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The Role of Tissue Factor and Downstream Coagulation Proteases in...
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The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 42187

Special Issue Editor

Prof. Dr. Florian Langer

E-Mail Website
Guest Editor
Department of Hematology and Oncology, University Cancer Center Hamburg (UCCH), University Medical Center Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
Interests: cancer & thrombosis, anticoagulation, tissue factor, platelets, hemophilia

Special Issue Information

Dear Colleagues,

In 1865, the French physician Armand Trousseau described the association between gastrointestinal cancer and superficial migratory thrombophlebitis. Trousseau himself succumbed to gastric or pancreatic cancer after he noticed an inflamed and thrombosed vein, nowadays referred to as the "Trousseau’s sign of malignancy." More than 150 years later, gastric and pancreatic cancer are still considered the most thrombogenic tumor entities, and tissue factor (TF) has been identified as a key player mediating paraneoplastic coagulation activation.

TF is a transmembrane glycoprotein that functions as the cellular receptor and cofactor for the coagulation serine protease, factor VIIa (FVIIa). TF is constitutively expressed by many cancer cells and may also be induced in non-transformed cells of the tumor microenvironment under inflammatory or hypoxic conditions. Over the last few decades, tremendous progress has been made in our understanding of how TF promotes not only thrombin generation and fibrin formation, the key events underlying cancer-associated thrombosis (CAT), but also primary tumor growth and hematogenous metastasis. Pro-inflammatory and pro-angiogenic cell signaling by TF/FVIIa and TF/FVIIa/FXa complexes through cleavage activation of protease-activated receptors (PARs) as well as downstream generation of coagulation proteases such as thrombin represent promising targets for both anti-cancer therapy and CAT management. Moreover, circulating TF has emerged as a potential diagnostic, prognostic and predictive biomarker in solid cancers and hematological malignancies.

This Special Issue of Cancers focuses on the intriguing roles of TF and downstream coagulation proteases in tumor biology and paraneoplastic clotting abnormalities, thus setting the base for future experimental and clinical research investigating the detrimental bidirectional relationships between cancer, inflammation and thrombosis.

Prof. Dr. Florian Langer
Guest Editor

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Keywords

  • PAR signaling 
  • Angiogenesis 
  • Hematogenous Metastasis 
  • Venous thromboembolism 
  • Disseminated intravascular coagulation 
  • Prediction of CAT

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Published Papers (15 papers)

