scholarly journals Tissue factor-bearing microparticles and CA19.9: two players in pancreatic cancer-associated thrombosis?

2016 ◽  
Vol 115 (3) ◽  
pp. 332-338 ◽  
Author(s):  
F J Sherida H Woei-A-Jin ◽  
Margot E T Tesselaar ◽  
Patrica Garcia Rodriguez ◽  
Fred P H T M Romijn ◽  
Rogier M Bertina ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tissue Factor ◽  
Cancer Associated Thrombosis

Trousseau’s Syndrome Revisited: Tissue Factor-Bearing Microparticles in Pancreatic Cancer.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 259-259 ◽  
Author(s):  
Jeffrey I. Zwicker ◽  
Barbara C. Furie ◽  
Cynthia A. Kos ◽  
Thomas LaRocca ◽  
Kenneth A. Bauer ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Particle Size ◽  
Tissue Factor ◽  
Incident Light ◽  
Advanced Pancreatic Cancer ◽  
Major Complication ◽  
Cancer Tissue ◽  
Single Individual ◽  
Cancer Associated Thrombosis ◽  
Mean Concentration

Abstract Thromboembolic disease is a major complication of malignant disease, and pancreatic cancer ranks among the malignancies associated with the highest rates of thrombosis. Using laser injury in a mouse model of thrombosis, we previously demonstrated that tissue factor-bearing microparticles circulating in normal plasma accumulate in the developing thrombus through an interaction mediated by P-selectin and PSGL-1. Microparticle tissue factor contributes significantly to fibrin propagation within the thrombus. Based upon this observation, we evaluated the hypothesis that elevated numbers of tissue factor-bearing microparticles might be one of the causes of cancer-associated thrombosis. Microparticles are cell-derived vesicular structures under 1000 nm in diameter. Since the light scattering methodology used in commercial flow cytometers cannot determine particle size when the diameter of the particle (200–1000 nm) is the same order of magnitude as the wavelength of the incident light employed (488 nm), we applied a novel instrumentation to determine the size, size distribution, and concentration of tissue factor-bearing microparticles. An NPE Systems Quanta flow cytometer, using impedance to measure particle size, was extensively modified for this microparticle application. Application of 780 nm fluorescent calibration beads yielded a major population from 740 to 820 nm. Application of 520 nm fluorescent beads yielded a major population from 500 to 540 nm. Using a high affinity antibody to tissue factor, tissue factor-bearing microparticles were measured in platelet-poor plasma derived from normal subjects and subjects with surgically unresectable or metastatic pancreatic cancer. Tissue factor bearing microparticles were detected in significantly more subjects with pancreatic cancer (12 of 17, 70%) than healthy individuals in whom tissue factor-bearing microparticles remained below the level of detection in all but a single individual (1 of 11, P=0.005). By comparison, tissue factor-bearing microparticles were not detected in subjects with advanced stage (III or IV) non-small cell lung cancer (N=9). In subjects with advanced pancreatic cancer, the mean concentration of tissue factor bearing microparticles was 444,000 particles/microliter with a mean diameter ranging between 371 nm to 727 nm. The two patients with pancreatic cancer in this study who suffered a recent lower extremity venous thrombosis had high measurable tissue factor-bearing microparticles levels with a mean concentration of 975,000 particles/microliter. These results indicate that tissue factor-bearing microparticles are present in the plasma of many patients with advanced pancreatic cancer and suggest that tissue factor-bearing microparticles may be central to the pathogenesis of cancer-associated thrombosis.

scholarly journals Glioblastoma cell populations with distinct oncogenic programs release podoplanin as procoagulant extracellular vesicles

2021 ◽  
Vol 5 (6) ◽  
pp. 1682-1694
Author(s):  
Nadim Tawil ◽  
Rayhaan Bassawon ◽  
Brian Meehan ◽  
Ali Nehme ◽  
Laura Montermini ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tissue Factor ◽  
Extracellular Vesicles ◽  
Coagulation System ◽  
Platelet Factor ◽  
Increased Risk ◽  
Cell Subpopulations ◽  
Cancer Associated Thrombosis

