Oncogenes and the coagulation system – forces that modulate dormant and aggressive states in cancer

Magnus, Nathalie; D’Asti, Esterina; Meehan, Brian; Garnier, Delphine; Rak, Janusz

doi:10.1016/s0049-3848(14)50001-1

Cited by 54 publications

(45 citation statements)

References 107 publications

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“…[43][44][45] Microparticles released by tumor cells have exposed PS on their surface, which in conjunction with TF, are potent initiators of the conversion of prothrombin to thrombin. As has been reported in human cancer patients, [46][47][48][49] we observed a significant increase in the number of circulating TF C microparticles in 4T1 tumorbearing mice compared with non-tumor bearing mice. Importantly, thrombin inhibition with dabigatran etexilate treatment completely prevented the tumor-induced increase in circulating TF C microparticles.…”

Section: Discussionsupporting

confidence: 86%

Thrombin inhibition and cyclophosphamide synergistically block tumor progression and metastasis

Alexander

Minton

Hayes

et al. 2015

Cancer Biology & Therapy

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Cancer is often associated with an increased risk of thrombotic events which are exacerbated by treatment with chemotherapeutics such as cyclosphosphamide (CP). Evidence suggests that thrombin can stimulate tumor progression via formation of fibrin and activation of protease-activated receptors (PARs) and platelets. We examined the effect of co-treatment with CP and dabigatran etexilate, a direct inhibitor of thrombin, using the murine orthotopic 4T1 tumor model. Mice receiving co-treatment with both low dose CP and dabigatran etexilate had significantly smaller mammary tumors and fewer lung metastases than mice treated with CP or dabigratran etexilate alone. Co-treatment with dabigatran etexilate and low dose CP also significantly decreased the number of arginase C Gr-1 C CD11b C myeloid derived suppressor cells as well as levels of TGF-b in spleens from tumor bearing mice. 4T1 tumors express procoagulant tissue factor (TF) and spontaneously release TF C microparticles which are potent procoagulant factors that promote thrombin generation. Treatment with dabigatran etexilate alone prevented tumor-induced increases in circulating TF C microparticles and also decreased the numbers of tumor-induced activated platelets by 40%. These results show that co-treatment with dabigatran etexilate and CP synergistically inhibits growth and metastasis of mammary tumors, suggesting that oral administration of the thrombin inhibitor dabigatran etexilate may be beneficial in not only preventing thrombotic events in cancer patients but also in treating malignant tumors themselves.

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Section: Discussionsupporting

confidence: 86%

Thrombin inhibition and cyclophosphamide synergistically block tumor progression and metastasis

Alexander

Minton

Hayes

et al. 2015

Cancer Biology & Therapy

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“…Tissue factor (TF), a membrane-associated glycoprotein, has emerged as the central player in the relationship between the hemostatic system and cancer progression (13,14,(22)(23)(24)(25)(26). TF binds and activates coagulation factor FVII, which in turn triggers the downstream coagulation cascade leading to thrombin generation and clot formation.…”

Section: Introductionmentioning

confidence: 99%

“…Enhanced TF expression has also been found in a variety of solid tumors including breast cancers, in which it associates with decreased overall survival or shorter recurrence-free survival (26). TF is a downstream target of several oncogenic pathways (RAS, HER2, MET, SHH), of the loss of tumor suppressors such as PTEN or p53, and of transcriptional regulation by NFkB, AP-1, or Egr-1 transcription factors (24,25). Adding to its expression at the cell surface, TF may also be released in microparticles harboring procoagulant activity (27).…”