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Research

Jump to: Review

17 pages, 3584 KiB  
Article
TF/PAR2 Signaling Axis Supports the Protumor Effect of Neutrophil Extracellular Traps (NETs) on Human Breast Cancer Cells
by Karina Martins-Cardoso, Aquiles Maçao, Juliana L. Souza, Alexander G. Silva, Sandra König, Remy Martins-Gonçalves, Eugenio D. Hottz, Araci M. R. Rondon, Henri H. Versteeg, Patrícia T. Bozza, Vitor H. Almeida and Robson Q. Monteiro
Cancers 2024, 16(1), 5; https://doi.org/10.3390/cancers16010005 - 19 Dec 2023
Cited by 2 | Viewed by 1763
Abstract
Neutrophil extracellular traps (NETs) have been implicated in several hallmarks of cancer. Among the protumor effects, NETs promote epithelial-mesenchymal transition (EMT) in different cancer models. EMT has been linked to an enhanced expression of the clotting-initiating protein, tissue factor (TF), thus favoring the [...] Read more.
Neutrophil extracellular traps (NETs) have been implicated in several hallmarks of cancer. Among the protumor effects, NETs promote epithelial-mesenchymal transition (EMT) in different cancer models. EMT has been linked to an enhanced expression of the clotting-initiating protein, tissue factor (TF), thus favoring the metastatic potential. TF may also exert protumor effects by facilitating the activation of protease-activated receptor 2 (PAR2). Herein, we evaluated whether NETs could induce TF expression in breast cancer cells and further promote procoagulant and intracellular signaling effects via the TF/PAR2 axis. T-47D and MCF7 cell lines were treated with isolated NETs, and samples were obtained for real-time PCR, flow cytometry, Western blotting, and plasma coagulation assays. In silico analyses were performed employing RNA-seq data from breast cancer patients deposited in The Cancer Genome Atlas (TCGA) database. A positive correlation was observed between neutrophil/NETs gene signatures and TF gene expression. Neutrophils/NETs gene signatures and PAR2 gene expression also showed a significant positive correlation in the bioinformatics model. In vitro analysis showed that treatment with NETs upregulated TF gene and protein expression in breast cancer cell lines. The inhibition of ERK/JNK reduced the TF gene expression induced by NETs. Remarkably, the pharmacological or genetic inhibition of the TF/PAR2 signaling axis attenuated the NETs-induced expression of several protumor genes. Also, treatment of NETs with a neutrophil elastase inhibitor reduced the expression of metastasis-related genes. Our results suggest that the TF/PAR2 signaling axis contributes to the pro-cancer effects of NETs in human breast cancer cells. Full article
(This article belongs to the Special Issue The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies)
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10 pages, 984 KiB  
Article
Plasma Clot Properties in Patients with Pancreatic Cancer
by Johannes Thaler, Gerald Prager, Ingrid Pabinger and Cihan Ay
Cancers 2023, 15(16), 4030; https://doi.org/10.3390/cancers15164030 - 9 Aug 2023
Viewed by 1055
Abstract
Pancreatic cancer is one of the most prothrombotic malignancies. Plasma clot properties may be altered in patients with pancreatic cancer, and circulating tissue factor (TF) may play an important role. We applied a modified plasma clot formation assay (only CaCl2 and phospholipids [...] Read more.
Pancreatic cancer is one of the most prothrombotic malignancies. Plasma clot properties may be altered in patients with pancreatic cancer, and circulating tissue factor (TF) may play an important role. We applied a modified plasma clot formation assay (only CaCl2 and phospholipids were added to initiate clotting) and a standard clotting assay (lipidated TF was also added) to investigate whether plasma clot properties are altered in pancreatic cancer patients (n = 40, 23 female) compared to sex-matched healthy controls. The modified assay was also performed in the presence of a TF blocking antibody. With this modified assay, we detected an increased plasma clot formation rate (Vmax) and an increased delta absorbance (ΔAbs, indicating fibrin fiber thickness) in patients compared to controls. These differences were not detected with the standard clotting assay. Following addition of a TF blocking antibody in in our modified assay, Vmax decreased significantly in patients only, ΔAbs significantly decreased in patients and in healthy controls, the lag phase did not change, and the time to peak fibrin generation increased in patients only. Taken together, these findings indicate the presence of a prothrombotic state in pancreatic cancer patients, which depends on TF and is detectable with our modified assay but not with a standard clotting assay. Full article
(This article belongs to the Special Issue The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies)
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13 pages, 6146 KiB  
Article
Temozolomide and Lomustine Induce Tissue Factor Expression and Procoagulant Activity in Glioblastoma Cells In Vitro
