Thrombin Generation and Cancer: Contributors and Consequences

Reddel, Caroline J.; Tan, Chuen Wen; Chen, Vivien

doi:10.3390/cancers11010100

Cited by 78 publications

(84 citation statements)

References 175 publications

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“…Using C5-producing tumor cell lines, it was shown that C5a can be generated by a still not identified cell membrane-bound serine protease 14 . Thrombin is produced in tumors and has potent pro-tumoral activity 25 . Therefore, it is tempting to speculate that the cleavage of C5 will be yet another mechanism of its pro-tumoral activity in situ.…”

Section: Canonical Mechanisms Of Initiationmentioning

confidence: 99%

Context-dependent roles of complement in cancer

et al. 2019

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The tumor microenvironment (TME) highly influences the growth, spreading of tumors and therefore patient's clinical outcome. In this context, complement system plays a major and complex role. It may either kill antibody-coated tumor cells or support local inflammation, hamper anti-tumor T cell responses favoring cancer spreading. Recent studies demonstrate that these opposite effects depend of the sites of its activation, the composition of the TME and the tumor cell sensitivity to complement attack. In this review, we present the implication of complement activation and its effects on cancer control and clinical outcome in different TME contexts. We also provide an overview of the publicly available transcriptomic data on the prognostic value of complement genes expression in 30 cancer types. We argue that the interplay of complement within each cancer is unique, governed by the properties of the tumor cells and the TME. This concept is of critical importance for the design of efficient therapeutic strategies.

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Section: Canonical Mechanisms Of Initiationmentioning

confidence: 99%

Context-dependent roles of complement in cancer

et al. 2019

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“…The plasticity of tumor cells permits them to adopt a range of migratory modes, of which the amoeboid phenotype is defined by plasma membrane blebbing, and is implicated in tumor metastasis 1 . The tumor environment is thrombotic (reviewed in 13 ), in part due to the low integrity of tumor vessels, and thrombin has been proposed to increase the invasiveness of MDA-MB-231 breast cancer cells 38 . Here we identify thrombin as a potent stimulus for blebbing in breast cancer cells, and establish that activation of its receptor PAR2 is sufficient to induce this effect.…”

Section: Discussionmentioning

confidence: 99%

“…Tumor vessels are notoriously leaky and the tumor environment has been described as being in a pathological state of coagulation, which may be exacerbated by certain chemotherapies 11 . Consequently, cancer cells may exist within, and contribute to, a milieu enriched in various components of the coagulation cascade, including thrombin 12 (reviewed in 13 ). Thrombin acts on the G protein-coupled protease activated receptors (PARs) 1-4 [14][15][16][17][18] to irreversibly sever a part of their N-terminal extracellular domain exposing a tethered ligand, which activates the receptor through an intramolecular interaction.…”