Abstract Vascular anomalies, including local and peripheral thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of deregulation of the cancer cell genome and epigenome. Although the molecular effectors of these changes are poorly understood, the upregulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk for venous thromboembolism (VTE) in GBM patients. Therefore, regulation of this platelet-activating protein by transforming events in cancer cells is of considerable interest. We used single-cell and bulk transcriptome data mining, as well as cellular and xenograft models in mice, to analyze the nature of cells expressing PDPN, as well as their impact on the activation of the coagulation system and platelets. We report that PDPN is expressed by distinct (mesenchymal) GBM cell subpopulations and downregulated by oncogenic mutations of EGFR and IDH1 genes, along with changes in chromatin modifications (enhancer of zeste homolog 2) and DNA methylation. Glioma cells exteriorize their PDPN and/or tissue factor (TF) as cargo of exosome-like extracellular vesicles (EVs) shed from cells in vitro and in vivo. Injection of glioma-derived podoplanin carrying extracelluar vesicles (PDPN-EVs) activates platelets, whereas tissue factor carrying extracellular vesicles (TF-EVs) activate the clotting cascade. Similarly, an increase in platelet activation (platelet factor 4) or coagulation (D-dimer) markers occurs in mice harboring the corresponding glioma xenografts expressing PDPN or TF, respectively. Coexpression of PDPN and TF by GBM cells cooperatively affects tumor microthrombosis. Thus, in GBM, distinct cellular subsets drive multiple facets of cancer-associated thrombosis and may represent targets for phenotype- and cell type–based diagnosis and antithrombotic intervention.

Alternatively spliced human tissue factor promotes tumor growth and angiogenesis in a pancreatic cancer tumor model

2007 ◽  
Vol 120 ◽  
pp. S13-S21 ◽  
Author(s):  
Jennifer E. Hobbs ◽  
Anaadriana Zakarija ◽  
Deborah L. Cundiff ◽  
Jennifer A. Doll ◽  
Emily Hymen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Tissue Factor ◽  
Human Tissue ◽  
Tumor Model ◽  
Cancer Tumor ◽  
Alternatively Spliced

The inhibition of pancreatic cancer invasion-metastasis cascade in both cellular signal and blood coagulation cascade of tissue factor by its neutralisation antibody

2011 ◽  
Vol 47 (14) ◽  
pp. 2230-2239 ◽  
Author(s):  
Yohei Saito ◽  
Yuki Hashimoto ◽  
Jun-ichiro Kuroda ◽  
Masahiro Yasunaga ◽  
Yoshikatsu Koga ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tissue Factor ◽  
Blood Coagulation ◽  
Cancer Invasion ◽  
Coagulation Cascade ◽  
Cellular Signal

scholarly journals Immuno-PET of Tissue Factor in Pancreatic Cancer

2012 ◽  
Vol 53 (11) ◽  
pp. 1748-1754 ◽  
Author(s):  
H. Hong ◽  
Y. Zhang ◽  
T. R. Nayak ◽  
J. W. Engle ◽  
H. C. Wong ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tissue Factor

Expression of Alternatively-Spliced Human Tissue Factor, but Not Full-Length Tissue Factor, Enhances Tumor Growth and Tumor-Associated Vasculature.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1746-1746
Author(s):  
Gerald A. Soff ◽  
Jennifer Hobbs ◽  
Emily Hyman ◽  
Deborah L. Cundiff
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Tissue Factor ◽  
Human Tissue ◽  
Primary Tumor ◽  
Conditioned Media ◽  
Full Length ◽  
Human Pancreatic Cancer ◽  
Primary Tumor Growth ◽  
Alternatively Spliced

