Abstract 1117: Platelet interaction induces Tissue Factor and a pro-metastatic phenotype in ovarian cancer cells

Background: A documented relationship between ovarian cancer and thrombosis does exist. Low-molecular-weight heparins (LMWHs) are cornerstone drugs in the primary prevention and treatment of venous thromboembolic events in patients with cancer. However, cancer cells may alter the efficiency of these antithrombotic agents. Objective: We aimed to characterize the procoagulant phenotype of human epithelial ovarian adenocarcinoma cells, IGROV1, and to compare the capacity of tinzaparin and enoxaparin to inhibit thrombin generation triggered by these cells. Methods: Thrombin generation induced by different concentrations of IGROV1 cells on platelet poor plasma (PPP) was assessed by the calibrated automated thrombogram assay. Tissue factor (TF) expression was studied using Western blot analysis. Then, the experimental model of thrombin generation was used to compare the inhibitory effect of clinically relevant concentrations of both tinzaparin and enoxaparin. The inhibitory concentration 50 (IC50) of the mean rate index and the endogenous thrombin potential and the 2-fold increase in lag time were analyzed on the basis of the anti-Xa and anti-IIa activities of the LMWHs. Results: IGROV1 cells suspended into PPP resulted in a significant increase in thrombin generation in the absence of any exogenous source of TF and phospholipids. Tissue factor was expressed by IGROV1 cells. Tinzaparin was a more potent inhibitor of thrombin generation than enoxaparin. The inhibition of thrombin generation induced by IGROV1 cancer cells depended mainly on the anti-Xa activity of the LMWHs. Conclusion: This experimental study in ovarian cancer cells demonstrates that the antithrombotic activity of LMWHs is not completely predicted by the anti-Xa or anti-IIa activities measured in PPP.

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Role of tissue-factor bearing extracellular vesicles released from ovarian cancer cells in platelet aggregation in vitro and venous thrombosis in mice

Thrombosis Update ◽

10.1016/j.tru.2020.100020 ◽

2021 ◽

Vol 2 ◽

pp. 100020

Author(s):

Tomoyuki Sasano ◽

Min Soon Cho ◽

Cristian Rodriguez-Aguayo ◽

Emine Bayraktar ◽

Mana Taki ◽

...

Keyword(s):

Ovarian Cancer ◽

Platelet Aggregation ◽

Venous Thrombosis ◽

Cancer Cells ◽

Tissue Factor ◽

Extracellular Vesicles ◽

Ovarian Cancer Cells

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Tissue Factor–Factor VII Complex as a Key Regulator of Ovarian Cancer Phenotypes

Biomarkers in Cancer ◽

10.4137/bic.s29318 ◽

2015 ◽

Vol 7s2 ◽

pp. BIC.S29318 ◽

Cited By ~ 3

Author(s):

Shiro Koizume ◽

Yohei Miyagi

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Tissue Factor ◽

Intracellular Signaling ◽

Coagulation Factor ◽

Coagulation Cascade ◽

Factor Vii ◽

Ovarian Cancer Cells ◽

Coagulation Factor Vii ◽

Cancer Tissues

Tissue factor (TF) is an integral membrane protein widely expressed in normal human cells. Blood coagulation factor VII (fVII) is a key enzyme in the extrinsic coagulation cascade that is predominantly secreted by hepatocytes and released into the bloodstream. The TF–fVII complex is aberrantly expressed on the surface of cancer cells, including ovarian cancer cells. This procoagulant complex can initiate intracellular signaling mechanisms, resulting in malignant phenotypes. Cancer tissues are chronically exposed to hypoxia. TF and fVII can be induced in response to hypoxia in ovarian cancer cells at the gene expression level, leading to the autonomous production of the TF–fVII complex. Here, we discuss the roles of the TF–fVII complex in the induction of malignant phenotypes in ovarian cancer cells. The hypoxic nature of ovarian cancer tissues and the roles of TF expression in endometriosis are discussed. Arguments will be extended to potential strategies to treat ovarian cancers based on our current knowledge of TF–fVII function.