by Maaike Y. Kapteijn, Shanna Zwaan, Esther ter Linden, El Houari Laghmani, Rob F. P. van den Akker, Araci M. R. Rondon, Sabina Y. van der Zanden, Jacques Neefjes, Henri H. Versteeg and Jeroen T. Buijs
Cancers 2023, 15(8), 2347; https://doi.org/10.3390/cancers15082347 - 18 Apr 2023
Cited by 4 | Viewed by 2093
Abstract
Glioblastoma (GBM) patients have one of the highest risks of venous thromboembolism (VTE), which is even further increased upon treatment with chemotherapy. Tissue factor (TF) is the initiator of the extrinsic coagulation pathway and expressed by GBM cells. In this study, we aimed [...] Read more.
Glioblastoma (GBM) patients have one of the highest risks of venous thromboembolism (VTE), which is even further increased upon treatment with chemotherapy. Tissue factor (TF) is the initiator of the extrinsic coagulation pathway and expressed by GBM cells. In this study, we aimed to examine the effect of routinely used chemotherapeutic agents Temozolomide (TMZ) and Lomustine (LOM) on TF procoagulant activity and expression in GBM cells in vitro. Three human GBM cell lines (U-251, U-87, U-118) were exposed to 100 µM TMZ or 30 µM LOM for 72 h. TF procoagulant activity was assessed via an FXa generation assay and TF gene and protein expression through qPCR and Western blotting. The externalization of phosphatidylserine (PS) was studied using Annexin V flow cytometry. Treatment with TMZ and LOM resulted in increased procoagulant activity in all cell lines. Furthermore, both agents induced procoagulant activity in the supernatant and tumor-cell-secreted extracellular vesicles. In line, TF gene and protein expression were increased upon TMZ and LOM treatment. Additionally, PS externalization and induction of inflammatory-associated genes were observed. Overall, the chemotherapeutic modalities TMZ and LOM induced procoagulant activity and increased TF gene and protein expression in all GBM cell lines tested, which may contribute to the increased VTE risk observed in GBM patients undergoing chemotherapy. Full article
(This article belongs to the Special Issue The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies)
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11 pages, 451 KiB  
Article
Thrombin Generation and D-Dimer for Prediction of Disease Progression and Mortality in Patients with Metastatic Gastrointestinal Cancer
by Cinzia Giaccherini, Cristina Verzeroli, Laura Russo, Sara Gamba, Carmen Julia Tartari, Silvia Bolognini, Francesca Schieppati, Chiara Ticozzi, Roberta Sarmiento, Luigi Celio, Giovanna Masci, Carlo Tondini, Fausto Petrelli, Francesco Giuliani, Andrea D’Alessio, Filippo De Braud, Armando Santoro, Roberto Labianca, Giampietro Gasparini, Marina Marchetti and Anna Falangaadd Show full author list remove Hide full author list
Cancers 2022, 14(18), 4347; https://doi.org/10.3390/cancers14184347 - 6 Sep 2022
Cited by 6 | Viewed by 2208
Abstract
Background: the tight and reciprocal interaction between cancer and hemostasis has stimulated investigations on the possible role of hemostatic biomarkers in predicting specific cancer outcomes, such as disease progression (DP) and overall survival (OS). In a prospective cohort of newly diagnosed metastatic gastrointestinal [...] Read more.
Background: the tight and reciprocal interaction between cancer and hemostasis has stimulated investigations on the possible role of hemostatic biomarkers in predicting specific cancer outcomes, such as disease progression (DP) and overall survival (OS). In a prospective cohort of newly diagnosed metastatic gastrointestinal (GI) cancer patients from the HYPERCAN study, we aimed to assess whether the hemostatic biomarker levels measured before starting any anticancer therapy may specifically predict for 6-months DP (6m-DP) and for 1-year OS (1y OS). Methods: plasma samples were collected and tested for thrombin generation (TG) as global hemostatic assay, and for D-dimer, fibrinogen, and prothrombin fragment 1 + 2 as hypercoagulation biomarkers. DP and mortality were monitored during follow-up. Results: A prospective cohort of 462 colorectal and 164 gastric cancer patients was available for analysis. After 6 months, DP occurred in 148 patients, providing a cumulative incidence of 24.8% (21.4–28.4). D-dimer and TG endogenous thrombin potential (ETP) were identified as independent risk factors for 6m-DP by multivariate Fine–Gray proportional hazard regression model corrected for age, cancer site, and >1 metastatic site. After 1 year, we observed an OS of 75.7% (71.9–79.0). Multivariate Cox regression analysis corrected for age, site of cancer, and performance status identified D-dimer and ETP as independent risk factors for 1y OS. Patients with one or both hemostatic parameters above the dichotomizing threshold were at higher risk for both 6m-DP and 1-year mortality. Conclusion.: in newly diagnosed metastatic GI cancer patients, pretreatment ETP and D-dimer appear promising candidate biomarkers for predicting 6m-DP and 1y OS. In this setting, for the first time, the role of TG as a prognostic biomarker emerges in a large prospective cohort. Full article
