A Combined Activity of Thrombin and P-Selectin Is Essential for Platelet Activation by Pancreatic Cancer Cells

Haschemi, Reza; Gockel, Lukas Maria; Bendas, Gerd; Schlesinger, Martin

doi:10.3390/ijms22073323

Cited by 13 publications

(14 citation statements)

References 44 publications

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“…TCIPA is mainly initialized by thrombin [ 25 ] via a TF coagulation pathway. Following the assumption that Sdc-1-OV cells induce stronger thrombin formation in contact with platelets, we performed a thrombin generation assay.…”

Section: Resultsmentioning

confidence: 99%

The Heparan Sulfate Proteoglycan Syndecan-1 Triggers Breast Cancer Cell-Induced Coagulability by Induced Expression of Tissue Factor

Hassan

Bückreiß

Efing

et al. 2023

Cells

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Syndecan-1 (Sdc-1) upregulation is associated with poor prognosis in breast cancer. Sdc-1 knockdown results in reduced angiogenesis and the dysregulation of tissue factor (TF) pathway constituents. Here, we evaluate the regulatory mechanisms and functional consequences of the Sdc-1/TF-axis using Sdc-1 knockdown and overexpression approaches in MCF-7 and MDA-MB-231 breast cancer cells. Gene expression was analyzed by means of qPCR. Thrombin generation and cell migration were detected. Cell-cycle progression and apoptosis were investigated using flow cytometry. In MDA-MB-231 cells, IL6, IL8, VEGF, and IGFR-dependent signaling affected TF pathway expression depending on Sdc-1. Notably, Sdc-1 depletion and TF pathway inhibitor (TFPI) synergistically affected PTEN, MAPK, and STAT3 signaling. At the functional level, the antiproliferative and pro-apoptotic effects of TFPI depended on Sdc-1, whereas Sdc-1’s modulation of cell motility was not affected by TFPI. Sdc-1 overexpression in MCF-7 and MDA-MB-231 cells led to increased TF expression, inducing a procoagulative phenotype, as indicated by the activation of human platelets and increased thrombin formation. A novel understanding of the functional interplay between Sdc-1 and the TF pathway may be compatible with the classical co-receptor role of Sdc-1 in cytokine signaling. This opens up the possibility of a new functional understanding, with Sdc-1 fostering coagulation and platelet communication as the key to the hematogenous metastatic spread of breast cancer cells.

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Section: Resultsmentioning

confidence: 99%

The Heparan Sulfate Proteoglycan Syndecan-1 Triggers Breast Cancer Cell-Induced Coagulability by Induced Expression of Tissue Factor

Hassan

Bückreiß

Efing

et al. 2023

Cells

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“…To follow this assumption of increased coagulability, we analyzed platelet activation after contacting MV3 EXT1kd and MV3 EXT1ctr cells with human platelets. Platelet activation, strongly induced by thrombin as a downstream product of the TF pathway, is indicated by aggregation, which can be followed by light transmission aggregometry [ 27 ]. Thrombin dependency is clearly confirmed by using a thrombin receptor (PAR-1) agonist TRAP-6, considered as a positive control activating protease-activated receptor-1 (PAR-1) on platelets.…”

Section: Resultsmentioning

confidence: 99%

“…Tumor-cell-induced platelet activation (TCIPA) strictly depends on thrombin formation [ 27 , 28 ], raising the question whether thrombin, accelerated in formation by the increased TF activity of EXT1 kd cells, also contributes to tumor cell resistance in MV3 EXT1kd cells. Notably, expression of PAR-1 by cancer cells is recognized as a tumor-progressive factor and has also been linked to resistance [ 29 ].…”

Section: Resultsmentioning

confidence: 99%

Exostosin 1 Knockdown Induces Chemoresistance in MV3 Melanoma Cells by Upregulating JNK and MEK/ERK Signaling

Pfeifer

Weber

Wang

et al. 2023

IJMS

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Heparan sulfate proteoglycans (HSPGs) possess various functions driving malignancy of tumors. However, their impact on tumor cell sensitivity to cytotoxic treatment is far less understood. Aiming to investigate this, we depleted HSPGs by downregulating Exostosin 1 (EXT1), a key enzyme in HS formation, or upregulating heparanase in human MV3 human melanoma cells, and investigated their response to cytotoxic drugs. Cytotoxicity of trametinib, doxorubicin, and mitoxantrone was detected by MTT assay. Insights into intracellular signaling was provided by kinome protein profiler array, and selected kinases were inhibited to investigate their impact on cell sensitization and migratory dynamics. EXT1 knockdown (EXT1kd) in MV3 cells affected the activity of doxorubicin and mitoxantrone, significantly increasing EC50 values two- or fourfold, respectively. Resistance formation was scarcely related to HSPG deficiency, suggested by enzymatic cleavage of HSPG in control cells. Notably, EXT1kd induced an upregulation of EGFR signaling via JNK and MEK/ERK, and hence blocking these kinases returned resistance to a sensitive level. JNK appeared as a key signal component, also inducing higher migratory activity of EXT1kd cells. Furthermore, EXT1kd upregulated thrombotic properties of MV3 cells, indicated by tissue factor and PAR-1 expression, functionally reflected by a stronger activation of platelet aggregation. EXT1 was confirmed to act as a tumor suppressor, shown here for the first time to affect chemosensitivity of melanoma cells.

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“…The high affinity between P-selectin on platelets and CD44 receptors on tumor cells explains this specific aggregation. Therefore, platelets are more likely to target CTCs when P-selectin binds specifically to CD44 [144,145]. To deliver functional small molecules with precise targeting, Hu et al created platelet-mimicking nanovehicles (PM-NV) [146].…”

Section: Platelets As Dynamic Carriersmentioning

confidence: 99%

Natural cell based biomimetic cellular transformers for targeted therapy of digestive system cancer

Tang¹,

Li²,

Gu³

et al. 2022

Theranostics

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Digestive system cancer is the most common cause of cancer death in the world. Although cancer treatment options are increasingly diversified, the mortality rate of malignant cancer of the digestive system remains high. Therefore, it is necessary to explore effective cancer treatment methods. Recently, biomimetic nanoparticle delivery systems based on natural cells that organically integrate the low immunogenicity, high biocompatibility, cancer targeting, and controllable, versatile functionality of smart nanocarrier design with natural cells have been expected to break through the bottleneck of tumor targeted therapy. In this review, we focus on the dynamic changes and complex cellular communications that occur in vivo in natural cells based vehicles. Recent studies on the development of advanced targeted drug delivery systems using the dynamic behaviors such as specific surface protein affinity, morphological changes, and phenotypic polarization of natural cells are summarized. In addition to drug delivery mediated by dynamic behavior, functional “delivery” based on the natural cell themselves is also involved. Aiming to make the best use of the functions of cells, providing clues for the development of advanced drug delivery platforms.

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A Combined Activity of Thrombin and P-Selectin Is Essential for Platelet Activation by Pancreatic Cancer Cells

Cited by 13 publications

References 44 publications

The Heparan Sulfate Proteoglycan Syndecan-1 Triggers Breast Cancer Cell-Induced Coagulability by Induced Expression of Tissue Factor

The Heparan Sulfate Proteoglycan Syndecan-1 Triggers Breast Cancer Cell-Induced Coagulability by Induced Expression of Tissue Factor

Exostosin 1 Knockdown Induces Chemoresistance in MV3 Melanoma Cells by Upregulating JNK and MEK/ERK Signaling

Natural cell based biomimetic cellular transformers for targeted therapy of digestive system cancer

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