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Platelets enhance tissue factor protein and metastasis initiating cell markers, and act as chemoattractants increasing the migration of ovarian cancer cells

BMC Cancer ◽

10.1186/s12885-015-1304-z ◽

2015 ◽

Vol 15 (1) ◽

Cited By ~ 49

Author(s):

Renan Orellana ◽

Sumie Kato ◽

Rafaela Erices ◽

María Loreto Bravo ◽

Pamela Gonzalez ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Tissue Factor ◽

Ovarian Cancer Cells ◽

Cell Markers

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High-level secretion of tissue factor-rich extracellular vesicles from ovarian cancer cells mediated by filamin-A and protease-activated receptors

Thrombosis and Haemostasis ◽

10.1160/th15-03-0213 ◽

2016 ◽

Vol 115 (02) ◽

pp. 299-310 ◽

Cited By ~ 25

Author(s):

Shin Ito ◽

Yusuke Yoshioka ◽

Tomohiko Kanayama ◽

Yoshiyasu Nakamura ◽

Mitsuyo Yoshihara ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Surface ◽

Cancer Cells ◽

Cancer Patients ◽

Tissue Factor ◽

Extracellular Vesicles ◽

Actin Binding ◽

Ovarian Cancer Cells ◽

Filamin A ◽

Protease Activated Receptors

SummaryThromboembolic events occur frequently in ovarian cancer patients. Tissue factor (TF) is often overexpressed in tumours, including ovarian clear-cell carcinoma (CCC), a subtype with a generally poor prognosis. TF-coagulation factor VII (fVII) complexes on the cell surface activate downstream coagulation mechanisms. Moreover, cancer cells secrete extracellular vesicles (EVs), which act as vehicles for TF. We therefore examined the characteristics of EVs produced by ovarian cancer cells of various histological subtypes. CCC cells secreted high levels of TF within EVs, while the high-TF expressing breast cancer cell line MDA-MB-231 shed fewer TF-positive EVs. We also found that CCC tumours with hypoxic tissue areas synthesised TF and fVII in vivo, rendering the blood of xenograft mice bearing these tumours hypercoagulable compared with mice bearing MDA-MB-231 tumours. Incorporation of TF into EVs and secretion of EVs from CCC cells exposed to hypoxia were both dependent on the actin-binding protein, filamin-A (filA). Furthermore, production of these EVs was dependent on different protease-activated receptors (PARs) on the cell surface. These results show that CCC cells could produce large numbers of TF-positive EVs dependent upon filA and PARs. This phenomenon may be the mechanism underlying the increased incidence of venous thromboembolism in ovarian cancer patients.Supplementary Material to this article is available online at www.thrombosis-online.com.

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Self-production of tissue factor-coagulation factor VII complex by ovarian cancer cells

British Journal of Cancer ◽

10.1038/sj.bjc.6605406 ◽

2009 ◽

Vol 101 (12) ◽

pp. 2023-2029 ◽

Cited By ~ 41

Author(s):

N Yokota ◽

S Koizume ◽

E Miyagi ◽

F Hirahara ◽

Y Nakamura ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Tissue Factor ◽

Coagulation Factor ◽

Factor Vii ◽

Ovarian Cancer Cells ◽

Coagulation Factor Vii ◽

Self Production

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Exosome-mediated transfer of CD44 from high-metastatic ovarian cancer cells promotes migration and invasion of low-metastatic ovarian cancer cells

Journal of Ovarian Research ◽

10.1186/s13048-021-00776-2 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Xiameng Shen ◽

Conghui Wang ◽

Huihui Zhu ◽

Yaping Wang ◽

Xinyu Wang ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Western Blotting ◽

Migration And Invasion ◽

Ovarian Cancer Cells ◽

Metastatic Phenotype ◽

Transmission Electron ◽

Promote Cell Migration ◽

And Biological Markers

Abstract Objective To investigate the detailed roles and mechanisms of tumor-derived exosomes in progression and metastasis of ovarian cancer in vitro. Methods Exosomes were isolated by differential centrifugation method; the morphology, size and biological markers of exosomes were separately defined by transmission electron microscopy, nanoS90 and Western blotting; Trans-well chambers assay was used to assess the ability of migration and invasion of recipient cells uptaking the exosomes from HO8910PM cells. The downstream molecule was screened by mass spectrometry.CD44 was identified by western blotting and the function of CD44 was identified by trans-well chambers assay and CCK8 assay. Results Exosomes derived from HO8910PM cells could be transferred to HO8910 cells and promote cell migration and invasion in the recipient cells of ovarian cancer. And CD44 could be transferred to the HO8910 cells through exosomes from HO8910PM cells and influence the migration and invasion ability of HO8910 cells. Conclusion The more aggressive subpopulation can transfer a metastatic phenotype to the less one via secreting exosomes within a heterogeneous tumor. CD44 may be a potential therapeutic approach for ovarian cancer.

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