner. We show that heparan sulfate proteoglycans (HSPGs) potentiate VEGF cleavage by increasing the VEGF clearance time in tissues. In addition, we find that the VEGF-HSPG complex is more sensitive to proteases than is soluble VEGF, which may imply its potential relevance in receptor signaling. Finally, according to our calculations, experimentally measured soluble protease levels are approximately two orders of magnitude lower than that needed to reconcile levels of VEGF cleavage seen in pathological situations

Senescent cells as a source of inflammatory factors for tumor progression

Cellular senescence, which is associated with aging, is a process by which cells enter a state of permanent cell cycle arrest, therefore constituting a potent tumor suppressive mechanism. Recent studies show that, despite the beneficial effects of cellular senescence, senescent cells can also exert harmful effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescent-associated secretory phenotype (SASP), which entails a striking increase in the secretion of pro-inflammatory cytokines. Here, we summarize our knowledge of the SASP and the impact it has on tissue microenvironments and ability to stimulate tumor progression

Protéolyse dirigée par la matrice extracellulaire

18 Septembr