(This article belongs to the Special Issue The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies)
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16 pages, 2206 KiB  
Article
Regulation of Tissue Factor by CD44 Supports Coagulant Activity in Breast Tumor Cells
by Amélie V. Villard, Anthony Genna, Justine Lambert, Marianna Volpert, Agnès Noël, Brett Hollier, Myriam Polette, Aline M. Vanwynsberghe and Christine Gilles
Cancers 2022, 14(13), 3288; https://doi.org/10.3390/cancers14133288 - 5 Jul 2022
Cited by 4 | Viewed by 2547
Abstract
Previous work identified Tissue Factor (TF), a key activator of the coagulation cascade, as a gene induced in cellular contexts of Epithelial-Mesenchymal Transitions (EMTs), providing EMT+ Circulating Tumor Cells (CTCs) with coagulant properties that facilitate their metastatic seeding. Deciphering further molecular aspects [...] Read more.
Previous work identified Tissue Factor (TF), a key activator of the coagulation cascade, as a gene induced in cellular contexts of Epithelial-Mesenchymal Transitions (EMTs), providing EMT+ Circulating Tumor Cells (CTCs) with coagulant properties that facilitate their metastatic seeding. Deciphering further molecular aspects of TF regulation in tumor cells, we report here that CD44 and TF coexpress in EMT contexts, and that CD44 acts as a regulator of TF expression supporting procoagulant properties and metastatic seeding. A transcriptional regulatory mechanism bridging CD44 to TF expression was further evidenced. Comparing different TF –promoter luciferase reporter constructs, we indeed found that the shortest -111 pb TF promoter fragment harboring three Specificity Protein 1 (Sp1) binding sites is still responsive to CD44 silencing. The observation that (i) mutation within Sp1 binding sites decreased the basal activity of the -111 pb TF promoter construct, (ii) CD44 silencing decreased Sp1 protein and mRNA levels and (iii) Sp1 silencing diminished TF expression further points to Sp1 as a key mediator linking CD44 to TF regulation. All together, these data thus report a transcriptional regulatory mechanism of TF expression by CD44 supporting procoagulant activity and metastatic competence of CTCs. Full article
(This article belongs to the Special Issue The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies)
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18 pages, 1695 KiB  
Article
Bacitracin and Rutin Regulate Tissue Factor Production in Inflammatory Monocytes and Acute Myeloid Leukemia Blasts
by Lennart Beckmann, Christina Charlotte Rolling, Minna Voigtländer, Jonathan Mäder, Felix Klingler, Anita Schulenkorf, Carina Lehr, Carsten Bokemeyer, Wolfram Ruf and Florian Langer
Cancers 2021, 13(16), 3941; https://doi.org/10.3390/cancers13163941 - 4 Aug 2021
Cited by 10 | Viewed by 3130
Abstract
Aberrant expression of tissue factor (TF) by transformed myeloblasts and inflammatory monocytes drives coagulation activation in acute myeloid leukemia (AML). Although regulation of TF procoagulant activity (PCA) involves thiol-disulfide exchange reactions, the specific role of protein disulfide isomerase (PDI) and other thiol isomerases [...] Read more.
Aberrant expression of tissue factor (TF) by transformed myeloblasts and inflammatory monocytes drives coagulation activation in acute myeloid leukemia (AML). Although regulation of TF procoagulant activity (PCA) involves thiol-disulfide exchange reactions, the specific role of protein disulfide isomerase (PDI) and other thiol isomerases in AML-associated TF biology is unclear. THP1 cells and peripheral blood mononuclear cells (PBMCs) from healthy controls or AML patients were analyzed for thiol isomerase-dependent TF production under various experimental conditions. Total cellular and membrane TF antigen, TF PCA and TF mRNA were analyzed by ELISA, flow cytometry, clotting or Xa generation assay and qPCR, respectively. PBMCs and THP1 cells showed significant insulin reductase activity, which was inhibited by bacitracin or rutin. Co-incubation with these thiol isomerase inhibitors prevented LPS-induced TF production by CD14-positive monocytes and constitutive TF expression by THP1 cells and AML blasts. Downregulation of the TF antigen was mainly restricted to the cryptic pool of TF, efficiently preventing phosphatidylserine-dependent TF activation by daunorubicin, and at least partially regulated on the mRNA level in LPS-stimulated monocytes. Our study thus delineates a complex role of thiol isomerases in the regulation of myeloid TF PCA, with PDI being a promising therapeutic target in the management of AML-associated coagulopathies. Full article
(This article belongs to the Special Issue The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies)
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20 pages, 2637 KiB  
Article
De-Palmitoylation of Tissue Factor Regulates Its Activity, Phosphorylation and Cellular Functions
by Camille Ettelaie, Sophie Featherby, Araci M. R. Rondon, John Greenman, Henri H. Versteeg and Anthony Maraveyas
