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Cancer Cell Aug 2023Radiation therapy (RT) provides therapeutic benefits for patients with glioblastoma (GBM), but inevitably induces poorly understood global changes in GBM and its...
Radiation therapy (RT) provides therapeutic benefits for patients with glioblastoma (GBM), but inevitably induces poorly understood global changes in GBM and its microenvironment (TME) that promote radio-resistance and recurrence. Through a cell surface marker screen, we identified that CD142 (tissue factor or F3) is robustly induced in the senescence-associated β-galactosidase (SA-βGal)-positive GBM cells after irradiation. F3 promotes clonal expansion of irradiated SA-βGal GBM cells and orchestrates oncogenic TME remodeling by activating both tumor-autonomous signaling and extrinsic coagulation pathways. Intratumoral F3 signaling induces a mesenchymal-like cell state transition and elevated chemokine secretion. Simultaneously, F3-mediated focal hypercoagulation states lead to activation of tumor-associated macrophages (TAMs) and extracellular matrix (ECM) remodeling. A newly developed F3-targeting agent potently inhibits the aforementioned oncogenic events and impedes tumor relapse in vivo. These findings support F3 as a critical regulator for therapeutic resistance and oncogenic senescence in GBM, opening potential therapeutic avenues.
Topics: Humans; Glioblastoma; Thromboplastin; Cell Line, Tumor; Neoplasm Recurrence, Local; Signal Transduction; Brain Neoplasms; Tumor Microenvironment
PubMed: 37451272
DOI: 10.1016/j.ccell.2023.06.007 -
ESMO Open Oct 2022Despite screening programs for early detection and the approval of human papillomavirus vaccines, around 6% of women with cervical cancer (CC) are discovered with... (Review)
Review
Despite screening programs for early detection and the approval of human papillomavirus vaccines, around 6% of women with cervical cancer (CC) are discovered with primary metastatic disease. Moreover, one-third of the patients receiving chemoradiation followed by brachytherapy for locally advanced disease will have a recurrence. At the end, the vast majority of recurrent or metastatic CC not amenable to locoregional treatments are considered incurable disease with very poor prognosis. Historically, cisplatin monotherapy, then a combination of cisplatin and paclitaxel were considered the standard of care. Ten years ago, the addition of bevacizumab to chemotherapy demonstrated favorable data in terms of response rate and overall survival. Even with this improvement, novel therapies are needed for the treatment of recurrent CC in first as well as later lines. In the last decades, a better understanding of the interactions between human papillomavirus infection and the host immune system response has focused interest on the use of immunotherapeutic drugs in CC patients. Indeed, immune checkpoint inhibitors (pembrolizumab, cemiplimab, and others) have recently emerged as novel therapeutic pillars that could provide durable responses with impact on overall survival in patients in the primary (in addition to chemotherapy) or recurrent (monotherapy) settings. Tisotumab vedotin, an antibody-drug conjugate targeting the tissue factor, is another emerging drug. Several trials in monotherapy or in combination with immunotherapy, chemotherapy, or bevacizumab showed very promising results. There is a high need for more potent biomarkers to better accurately determine which patients would receive the greatest benefit from all these aforementioned drugs, but also to identify patients with specific molecular characteristics that could benefit from other targeted therapies. The Cancer Genome Atlas Research Network identified several genes significantly mutated, potentially targetable. These molecular data have highlighted the molecular heterogeneity of CC.
Topics: Humans; Female; Uterine Cervical Neoplasms; Bevacizumab; Cisplatin; Immune Checkpoint Inhibitors; Thromboplastin; Neoplasm Recurrence, Local; Paclitaxel; Biomarkers; Papillomavirus Vaccines; Immunoconjugates
PubMed: 36108558
DOI: 10.1016/j.esmoop.2022.100579 -
The Journal of Clinical Investigation Nov 2020Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby... (Clinical Trial)
Clinical Trial
Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.
Topics: Aged; Betacoronavirus; COVID-19; Complement Activation; Complement Membrane Attack Complex; Coronavirus Infections; Extracellular Traps; Female; Humans; Male; Middle Aged; Neutrophils; Pandemics; Peptides, Cyclic; Pneumonia, Viral; Receptor, Anaphylatoxin C5a; Respiratory Distress Syndrome; SARS-CoV-2; Thrombin; Thromboplastin; Thrombosis
PubMed: 32759504
DOI: 10.1172/JCI141374 -
Immunity Dec 2019Excessive activation of the coagulation system leads to life-threatening disseminated intravascular coagulation (DIC). Here, we examined the mechanisms underlying the...