Abstract It is well-established that cancer is associated with activation of the blood coagulation system, with associated thrombosis as a major cause of morbidity and mortality. Increased expression of Tissue Factor (TF) by cancer cells correlates with a more aggressive grade and clinical course. It is widely presumed that activation of coagulation facilitates cancer growth, and in mouse models, anticoagulation can reduce development of lung metastases. Yet primary tumors are not reduced in a fibrinogen knock-out mouse host, and most importantly, anticoagulation has not been shown to reduce tumor growth in cancer patients. We therefore studied the effect of expression of full-length Tissue Factor (FLTF) and alternatively-spliced human Tissue Factor (asHTF) in a mouse model of human pancreatic cancer. Due to the loss of exon 5, asHTF has a truncated extracellular domain with incomplete procoagulant activity. And due to a frame shift, exon 6 does not code for the transmembrane domain and cytoplasmic tail of FLTF, but codes for a novel peptide sequence. asHTF is soluble and of unknown function. We show that 5 of 6 human pancreatic cancer cell lines tested expressed both FLTF as well as asHTF. The MiaPaca-2 line did not express detectable mRNA or protein of either TF isoform. We generated mammalian expression vectors for both FLTF and asHTF, and established Miapaca-2 clones, stably expressing FLTF, asHTF, or control clones with an empty vector. As anticipated, conditioned media from all FLTF clones shortened the whole blood clotting times by approximately 75%. Conditioned media from control cells and asHTF expressing cells had no effect on clotting times. To evaluate the effect of the TF isoforms on primary tumor growth, 5 X 106 cells from three independent clones of stably transfected clones of FLTF, asHTF, or control clones were injected into the flanks of nude mice (4 mice per clone). At 31 days, the mice were sacrificed and tumor mass measured. Tumors grew in 10 of 12 control mice, but were small (mean tumors 90 mg, SEM 21 mg). Interestingly, FLTF was associated with reduced primary tumor growth; only 4 of 12 developed measurable tumors (mean tumors 10 mg, SEM 4 mg, p = 0.002). In contrast, asHTF expression was associated with enhanced tumor growth; 12 of 12 animals developed tumors (mean tumors 390 mg, SEM 102 mg, p=0.018). In animals with asHTF expressing tumors, circulating asHTF protein was observed in the plasma. The asHTF tumors had increased vascular density compared with controls, suggesting a role of asHTF promoting angiogenesis. In contrast to the prevailing paradigm, our data suggest that FLTF, with procoagulant activity, not only fails to promote primary tumor growth, but may actually inhibit tumor growth. In contrast, asHTF, may be the more important TF isoform in the enhancement of tumor growth.

Cancer-Associated Thrombosis: Cancer Cell-Derived Microparticles As a Trigger of Venous Thrombosis in a Mouse Model of Flow Restriction

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 34-34
Author(s):  
Grace M. Thomas ◽  
Alexander Brill ◽  
Denisa D. Wagner
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Venous Thrombosis ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Flow Restriction ◽  
Tumor Bearing ◽  
Pancreatic Cancer Cells ◽  
Venous Thromboembolic Events ◽  
Cancer Associated Thrombosis