Cancers 2021, 13(15), 3837; https://doi.org/10.3390/cancers13153837 - 30 Jul 2021
Cited by 3 | Viewed by 2483
Abstract
In this study, the role of de-palmitoylation of tissue factor (TF) in the decryption of its activity was explored. TF-tGFP constructs were prepared by mutagenesis-substitution at Cys245 to prevent or mimic palmitolyation. Additionally, to reduce TF de-palmitoylation, the expression of palmitoyl-protein thioesterases (PPT) [...] Read more.
In this study, the role of de-palmitoylation of tissue factor (TF) in the decryption of its activity was explored. TF-tGFP constructs were prepared by mutagenesis-substitution at Cys245 to prevent or mimic palmitolyation. Additionally, to reduce TF de-palmitoylation, the expression of palmitoyl-protein thioesterases (PPT) was suppressed. Other TF mutants were prepared with altered flexibility, hydrophobicity or length of the transmembrane domain. The outcome of these alterations on fXa-generation, fVIIa binding, Ser253 phosphorylation and TF-microvesicle release were assessed in endothelial cells, and the influence on endothelial and MCF-7 cell proliferation and apoptosis was analysed. Preventing TF palmitoylation (TFSer245-tGFP), increasing the hydrophobicity (TFPhe241-tGFP) or lengthening (TFLongTM-tGFP) of the transmembrane domain enhanced fXa-generation in resting cells compared to cells expressing TFWt-tGFP, but fXa-generation was not further increased following PAR2 activation. Extending the available length of the transmembrane domain enhanced the TF-tGFP release within microvesicles and Ser253 phosphorylation and increased cell proliferation. Moreover, prevention of PKCα-mediated Ser253 phosphorylation with Gö6976 did not preclude fXa-generation. Conversely, reducing the hydrophobicity (TFSer242-tGFP), shortening (TFShortTM-tGFP) or reducing the flexibility (TFVal225-tGFP) of the transmembrane domain suppressed fXa-generation, fVIIa-HRP binding and Ser253 phosphorylation following PAR2 activation. PPT knock-down or mimicking palmitoylation (TFPhe245-tGFP) reduced fXa-generation without affecting fVIIa binding. This study has for the first time shown that TF procoagulant activity is regulated through de-palmitoylation, which alters the orientation of its transmembrane domain and is independent of TF phosphorylation. However, Ser253 phosphorylation is facilitated by changes in the orientation of the transmembrane domain and can induce TF-cellular signalling that influences cellular proliferation/apoptosis. Full article
(This article belongs to the Special Issue The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies)
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17 pages, 8667 KiB  
Article
Factor VIIa Regulates the Level of Cell-Surface Tissue Factor through Separate but Cooperative Mechanisms
by Yahya Madkhali, Araci M. R. Rondon, Sophie Featherby, Anthony Maraveyas, John Greenman and Camille Ettelaie
Cancers 2021, 13(15), 3718; https://doi.org/10.3390/cancers13153718 - 23 Jul 2021
Cited by 1 | Viewed by 2359
Abstract
Procoagulant activity of tissue factor (TF) in response to injury or inflammation is accompanied with cellular signals which determine the fate of cells. However, to prevent excessive signalling, TF is rapidly dissipated through release into microvesicles, and/or endocytosis. To elucidate the mechanism by [...] Read more.
Procoagulant activity of tissue factor (TF) in response to injury or inflammation is accompanied with cellular signals which determine the fate of cells. However, to prevent excessive signalling, TF is rapidly dissipated through release into microvesicles, and/or endocytosis. To elucidate the mechanism by which TF signalling may become moderated on the surface of cells, the associations of TF, fVII/fVIIa, PAR2 and caveolin-1 on MDA-MB-231, BxPC-3 and 786-O cells were examined and compared to that in cells lacking either fVII/fVIIa or TF. Furthermore, the localisation of labelled-recombinant TF with cholesterol-rich lipid rafts was explored on the surface of primary human blood dermal endothelial cells (HDBEC). Finally, by disrupting the caveolae on the surface of HDBEC, the outcome on TF-mediated signalling was examined. The association between TF and PAR2 was found to be dependent on the presence of fVIIa. Interestingly, the presence of TF was not pre-requisite for the association between fVII/fVIIa and PAR2 but was significantly enhanced by TF, which was also essential for the proliferative signal. Supplementation of HDBEC with exogenous TF resulted in early release of fVII/fVIIa from caveolae, followed by re-sequestration of TF-fVIIa. Addition of labelled-TF resulted in the accumulation within caveolin-1-containing cholesterol-rich regions and was also accompanied with the increased assimilation of cell-surface fVIIa. Disruption of the caveolae/rafts in HDBEC using MβCD enhanced the TF-mediated cellular signalling. Our data supports a hypothesis that cells respond to the exposure to TF by moderating the signalling activities as well as the procoagulant activity of TF, through incorporation into the caveolae/lipid rafts. Full article