Excessive activation of the coagulation system leads to life-threatening disseminated intravascular coagulation (DIC). Here, we examined the mechanisms underlying the activation of coagulation by lipopolysaccharide (LPS), the major cell-wall component of Gram-negative bacteria. We found that caspase-11, a cytosolic LPS receptor, activated the coagulation cascade. Caspase-11 enhanced the activation of tissue factor (TF), an initiator of coagulation, through triggering the formation of gasdermin D (GSDMD) pores and subsequent phosphatidylserine exposure, in a manner independent of cell death. GSDMD pores mediated calcium influx, which induced phosphatidylserine exposure through transmembrane protein 16F, a calcium-dependent phospholipid scramblase. Deletion of Casp11, ablation of Gsdmd, or neutralization of phosphatidylserine or TF prevented LPS-induced DIC. In septic patients, plasma concentrations of interleukin (IL)-1α and IL-1β, biomarkers of GSDMD activation, correlated with phosphatidylserine exposure in peripheral leukocytes and DIC scores. Our findings mechanistically link immune recognition of LPS to coagulation, with implications for the treatment of DIC.
Topics: Animals; Blood Coagulation; Caspases, Initiator; Cell Line, Tumor; Disseminated Intravascular Coagulation; Endotoxemia; Enzyme Activation; HT29 Cells; HeLa Cells; Humans; Interleukin-1alpha; Interleukin-1beta; Intracellular Signaling Peptides and Proteins; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphate-Binding Proteins; Phosphatidylserines; Pyroptosis; Signal Transduction; Thromboplastin
PubMed: 31836429
DOI: 10.1016/j.immuni.2019.11.005 -
Immunity Jun 2019Inflammasome activation and subsequent pyroptosis are critical defense mechanisms against microbes. However, overactivation of inflammasome leads to death of the host....
Inflammasome activation and subsequent pyroptosis are critical defense mechanisms against microbes. However, overactivation of inflammasome leads to death of the host. Although recent studies have uncovered the mechanism of pyroptosis following inflammasome activation, how pyroptotic cell death drives pathogenesis, eventually leading to death of the host, is unknown. Here, we identified inflammasome activation as a trigger for blood clotting through pyroptosis. We have shown that canonical inflammasome activation by the conserved type III secretion system (T3SS) rod proteins from Gram-negative bacteria or noncanonical inflammasome activation by lipopolysaccharide (LPS) induced systemic blood clotting and massive thrombosis in tissues. Following inflammasome activation, pyroptotic macrophages released tissue factor (TF), an essential initiator of coagulation cascades. Genetic or pharmacological inhibition of TF abolishes inflammasome-mediated blood clotting and protects against death. Our data reveal that blood clotting is the major cause of host death following inflammasome activation and demonstrate that inflammasome bridges inflammation with thrombosis.
Topics: Animals; Bacterial Infections; Biomarkers; Blood Coagulation; Caspases; Cell-Derived Microparticles; Disease Models, Animal; Humans; Inflammasomes; Lipopolysaccharides; Macrophages; Mice; Monocytes; Pyroptosis; Signal Transduction; Thromboplastin; Thrombosis
PubMed: 31076358
DOI: 10.1016/j.immuni.2019.04.003 -
Biomolecules Oct 2021SARS-CoV-2 contains certain molecules that are related to the presence of immunothrombosis. Here, we review the pathogen and damage-associated molecular patterns. We... (Review)
Review
SARS-CoV-2 contains certain molecules that are related to the presence of immunothrombosis. Here, we review the pathogen and damage-associated molecular patterns. We also study the imbalance of different molecules participating in immunothrombosis, such as tissue factor, factors of the contact system, histones, and the role of cells, such as endothelial cells, platelets, and neutrophil extracellular traps. Regarding the pathogenetic mechanism, we discuss clinical trials, case-control studies, comparative and translational studies, and observational studies of regulatory or inhibitory molecules, more specifically, extracellular DNA and RNA, histones, sensors for RNA and DNA, as well as heparin and heparinoids. Overall, it appears that a network of cells and molecules identified in this axis is simultaneously but differentially affecting patients at different stages of COVID-19, and this is characterized by endothelial damage, microthrombosis, and inflammation.