Abstract Abstract 34 Thrombotic complications are common side effects in cancer patients and up to 20% of all symptomatic cases of deep vein thrombosis (DVT) are thought to be cancer-related. Since Armand Trousseau established a direct correlation between thrombophlebitis and cancer in 1865, cancer-associated thrombosis has been the focus of several studies. All tumor types are associated with thrombosis but the incidence is particularly high (up to 57%) in patients suffering from pancreatic cancer (Sack et al Medicine 1977; Blom et al Eur J Cancer 2006; Cronin-Fenton et al Br J Cancer 2010). Cancer cells shed procoagulant microparticles (MPs) that can reach the bloodstream of pancreatic tumor-bearing mice and of patients with pancreatic cancer (Thomas et al J Exp Med 2009, Zwicker et al Thromb Res 2009). At their surface, these vesicles express a higher density of active tissue factor (TF) when compared to their parental cell (> 100-fold), and were shown to contribute to vessel injury-induced thrombosis (Thomas et al J Exp Med 2009). Furthermore, the concentration of circulating TF-bearing tumor-derived MPs has been correlated with cancer-associated venous thromboembolic events in patients (Del Conde et al J Thromb Haem 2007; Hron et al Thromb Haemost 2007; Langer et al Ann Hematol 2008; Zwicker et al Thromb Res 2009). In this study, we addressed experimentally whether circulating tumor microparticles play a role in DVT associated with cancer. We used a mouse model of DVT where thrombosis is induced by flow restriction (90% reduction in the lumen size) of the inferior vena cava (IVC) (Brill et al Blood 2010). In contrast to most DVT models, this model maintains blood flow in the IVC and it does not induce injury or endothelial denudation and thus is suitable for comparisons to human patients. The DVT model was used in combination with a model of murine pancreatic cancer (Thomas et al J Exp Med 2009). We observed that all the mice implanted subcutaneously with pancreatic cancer cells (Panc02 cell line) and submitted 35 days later to partial flow restriction of the IVC (n=8) developed an occlusive thrombus after 3 hours of flow restriction, while only 2 out of 7 control mice did (P < 0.05). We observed in this DVT model that mice infused with cancer cell-derived MPs have the same phenotype as the tumor-bearing mice since 100% of them developed a thrombus (P < 0.05 when compared to control mice), indicating that circulating tumoral microparticles play an important part in the triggering of cancer-associated DVT. A pro-thrombotic effect could be observed as early as 1 hour after stenosis in cancer cell-derived MPs-injected mice (P < 0.05 when compared to control mice). Moreover, thrombus formation after 1 hour of stenosis could be abolished when mice were pretreated with hirudin, suggesting the importance of the MP-generated thrombin likely by MP-derived TF activity. In conclusion, our results support the hypothesis that tumoral microparticles trigger cancer-associated venous thrombosis. Thus targeting their recruitment or activity could help to prevent cancer-associated DVT and its complication, pulmonary embolism. Disclosures: No relevant conflicts of interest to declare.

Relationship between tissue factor expression by human pancreatic cancer cells and activation of coagulation and thrombosis in a mouse model.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14505-e14505
Author(s):  
Julia E. Geddings ◽  
Jian-guo Wang ◽  
Jessica C Cardenas ◽  
Pichika Chantrathammachart ◽  
Julie C Williams ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Tissue Factor ◽  
Saphenous Vein ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells ◽  
Increased Risk ◽  
Patients At Risk

e14505 Background: The increased risk of thrombosis in patients with cancer has been well established. However, the triggers in these patients have yet to be fully defined. Under pathological conditions, the potent procoagulant protein Tissue Factor (TF) is found in the circulation and may trigger thrombosis. Methods: We evaluated the level of TF expression in 4 different human pancreatic cancer cell lines. We also measured TF microparticle (MP) release from these tumors in vivo by flow cytometry and TF activity assay. We then used these lines in a mouse model of pancreatic cancer to evaluate the sources of TF that activate coagulation and contribute to thrombosis using a saphenous vein model. Results: We found that mice bearing orthotopic pancreatic tumors which express higher levels of TF (HPAC and HPAF) show increased activation of coagulation (measured by thrombin-antithrombin complex) as compared to mice bearing TF negative tumors (MIA-PaCa-2 and PANC-1). This activation of coagulation could be reduced by treatment with a human TF antibody. Further, mice bearing tumors derived from TF high cell line HPAC demonstrated an activation of coagulation despite a lack of circulating TF-positive MPs. Mice bearing TF expressing pancreatic tumors also demonstrated increased thrombosis by a saphenous vein model. Treatment of tumor-free mice with TF MPs did not result in an activation of coagulation or increased thrombosis unless mice were given 40-100 fold higher levels of TF bearing MPs than are found in the circulation of tumor bearing mice. Conclusions: The data suggest that TF on the tumor itself is involved in the activation of coagulation whereas circulating TF-positive MPs is likely to contribute to thrombosis. Elevated levels of TF-positive MPs may be used as a biomarker to identify cancer patients at risk for thrombosis.

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