(This article belongs to the Special Issue The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies)
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28 pages, 3652 KiB  
Article
Alterations of the Platelet Proteome in Lung Cancer: Accelerated F13A1 and ER Processing as New Actors in Hypercoagulability
by Huriye Ercan, Lisa-Marie Mauracher, Ella Grilz, Lena Hell, Roland Hellinger, Johannes A. Schmid, Florian Moik, Cihan Ay, Ingrid Pabinger and Maria Zellner
Cancers 2021, 13(9), 2260; https://doi.org/10.3390/cancers13092260 - 8 May 2021
Cited by 17 | Viewed by 4299
Abstract
In order to comprehensively expose cancer-related biochemical changes, we compared the platelet proteome of two types of cancer with a high risk of thrombosis (22 patients with brain cancer, 19 with lung cancer) to 41 matched healthy controls using unbiased two-dimensional differential in-gel [...] Read more.
In order to comprehensively expose cancer-related biochemical changes, we compared the platelet proteome of two types of cancer with a high risk of thrombosis (22 patients with brain cancer, 19 with lung cancer) to 41 matched healthy controls using unbiased two-dimensional differential in-gel electrophoresis. The examined platelet proteome was unchanged in patients with brain cancer, but considerably affected in lung cancer with 15 significantly altered proteins. Amongst these, the endoplasmic reticulum (ER) proteins calreticulin (CALR), endoplasmic reticulum chaperone BiP (HSPA5) and protein disulfide-isomerase (P4HB) were significantly elevated. Accelerated conversion of the fibrin stabilising factor XIII was detected in platelets of patients with lung cancer by elevated levels of a coagulation factor XIII (F13A1) 55 kDa fragment. A significant correlation of this F13A1 cleavage product with plasma levels of the plasmin–α-2-antiplasmin complex and D-dimer suggests its enhanced degradation by the fibrinolytic system. Protein association network analysis showed that lung cancer-related proteins were involved in platelet degranulation and upregulated ER protein processing. As a possible outcome, plasma FVIII, an immediate end product for ER-mediated glycosylation, correlated significantly with the ER-executing chaperones CALR and HSPA5. These new data on the differential behaviour of platelets in various cancers revealed F13A1 and ER chaperones as potential novel diagnostic and therapeutic targets in lung cancer patients. Full article
(This article belongs to the Special Issue The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies)
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12 pages, 1816 KiB  
Article
Extracellular Vesicle-Associated Tissue Factor Activity in Prostate Cancer Patients with Disseminated Intravascular Coagulation
by Lena Hell, Thomas Däullary, Vanessa Burghart, Lisa-Marie Mauracher, Ella Grilz, Bernhard Moser, Gero Kramer, Johannes A. Schmid, Cihan Ay, Ingrid Pabinger and Johannes Thaler
Cancers 2021, 13(7), 1487; https://doi.org/10.3390/cancers13071487 - 24 Mar 2021
Cited by 19 | Viewed by 2784
Abstract
Patients with advanced prostate cancer may develop fulminant disseminated intravascular coagulation (DIC). Circulating extracellular vesicles (EVs)-exposing tissue factor (TF), the initiator of the coagulation cascade, may play an important role. We included 7 prostate cancer patients with DIC, 10 age- and stage-matched cancer [...] Read more.
Patients with advanced prostate cancer may develop fulminant disseminated intravascular coagulation (DIC). Circulating extracellular vesicles (EVs)-exposing tissue factor (TF), the initiator of the coagulation cascade, may play an important role. We included 7 prostate cancer patients with DIC, 10 age- and stage-matched cancer controls without DIC, and 10 age-matched healthy male individuals. EV-TF activity was highly elevated in prostate cancer patients with DIC (11.40 pg/mL; range: 4.34–27.06) compared with prostate cancer patients without DIC (0.09 pg/mL; range: 0.00–0.30, p = 0.001) and healthy controls (0.18 pg/mL; range: 0.09–0.54; p = 0.001). Only EVs from patients with DIC reduced fibrin clot formation time of pooled plasma in a TF-dependent manner. Next, we performed in vitro co-culture experiments including EVs derived from a prostate cancer cell line with high (DU145) and low (LNCaP) TF expression, peripheral blood mononuclear cells (PBMCs), and platelets. Co-incubation of DU145 EVs with PBMCs and platelets significantly increased EV-TF activity in conditioned medium and induced TF activity on monocytes. No such effects were seen in co-culture experiments with LNCaP EVs. In conclusion, the findings indicate that elevated EV-TF activity plays a role in the development of prostate-cancer-related DIC and may result from interactions between tumor-derived EVs, monocytes, and platelets. Full article
(This article belongs to the Special Issue The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies)
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Review