Topics: Alarmins; Angiotensin-Converting Enzyme 2; Animals; Blood Coagulation; Blood Platelets; COVID-19; DNA; Extracellular Traps; Heparin; Histones; Humans; Mice; Neuropilin-1; RNA; SARS-CoV-2; Signal Transduction; Thrombin; Thromboinflammation; Thromboplastin; Thrombosis
PubMed: 34827548
DOI: 10.3390/biom11111550 -
Journal of Thrombosis and Haemostasis :... Jun 2022Tissue factor pathway inhibitor (TFPI) is an alternatively spliced anticoagulant protein that primarily dampens the initiation phase of coagulation before thrombin is... (Review)
Review
Tissue factor pathway inhibitor (TFPI) is an alternatively spliced anticoagulant protein that primarily dampens the initiation phase of coagulation before thrombin is generated. As such, TFPI's actions are localized to cells expressing TF and to sites of injury, where it is an important regulator of bleeding in hemophilia. The major splice isoforms TFPIα and TFPIβ localize to different sites within and surrounding the vasculature. Both forms directly inhibit factor Xa (FXa) via their Kunitz 2 domain and inhibit TF-FVIIa via their Kunitz 1 domain in a tight complex primarily localized to cells. By forming complexes localized to distinct cellular microenvironments and engaging additional cell surface receptors, TFPI alters cellular trafficking and signaling pathways driven by coagulation proteases of the TF pathway. TFPIα, which circulates in complex with FV and protein S, also serves an inhibitor of FXa independent of the TF initiation complex and prevents the formation of an active prothrombinase. This regulation of thrombin generation in the context of vessel injury is effectively blocked by antibodies to Kunitz 2 domain of TFPI and exploited as a therapy to restore efficient hemostasis in hemophilia.
Topics: Blood Coagulation; Factor Xa; Hemophilia A; Humans; Lipoproteins; Thrombin; Thromboplastin
PubMed: 35279938
DOI: 10.1111/jth.15697 -
JCI Insight Sep 2021Innate immunity and chronic inflammation are involved in atherosclerosis and atherothrombosis, leading to target organ damage in essential hypertension (EH). However,...
Innate immunity and chronic inflammation are involved in atherosclerosis and atherothrombosis, leading to target organ damage in essential hypertension (EH). However, the role of neutrophils in EH is still elusive. We investigated the association between angiotensin II (Ang II) and neutrophil extracellular traps (NETs) in pathogenesis of EH. Plasma samples, kidney biopsies, and surgical specimens of abdominal aortic aneurysms (AAAs) from patients with EH were used. Cell-based assays, NETs/human aortic endothelial cell cocultures, and in situ studies were performed. Increased plasma levels of NETs and tissue factor (TF) activity were detected in untreated, newly diagnosed patients with EH. Stimulation of control neutrophils with plasma from patients with untreated EH generated TF-enriched NETs promoting endothelial collagen production. Ang II induced NETosis in vitro via an ROS/peptidylarginine deiminase type 4 and autophagy-dependent pathway. Circulating NETs and thrombin generation levels were reduced substantially in patients with EH starting treatment with Ang II receptor blockers, whereas their plasma was unable to trigger procoagulant NETs. Moreover, TF-bearing NETotic neutrophils/remnants accumulated in sites of interstitial renal fibrosis and in the subendothelial layer of AAAs. These data reveal the important pathogenic role of an Ang II/ROS/NET/TF axis in EH, linking thromboinflammation with endothelial dysfunction and fibrosis.
Topics: Angiotensin II; Angiotensin Receptor Antagonists; Aortic Aneurysm, Abdominal; Autophagy; Case-Control Studies; Cells, Cultured; Coculture Techniques; Collagen; Endothelium; Essential Hypertension; Extracellular Traps; Humans; Kidney; Neutrophils; Reactive Oxygen Species; Thrombin; Thromboinflammation; Thromboplastin; Vasoconstrictor Agents
PubMed: 34324440
DOI: 10.1172/jci.insight.148668 -
Blood Jun 2022
Topics: Cryoelectron Microscopy; Factor V; Factor X; Factor Xa; Prothrombin; Thrombin; Thromboplastin
PubMed: 35708725
DOI: 10.1182/blood.2022016537