Section: Introductionmentioning

confidence: 99%

Piezo1 activation attenuates thrombin-induced blebbing in breast cancer cells

O’Callaghan

Engberg

Fatsis-Kavalopoulos

et al. 2020

Preprint

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Cancer cells exploit a variety of migration modes to leave primary tumors and establish metastases, including amoeboid cell migration facilitated by bleb formation. Here we demonstrate that thrombin induces dynamic blebbing in the MDA-MB-231 breast cancer cell line, and confirm that PAR2 activation is sufficient to induce this effect. Cell confinement has been implicated as a driving force in bleb-based migration. Unexpectedly, we find that gentle contact compression, exerted using a "Cell Press" to mechanically stimulate cells, attenuated thrombin-induced blebbing with an associated increase in cytosolic calcium. Thrombin-induced blebbing was similarly attenuated using Yoda1, an agonist of the mechanosensitive calcium channel Piezo1, and its capacity to attenuate blebbing was impaired in Piezo1 depleted cells. Additionally, Piezo1 activation suppressed and reversed the thrombininduced phosphorylation of ERM proteins, which are implicated in the blebbing process, and this activity was in part mediated through activation of the PP1A/PP2A family of serine/threonine phosphatases. Our results provide mechanistic insights into Piezo1 activation as a suppressor of dynamic blebbing, specifically that which is induced by thrombin.2 increase hydrostatic pressure within the cell 21 ; in parallel, actomyosin contractility is essential for the retraction of expanded PM blebs 5 .Piezo1 is a mechanosensitive cation channel 22,23 implicated in diverse areas of cell biology including shear stress sensing in endothelial cells 24 ; regulation of red blood cell volume 25 ; cell division in epithelial cells 26 ; and as a confinement sensor that suppresses PKA activity to optimize cell motility 27 . Piezo1 is found in the plasma membrane as a homotrimer and in closed conformation induces a bowlshaped indentation in the PM. In response to increased membrane tension Piezo1 transitions to a more planar arrangement and gates Ca 2+ influx 28,29 . Furthermore, loss of cortical actin, as seen during the initial expansion of PM blebs, reduces the activation threshold of Piezo1 30 .Here, we identify thrombin as a bleb induction stimulus, and Piezo1 activation, through contact compression or stimulation with the Piezo1 agonist Yoda1, as an effective mechanism to suppress dynamic blebbing in breast cancer cells. Thrombin induced blebbing was associated with increased ERM phosphorylation that was suppressed or reversed through Piezo1 activation, which in turn was dependent on the downstream activity of PP1/PP2A serine/threonine phosphatases. We propose that Ca 2+ influx via Piezo1 activates PP1/PP2A phosphatases to dephosphorylate ERMs, which in turn reduces the actomyosin contraction forces applied to the PM; thereby reducing the likelihood of dynamic blebbing. Materials and Methods Reagents and chemicalsSiR-Actin (Spirochrome, Tebu-bio, Roskilde, Denmark) was diluted to 1 mM in dimethyl sulfoxide (DMSO; ThermoFisher Scientific, Uppsala, Sweden) and stored at -20 o C. Fluo-4 and Fura Red calcium indicators (ThermoFisher Scientific) were resuspe...

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“…We also specifically looked at the clotting global tests as their availability in clinical settings is widely known [11,[25][26][27]. Mean PT was statistically longer in the high tPA group but didn't exceed the upper reference value at the onset and after 3 and 6 cycles of chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of tissue plasminogen activator (tPA) in patients with epithelial ovarian cancer undergoing chemotherapy

et al. 2019

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Objectives: Tissue plasminogen activator (tPA) is a key enzyme for fibrin degradation and the proteolytic defense against formation of the thrombotic endothelial deposits. tPA is involved in carcinogenesis but its exact role in tumor biology is not very well understood and a prognostic value of tPA remains ambiguous in different cancers. The aim of the study was to assess the prognostic value of plasma tPA in patients with epithelial ovarian cancer (EOC) in the course of the first line chemotherapy. Material and methods: the study covered 60 patients with EOC who underwent the 1 st line chemotherapy. Plasma tPA was assessed at onset, after 3 and 6 cycles of chemotherapy. The groups were stratified according to tPA level at onset of chemotherapy (low tPA group < 6.5 mg/L, N = 37 and high tPA group > 6.5 mg/L, N = 23). Survival analysis was repeated for the cutoff of tPA level at 6.5 mg/L and 5.1 mg/L after 3 and 6 cycles. Results: Only subjects with tPA > 6.5 mg/L at onset of chemotherapy had a significantly lower probability of a 5-year survival (34.8% vs. 72.7%, P < 0.006) and lower chance for disease free survival within 5 years (39.3% vs. 72.7%, P < 0.014). tPA < 6.5 mg/L plasma level evaluated at onset of chemotherapy was an independent marker of better overall survival (RR = 0.44, 95%CI = 0.19-0.98) but not disease-free survival. Conclusions: Plasma tPA may serve as a marker of survival if assessed at onset of the first line chemotherapy in patients with ovarian cancer.

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Thrombin Generation and Cancer: Contributors and Consequences

Cited by 78 publications

References 175 publications

Context-dependent roles of complement in cancer

Context-dependent roles of complement in cancer

Piezo1 activation attenuates thrombin-induced blebbing in breast cancer cells

Prognostic value of tissue plasminogen activator (tPA) in patients with epithelial ovarian cancer undergoing chemotherapy

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