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36 pages, 3354 KiB  
Review
Thrombin Cleavage of Osteopontin and the Host Anti-Tumor Immune Response
by Lawrence L. Leung, Timothy Myles and John Morser
Cancers 2023, 15(13), 3480; https://doi.org/10.3390/cancers15133480 - 3 Jul 2023
Cited by 8 | Viewed by 2330
Abstract
Osteopontin (OPN) is a multi-functional protein that is involved in various cellular processes such as cell adhesion, migration, and signaling. There is a single conserved thrombin cleavage site in OPN that, when cleaved, yields two fragments with different properties from full-length OPN. In [...] Read more.
Osteopontin (OPN) is a multi-functional protein that is involved in various cellular processes such as cell adhesion, migration, and signaling. There is a single conserved thrombin cleavage site in OPN that, when cleaved, yields two fragments with different properties from full-length OPN. In cancer, OPN has tumor-promoting activity and plays a role in tumor growth and metastasis. High levels of OPN expression in cancer cells and tumor tissue are found in various types of cancer, including breast, lung, prostate, ovarian, colorectal, and pancreatic cancer, and are associated with poor prognosis and decreased survival rates. OPN promotes tumor progression and invasion by stimulating cell proliferation and angiogenesis and also facilitates the metastasis of cancer cells to other parts of the body by promoting cell adhesion and migration. Furthermore, OPN contributes to immune evasion by inhibiting the activity of immune cells. Thrombin cleavage of OPN initiates OPN’s tumor-promoting activity, and thrombin cleavage fragments of OPN down-regulate the host immune anti-tumor response. Full article
(This article belongs to the Special Issue The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies)
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15 pages, 1541 KiB  
Review
Crosstalk between Circulating Tumor Cells and Plasma Proteins—Impact on Coagulation and Anticoagulation
by Yuanyuan Wang, Stefan W. Schneider and Christian Gorzelanny
Cancers 2023, 15(11), 3025; https://doi.org/10.3390/cancers15113025 - 1 Jun 2023
Viewed by 1946
Abstract
Cancer metastasis is a complex process. After their intravasation into the circulation, the cancer cells are exposed to a harsh environment of physical and biochemical hazards. Whether circulating tumor cells (CTCs) survive and escape from blood flow defines their ability to metastasize. CTCs [...] Read more.
Cancer metastasis is a complex process. After their intravasation into the circulation, the cancer cells are exposed to a harsh environment of physical and biochemical hazards. Whether circulating tumor cells (CTCs) survive and escape from blood flow defines their ability to metastasize. CTCs sense their environment with surface-exposed receptors. The recognition of corresponding ligands, e.g., fibrinogen, by integrins can induce intracellular signaling processes driving CTCs’ survival. Other receptors, such as tissue factor (TF), enable CTCs to induce coagulation. Cancer-associated thrombosis (CAT) is adversely connected to patients’ outcome. However, cancer cells have also the ability to inhibit coagulation, e.g., through expressing thrombomodulin (TM) or heparan sulfate (HS), an activator of antithrombin (AT). To that extent, individual CTCs can interact with plasma proteins, and whether these interactions are connected to metastasis or clinical symptoms such as CAT is largely unknown. In the present review, we discuss the biological and clinical relevance of cancer-cell-expressed surface molecules and their interaction with plasma proteins. We aim to encourage future research to expand our knowledge of the CTC interactome, as this may not only yield new molecular markers improving liquid-biopsy-based diagnostics but also additional targets for better cancer therapies. Full article
(This article belongs to the Special Issue The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies)
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25 pages, 2430 KiB  
Review
Functional Characteristics and Regulated Expression of Alternatively Spliced Tissue Factor: An Update
by Kateryna Matiash, Clayton S. Lewis and Vladimir Y. Bogdanov
Cancers 2021, 13(18), 4652; https://doi.org/10.3390/cancers13184652 - 16 Sep 2021
Cited by 6 | Viewed by 3161
Abstract
In human and mouse, alternative splicing of tissue factor’s primary transcript yields two mRNA species: one features all six TF exons and encodes full-length tissue factor (flTF), and the other lacks exon 5 and encodes alternatively spliced tissue factor (asTF). flTF, which is [...] Read more.