Section: Introductionmentioning

confidence: 99%

Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells

et al. 2016

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Epithelial-mesenchymal transition (EMT) is prominent in circulating tumor cells (CTC), but how it influences metastatic spread in this setting is obscure. Insofar as blood provides a specific microenvironment for tumor cells, we explored a potential link between EMT and coagulation that may provide EMT-positive CTCs with enhanced colonizing properties. Here we report that EMT induces tissue factor (TF), a major cell-associated initiator of coagulation and related procoagulant properties in the blood. TF blockade by antibody or shRNA diminished the procoagulant activity of EMT-positive cells, confirming a functional role for TF in these processes. Silencing the EMT transcription factor ZEB1 inhibited both EMT-associated TF expression and coagulant activity, further strengthening the link between EMT and coagulation. Accordingly, EMT-positive cells exhibited a higher persistance/survival in the lungs of mice colonized after intravenous injection, a feature diminished by TF or ZEB1 silencing. In tumor cells with limited metastatic capability, enforcing expression of the EMT transcription factor Snail increased TF, coagulant properties, and early metastasis. Clinically, we identified a subpopulation of CTC expressing vimentin and TF in the blood of metastatic breast cancer patients consistent with our observations. Overall, our findings define a novel EMT-TF regulatory axis that triggers local activation of coagulation pathways to support metastatic colonization of EMT-positive CTCs.

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“…Increased angiogenesis serves to restore the influx of nutrients and oxygen to the tumor environment (16). It has been proposed that the TF signaling pathway has a relevant role in GBM progression (17,18). Therefore, oncogenic signaling pathways, such as the expression of epidermal growth factor receptor (EGFR) and its mutant, EGFRvIII, as well as inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN), correlate with the elevated expression of TF in GBM cell lines and patient samples (19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia regulates the expression of tissue factor pathway signaling elements in a rat glioma model

et al. 2016

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Abstract. Hypoxia and necrosis are fundamental features of glioma, and their emergence is critical for the rapid biological progression of this fatal tumor. The presence of vaso-occlusive thrombus is higher in grade IV tumors [glioblastoma multiforme (GBM)] compared with lower grade tumors, suggesting that the procoagulant properties of the tumor contribute to its aggressive behavior, as well as the establishment of tumor hypoxia and necrosis. Tissue factor (TF), the primary cellular initiator of coagulation, is overexpressed in GBMs and likely favors a thrombotic microenvironment. Phosphatase and tensin homolog (PTEN) loss and hypoxia are two common alterations observed in glioma that may be responsible for TF upregulation. In the present study, ST1 and P7 rat glioma lines, with different levels of aggressiveness, were comparatively analyzed with the aim of identifying differences in procoagulant mechanisms. The results indicated that P7 cells display potent procoagulant activity compared with ST1 cells. Flow cytometric analysis showed less pronounced levels of TF in ST1 cells compared with P7 cells. Notably, P7 cells supported factor X (FX) activation via factor VIIa, whereas no significant FXa generation was observed in ST1 cells. Furthermore, the exposure of phosphatidylserine on the surface of P7 and ST1 cells was investigated. The results supported the assembly of prothrombinase complexes, accounting for the production of thrombin. Furthermore, reverse transcription-quantitative polymerase chain reaction showed that CoCl 2 (known to induce a hypoxic-like stress) led to an upregulation of TF levels in P7 and ST1 cells. Therefore, increased TF expression in P7 cells was accompanied by increased TF procoagulant activity. In addition, hypoxia increased the shedding of procoagulant TF-bearing microvesicles in both cell lines. Finally, hypoxic stress induced by treatment with CoCl 2 upregulated the expression of the PAR1 receptor in both P7 and ST1 cells. In addition to PAR1, P7, but not ST1 cells, expressed higher levels of PAR2 under hypoxic stress. Thus, modulating these molecular interactions may provide additional insights for the development of more efficient therapeutic strategies against aggressive glioma.

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Oncogenes and the coagulation system – forces that modulate dormant and aggressive states in cancer

Cited by 54 publications

References 107 publications

Thrombin inhibition and cyclophosphamide synergistically block tumor progression and metastasis

Thrombin inhibition and cyclophosphamide synergistically block tumor progression and metastasis

Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells

Hypoxia regulates the expression of tissue factor pathway signaling elements in a rat glioma model

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