Crosstalk between TF/FVIIa and EGFR signaling in colorectal cancer cells

Chen, Hekai; Wang, Xin; Wan, Yao; Tang, Jianqiang

doi:10.1080/15384047.2018.1529123

Cited by 5 publications

(6 citation statements)

References 24 publications

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“…Since 5-FU and GEM have different effects on cell signaling pathways and mechanisms, it is tempting to speculate that the observed differences between these two cell lines after 5-FU exposure are—at least in part—related to the KRAS status, whereas the effect of GEM could be due to different, possibly even post-transcriptional (protein stabilizing) events, which we did not investigate further here. This supports the notion that the crosstalk between TF/FVIIa and EGFR signaling pathways in CRC is dependent on KRAS mutation 35 . Indeed, another recent publication confirmed our hypothesis of a KRAS mutant-driven hypercoagulable state in colorectal cancer cell lines (vs. their Kras wt counterpart) 36 .…”

Section: Discussionsupporting

confidence: 87%

Selective but not pan-CDK inhibition abrogates 5-FU-driven tissue factor upregulation in colon cancer

Kayser,

Wolff,

Berlin

et al. 2024

Sci Rep

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Thromboembolic events are complications in cancer patients and hypercoagulability has been linked to the tissue factor (TF) pathway, making this an attractive target. Here, we investigated the effects of chemotherapeutics and CDK inhibitors (CDKI) abemaciclib/palbociclib (CDK4/6), THZ-1 (CDK7/12/13), and dinaciclib (CDK1/2/5/9) alone and in combination regimens on TF abundance and coagulation. The human colorectal cancer (CRC) cell line HROC173 was treated with 5-FU or gemcitabine to stimulate TF expression. TF+ cells were sorted, recultured, and re-analyzed. The effect of treatment alone or in combination was assessed by functional assays. Low-dose chemotherapy induced a hypercoagulable state and significantly upregulated TF, even after reculture without treatment. Cells exhibited characteristics of epithelial-mesenchymal transition, including high expression of vimentin and mucin. Dinaciclib and THZ-1 also upregulated TF, while abemaciclib and palbociclib downregulated it. Similar results were observed in coagulation assays. The same anticoagulant activity of abemaciclib was seen after incubation with peripheral immune cells from healthy donors and CRC patients. Abemaciclib reversed 5-FU-induced TF upregulation and prolonged clotting times in second-line treatment. Effects were independent of cytotoxicity, senescence, and p27kip1 induction. TF-antibody blocking experiments confirmed the importance of TF in plasma coagulation, with Factor XII playing a minor role. Short-term abemaciclib counteracts 5-FU-induced hypercoagulation and eventually even prevents thromboembolic events.

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Section: Discussionsupporting

confidence: 87%

Selective but not pan-CDK inhibition abrogates 5-FU-driven tissue factor upregulation in colon cancer

Kayser,

Wolff,

Berlin

et al. 2024

Sci Rep

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“…Tumour-mutated KRAS status is associated with an increased risk of venous thromboembolism (VTE) in patients with metastatic colorectal cancer, according to a retrospective multicenter cohort study conducted by Ades 9 . KRAS mutations influence malignancy progression by affecting tissue factor/FVIIa colorectal cancer cells and the EGFR signalling pathway 10 . Compared to KRAS wild-type tumours, KRAS-mutated colorectal cancers have a poorer overall prognosis, a shorter median overall survival, and an increased incidence of deep vein thrombosis 9 , 10 .…”

Section: Introductionmentioning

confidence: 99%

KRAS-mutant colorectal cancer cell lines cause a prothrombotic state through the upregulation of thrombin: experimental study

Xu,

Liao,

Tan

2023

Annals of Medicine &Amp; Surgery

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Background: The KRAS genotype status is strongly associated with a prothrombotic state in colorectal cancer, and hypercoagulability and cancer-related thrombosis are among the significant events leading to poor prognosis. However, this correlation has not been confirmed at the cellular level. This study aimed to assess the maximum platelet aggregation rate and thrombin expression induced by colorectal cancer cells under different KRAS genotypes. Materials and Methods: Platelet aggregation rate assay and western blotting analysis were used to detect platelet aggregation and thrombin expression induced by four colorectal cancer cells with different KRAS genotypes, including RKO, HCT116, SW480, and SW620. FVIIa/tissue factor and thrombin inhibitors were added to explore changes in platelet aggregation rates induced by colorectal cancer cells and the association between KRAS genotype status and hypercoagulable state. Results: KRAS mutant cells were more likely to increase maximal platelet aggregation, with RKO, HCT116, SW480, and SW620 inducing 34.7%, 55.4%, 44.4%, and 63.8% of platelet aggregation, respectively. The maximum platelet aggregation rate was higher in the metastatic rectal cancer tumor strain SW620 than in the primary rectal cancer strain SW480. RKO cells had lower thrombin expression than the other three cells. Furthermore, the addition of thrombin inhibitors caused a more significant decrease in the platelet aggregation rate in KRAS mutant cell lines compared to KRAS wild-type cell lines. Conclusion: Compared to KRAS wild-type colorectal cancer cells, KRAS mutant colorectal cancer cell lines were more likely to be hypercoagulable through the upregulation of thrombin expression, which was mainly achieved through the TF-thrombin pathway.