In human and mouse, alternative splicing of tissue factor’s primary transcript yields two mRNA species: one features all six TF exons and encodes full-length tissue factor (flTF), and the other lacks exon 5 and encodes alternatively spliced tissue factor (asTF). flTF, which is oftentimes referred to as “TF”, is an integral membrane glycoprotein due to the presence of an alpha-helical domain in its C-terminus, while asTF is soluble due to the frameshift resulting from the joining of exon 4 directly to exon 6. In this review, we focus on asTF—the more recently discovered isoform of TF that appears to significantly contribute to the pathobiology of several solid malignancies. There is currently a consensus in the field that asTF, while dispensable to normal hemostasis, can activate a subset of integrins on benign and malignant cells and promote outside-in signaling eliciting angiogenesis; cancer cell proliferation, migration, and invasion; and monocyte recruitment. We provide a general overview of the pioneering, as well as more recent, asTF research; discuss the current concepts of how asTF contributes to cancer progression; and open a conversation about the emerging utility of asTF as a biomarker and a therapeutic target. Full article
(This article belongs to the Special Issue The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies)
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12 pages, 7115 KiB  
Review
Tissue Factor and Extracellular Vesicles: Activation of Coagulation and Impact on Survival in Cancer
by Yohei Hisada and Nigel Mackman
Cancers 2021, 13(15), 3839; https://doi.org/10.3390/cancers13153839 - 30 Jul 2021
Cited by 25 | Viewed by 3721
Abstract
Tissue factor (TF) is a transmembrane glycoprotein that functions as a receptor for FVII/FVIIa and initiates the extrinsic coagulation pathway. Tumors and cancer cells express TF that can be released in the form of TF positive (TF+) extracellular vesicles (EVs). In this review, [...] Read more.
Tissue factor (TF) is a transmembrane glycoprotein that functions as a receptor for FVII/FVIIa and initiates the extrinsic coagulation pathway. Tumors and cancer cells express TF that can be released in the form of TF positive (TF+) extracellular vesicles (EVs). In this review, we summarize the studies of tumor TF and TF + EVs, and their association with activation of coagulation and survival in cancer patients. We also summarize the role of tumor-derived TF + EVs in venous thrombosis in mouse models. Levels of tumor TF and TF + EVs are associated with venous thromboembolism in pancreatic cancer patients. In addition, levels of EVTF activity are associated with disseminated intravascular coagulation in cancer patients. Furthermore, tumor-derived TF + EVs enhance venous thrombosis in mice. Tumor TF and TF + EVs are also associated with worse survival in cancer patients, particularly in pancreatic cancer patients. These studies indicate that EVTF activity could be used as a biomarker to identify pancreatic cancer patients at risk for venous thrombosis and cancer patients at risk for disseminated intravascular coagulation. EVTF activity may also be a useful prognostic biomarker in cancer patients. Full article
(This article belongs to the Special Issue The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies)
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18 pages, 2448 KiB  
Review
Targeting Tissue Factor to Tumor Vasculature to Induce Tumor Infarction
by Andrew F. Berdel, Christian Schwöppe, Caroline Brand, Saliha Harrach, Kathrin Brömmel, Heike Hintelmann, Georg Lenz, Ruediger Liersch, Hauke Heinzow, Christoph Schliemann, Rolf M. Mesters, Wolfgang E. Berdel and Torsten Kessler
Cancers 2021, 13(11), 2841; https://doi.org/10.3390/cancers13112841 - 7 Jun 2021
Cited by 7 | Viewed by 4277
Abstract
Besides its central functional role in coagulation, TF has been described as being operational in the development of malignancies and is currently being studied as a possible therapeutic tool against cancer. One of the avenues being explored is retargeting TF or its truncated [...] Read more.
Besides its central functional role in coagulation, TF has been described as being operational in the development of malignancies and is currently being studied as a possible therapeutic tool against cancer. One of the avenues being explored is retargeting TF or its truncated extracellular part (tTF) to the tumor vasculature to induce tumor vessel occlusion and tumor infarction. To this end, multiple structures on tumor vascular wall cells have been studied at which tTF has been aimed via antibodies, derivatives, or as bifunctional fusion protein through targeting peptides. Among these targets were vascular adhesion molecules, oncofetal variants of fibronectin, prostate-specific membrane antigens, vascular endothelial growth factor receptors and co-receptors, integrins, fibroblast activation proteins, NG2 proteoglycan, microthrombus-associated fibrin-fibronectin, and aminopeptidase N. Targeting was also attempted toward cellular membranes within an acidic milieu or toward necrotic tumor areas. tTF-NGR, targeting tTF primarily at aminopeptidase N on angiogenic endothelial cells, was the first drug candidate from this emerging class of coaguligands translated to clinical studies in cancer patients. Upon completion of a phase I study, tTF-NGR entered randomized studies in oncology to test the therapeutic impact of this novel therapeutic modality. Full article
(This article belongs to the Special Issue The Role of Tissue Factor and Downstream Coagulation Proteases in Solid Cancers and Hematological Malignancies)
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