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Role of Blood Coagulation-Fibrinolytic System and Endothelial Cells in Malignancy
Published in László Muszbek, Hemostasis and Cancer, 2019
Besides, endothelial cells have other components either with anticoagulant character or with fibrinolytic activity. Several types of cells synthesize sulfated mucopolysaccharides, but only endothelial cells secrete a species of heparan sulfate with anticoagulant activity.36 Heparin also binds to endothelial cells,37 and this interaction may influence thrombin functions. Another mechanism by which endothelium is related to the resistance to thrombogenesis is the presence of an ectonucleotidase system on the cells, namely, nucleoside triphosphatase, diphosphatase, and 5′-nucleotidase catabolized ATP, ADP, and AMP, leading to adenosine formation.38,39 The reactions are stimulated by thrombin.40,41 This system may play a role in hemostasis, because ADP is an inducer of platelet aggregation, while adenosine is an inhibitor.42 The role of prostacycline as an anticoagulant, synthesized by endothelial cells, is discussed later. Endothelial cells contribute to the resolution of fibrin by plasmin via conversion of plasminogen by a plasminogen activator synthesized in these cells.43 The activator, with Mr 50,000, is membrane associated and is in the “latent” form intracellularly.44 While some tumor-promoting agents increase the rate of plasminogen activator production, thrombin may decrease it.45
Cell and Extracellular Matrix Interactions in a Dynamic Biomechanical Environment:
Published in Michel R. Labrosse, Cardiovascular Mechanics, 2018
Pathological cyclic stretch also works in concert with TGF-β1 to promote more collagen synthesis and αSMA expression than TGF-β1 or stretch alone (Merryman et al. 2007). Stretched VIC monolayers treated with TGF-β1 developed nodules that began as aggregates of apoptotic cells before developing into a necrotic core surrounded by apoptotic cells, mirroring dystrophic calcification (Fisher et al. 2013). Interestingly, cyclic stretch plays a key role in nodule growth by preventing cells from migrating out of the nodule. While Fisher proposed that the initiating event for apoptosis might be mechanical damage, cyclic stretch also promotes apoptotic cell signaling directly (Bouchareb et al. 2014). Pathological cyclic stretch increases ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), an ectonucleotidase enzyme, which causes apoptosis in VICs in vitro through a process that includes the formation of spheroid microparticles rich in calcium and phosphorus. These microparticles have been found in diseased valves colocalized with high ENPP1. Mechanical control of ENPP1 transport to the cell surface, its site of action, is controlled by the Rho/ROCK pathway, where ROCK inhibition prevents ENPP1 localization and stretch-induced mineralization.
Inorganic Chemical Pollutants
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
In addition to acting as a calcium channel blocker, gadolinium, at low concentration, can interact with the signaling involved in intracellular and extracellular ATP hydrolysis.589 Escalada et al.590 reported that 3 μM gadolinium, a concentration that does not block calcium channels, has a potent inhibitory action on ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) activity from the electric organ of Torpedo marmorata. Extracellular nucleotides are important molecules involved in the regulation of different biological processes, including vascular tone. When released as a neurotransmitter from the sympathetic terminals, ATP binds to P2X receptors of vascular smooth muscle cells, producing vasoconstriction. When binding to endothelial P2Y receptors, ATP leads to vasodilatation.589,591 ATP exerts other effects on the vascular beds, such as control of smooth muscle and endothelial cell proliferation.589,591 The action of extracellular nucleotides is terminated by the E-NTPDase family. NTPDase 1 is the major ectonucleotidase expressed in the vasculature589,591 and its action limits platelet activation by ATP hydrolysis.589,591 NTPDase 2 is another ectonucleotidase associated with the vasculature that preferentially converts ATP to ADP.592 Following the action of E-NTPDases, ecto-5′-nucleotidase is responsible for the end of nucleotide signaling by converting AMP to adenosine.593
Targeting the spectrum of immune checkpoints in prostate cancer
Published in Expert Review of Clinical Pharmacology, 2021
Laura A. Sena, Samuel R. Denmeade, Emmanuel S. Antonarakis
Damaged or dying tumor cells release ATP, which may function as a DAMP. Over time, ATP is converted to AMP and adenosine by ectonucleotidases, such as CD73, which subsequently suppress immune responses by binding the adenosine A2A receptor expressed on T cells and NK cells, and inhibiting effector function [126]. High CD73 expression in normal prostate epithelium adjacent to tumor correlated with shorter biochemical recurrence in patients who had prostatectomy [127], and CD73 expression in prostate tumor cells was enhanced in those known to have metastasized to lymph nodes [128]. Additionally, PAP can function as an ectonucleotidase to contribute to pools of adenosine in the prostate tumor microenvironment [129]. Multiple trials of A2A receptor inhibitors in combination with PD1 inhibitors and/or CD73 inhibitors are underway and listed in Table 1.
Post-thyroidectomy hypothyroidism increases the expression and activity of ectonucleotidases in platelets: Possible involvement of reactive oxygen species
Published in Platelets, 2018
Jucimara Baldissarelli, Micheli M. Pillat, Roberta Schmatz, Andréia M. Cardoso, Fátima H. Abdalla, Juliana S. de Oliveira, Carla R. N. Polachini, Emerson Casali, Clarissa Pereira Bornemann, Henning Ulrich, Vera M. Morsch, Maria R. C. Schetinger
Moreover, our correlation results demonstrated a weak Pearson’s correlation between ROS levels and TBARS or NPSH levels. Nevertheless, if analyzed together, it is possible to observe that the increased ROS levels correlate positively or negatively with all other oxidative parameters. In addition, it should be highlighted that nucleotides can also be released in response to cellular damage from oxidative injury and thus the remarkable degree of oxidative stress in patients might be due to the increased release of nucleotides by the body, which also caused an increase in ectonucleotidase activity, demonstrated by the positive correlation between ROS production and enzyme activities, which was confirmed by our results (Figure 8). Thus, we can conclude that enzymatic activity is modulated to offset the pathological release of nucleotides and to maintain homeostasis.
Ectonucleotidase CD39 expression in regional metastases in head and neck cancer
Published in Acta Oto-Laryngologica, 2018
Magis Mandapathil, Mehtap Boduc, Marion Roessler, Christian Güldner, Ute Walliczek-Dworschak, Robert Mandic
The underlying mechanisms of CD39 overexpression in different types of cells, including its role in tumor progression, are not fully understood. Some studies have suggested that CD39 mediates the promotion of tumor growth and metastases by suppressing antitumor immune responses and promoting neoangiogenesis [15]. Extracellular ATP, which is effectively metabolized by CD39, directly suppresses tumor cell growth. Therefore, activity of CD39 in this setting in the tumor microenvironment already favors tumor cell growth. Further, adenosine the end product of ectonucleotidase activities has been described to mediate immunosuppressive effects in various ways, for example, suppressing effector T cell functions through adenosine 2a (A2a) receptor signaling with subsequent intracellular elevation of cycling AMP (cAMP) [7,16,17]. cAMP has been shown to be a crucial regulator of CD39 expression by acting through the PKA/CREB, PKA/PI3K/ATF2 and PKA/ERK/ATF2 pathways [18].