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“…Interestingly, activation of gonadotropin‐releasing hormone receptor caused G‐protein αi‐mediated activation of phospho‐tyrosine phosphatase, resulting in dephosphorylated EGF receptor (EGFR) and inhibited EGFR signal transduction through the phosphorylated ERK1/2 or the phosphorylated PI3K/AKT pathway. 22 , 23 , 24 EGFR‐signaling has consistently been found to upregulate tissue factor (TF) in glioma, hepatocellular carcinoma and colorectal cancer cells, providing a potential link to the cause of VTE. 22 , 23 , 24 , 25 Alternatively, TF can activate the pERK and pAKT pathway and subsequently activate the EGFR pathway, thus creating a positive feedback loop.…”

Section: Resultsmentioning

confidence: 99%

“…Seven of the 19 identified miRNAs were predicted to regulate the gonadotropin‐releasing hormone receptor pathway. Interestingly, activation of gonadotropin‐releasing hormone receptor caused G‐protein αi‐mediated activation of phospho‐tyrosine phosphatase, resulting in dephosphorylated EGF receptor (EGFR) and inhibited EGFR signal transduction through the phosphorylated ERK1/2 or the phosphorylated PI3K/AKT pathway 22–24 . EGFR‐signaling has consistently been found to upregulate tissue factor (TF) in glioma, hepatocellular carcinoma and colorectal cancer cells, providing a potential link to the cause of VTE 22–25 .…”

Section: Resultsmentioning

confidence: 99%

“…[22][23][24] EGFR-signaling has consistently been found to upregulate tissue factor (TF) in glioma, hepatocellular carcinoma and colorectal cancer cells, providing a potential link to the cause of VTE. [22][23][24][25] Alternatively, TF can activate the pERK and pAKT pathway and subsequently activate the EGFR pathway, thus creating a positive feedback loop. 25 Because of our study's exploratory nature, an FDR cutoff of 0.1 was chosen; therefore, it could be expected that two miRNAs…”

Section: Re Sults and Discussionmentioning

confidence: 99%

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Tumor‐expressed microRNAs associated with venous thromboembolism in colorectal cancer

Anijs

Laghmani

Ünlü

et al. 2022

Research and Practice in Thrombosis and Haemostasis

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Background Colorectal cancer patients have an increased risk of developing venous thromboembolism (VTE), resulting in increased morbidity and mortality. Because the exact mechanism is yet unknown, risk prediction is still challenging; therefore, new biomarkers are needed. MicroRNAs (miRNAs) are small, relatively stable RNAs, that regulate a variety of cellular processes, and are easily measured in body fluids. Objective The aim of this study was to identify novel tumor‐expressed miRNAs associated with VTE. Methods In a cohort of 418 colorectal cancer patients diagnosed between 2001 and 2015 at the Leiden University Medical Center, 23 patients (5.5%) developed VTE 1 year before or after cancer diagnosis. Based on availability of frozen tumor material, tumor cells of 17 patients with VTE and 18 patients without VTE were isolated using laser capture microdissection and subsequently analyzed on the Illumina sequencing platform NovaSeq600 using 150‐bp paired‐end sequencing. Cases and controls were matched on age, sex, tumor stage, and grade. Differential miRNA expression was analyzed using edgeR. Results A total of 547 miRNAs were detected. Applying a 1.5‐fold difference and false discovery rate of <0.1, 19 tumor‐miRNAs were differentially regulated in VTE cases versus controls, with hsa‐miR‐3652, hsa‐miR‐92b‐5p, and hsa‐miR‐10,394‐5p as most significantly downregulated. Seven of the 19 identified miRNAs were predicted to regulate the gonadotropin‐releasing hormone receptor pathway. Conclusion We identified 19 differentially regulated tumor‐expressed miRNAs in colorectal cancer‐associated VTE, which may provide insights into the biological mechanism and in the future might have potential to serve as novel, predictive biomarkers.

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Crosstalk between TF/FVIIa and EGFR signaling in colorectal cancer cells

Cited by 5 publications

References 24 publications

Selective but not pan-CDK inhibition abrogates 5-FU-driven tissue factor upregulation in colon cancer

Selective but not pan-CDK inhibition abrogates 5-FU-driven tissue factor upregulation in colon cancer

KRAS-mutant colorectal cancer cell lines cause a prothrombotic state through the upregulation of thrombin: experimental study

Tumor‐expressed microRNAs associated with venous thromboembolism in colorectal cancer

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