Targeting clotting proteins in cancer therapy – progress and challenges

Ruf, Wolfram; Rothmeier, Andrea S.; Graf, Claudine

doi:10.1016/s0049-3848(16)30090-1

Cited by 22 publications

(31 citation statements)

References 117 publications

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“…Vimentin silencing also decreased the ability of tumor cells to accomplish metastatic colonization when injected as CTCs in experimental metastasis assays. These data bridge two independent sets of literature data including ours supporting, on one hand, that EMT-shifted CTCs represent a subpopulation of CTCs with enhanced metastatic competence and, on the other hand, that TF-dependent coagulant properties of CTCs facilitate their survival in the blood stream and metastatic colonization [10][11][12]30]. Accordingly, we previously reported the existence of CTCs co-expressing vimentin and TF in the blood of breast cancer patients [21].…”

Section: Discussionsupporting

confidence: 85%

“…Several pieces of work support a contribution of coagulation in the process. Hypercoagulability is actually a long known correlate of malignancy and venous thromboembolism has been associated with worse prognosis [10][11][12]. In particular, CTCs have recently been associated with increased risk of venous thrombosis in cancer patients [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

“…If TF also triggers cellular signaling events that facilitate tumor progression [12,28,29], a determinant role of TF-associated coagulation mechanisms in supporting metastasis has been demonstrated [10,12,17,30,31]. Notwithstanding the implication of TF-bearing tumorderived microparticles in hypercoagulability, a local activation of coagulation is more particularly considered to contribute to the creation of a pericellular fibrin/platelet-rich cocoon protecting CTCs against shear stress, anoikis and immune attack and also providing a favorable niche for their early metastatic seeding [10,12,13,17,30,32].…”

Section: Introductionmentioning

confidence: 99%

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Vimentin prevents a miR-dependent negative regulation of tissue factor mRNA during epithelial–mesenchymal transitions and facilitates early metastasis

et al. 2020

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Epithelial-mesenchymal transitions (EMTs) are high-profile in the field of circulating tumor cells (CTCs). EMT-shifted CTCs are considered to encompass pre-metastatic subpopulations though underlying molecular mechanisms remain elusive. Our previous work identified tissue factor (TF) as an EMT-induced gene providing tumor cells with coagulant properties and supporting metastatic colonization by CTCs. We here report that vimentin, the type III intermediate filament considered a canonical EMT marker, contributes to TF regulation and positively supports coagulant properties and early metastasis. Different evidence further pointed to a new post-transcriptional regulatory mechanism of TF mRNA by vimentin: (1) vimentin silencing accelerated TF mRNA decay after actinomycin D treatment, reflecting TF mRNA stabilization, (2) RNA immunoprecipitation revealed enriched levels of TF mRNA in vimentin immunoprecipitate, (3) TF 3′-UTR-luciferase reporter vector assays implicated the 3′-UTR of TF mRNA in vimentin-dependent TF regulation, and (4) using different TF 3′UTR-luciferase reporter vectors mutated for potential miR binding sites and specific Target Site Blockers identified a key miR binding site in vimentin-dependent TF mRNA regulation. All together, these data support a novel mechanism by which vimentin interferes with a miR-dependent negative regulation of TF mRNA, thereby promoting coagulant activity and early metastasis of vimentin-expressing CTCs.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Vimentin prevents a miR-dependent negative regulation of tissue factor mRNA during epithelial–mesenchymal transitions and facilitates early metastasis

et al. 2020

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“…Although coagulation disorders in individuals with cancer are multifactorial in origin, several studies have reported the important role of coagulation activity in cancer progression (16,17). Vitamin K, a fat-soluble vitamin, is necessary for the blood coagulation cascade.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Impact of Coagulation Activity in Patients Undergoing Curative Resection for Pancreatic Ductal Adenocarcinoma

Matsumura

Hayashi

Uemura

et al. 2020

In Vivo

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Background/Aim: The aim of this study was to elucidate the clinical impact of coagulation disorders on outcomes after curative resection of pancreatic ductal adenocarcinoma. Patients and Methods: Preoperative coagulation activity in 135 patients, who had undergone curative resections for pancreatic ductal adenocarcinoma was retrospectively evaluated and the impact on survival outcomes analyzed. Results: A prolonged prothrombin timeinternational normalized ratio (PT-INR) (≥1.1) was detected in 23/135 patients (17%). Univariate analysis that showed prolonged PT-INR was associated with worse relapse-free (hazard ratio=1.79, p=0.044) and overall (hazard ratio=2.18, p=0.004) survival. Multivariate analyses showed prolonged PT-INR, large tumor (>30 mm), and lymph node metastasis were independent predictors of poor overall survival. Conclusion: Prolonged PT-INR may be a predictor of poor prognosis in patients with pancreatic ductal adenocarcinoma who have undergone curative resection. Coagulation disorders may be a therapeutic target for improving outcomes of pancreatic ductal adenocarcinoma. Pancreatic ductal adenocarcinoma (PDAC) comprises 85% of pancreatic cancer cases and remains one of the most common and aggressive malignancies, with a 5-year survival rate of approximately 20% despite improvements in achieving macroscopically curative resection with surgical procedures and adjuvant chemotherapy (1). Several clinical trials have shown that neoadjuvant therapies can prolong survival in patients with PDAC because such therapies can down-stage PDAC and thus improve the curative resection rate. However, it remains to be determined which regimen is the most suitable for PDAC according to each patient's clinical, genetic, and performance status (2). To improve selection of treatment strategies for PDAC and its outcomes, prognostic biomarkers that can be measured easily and reliably are needed to optimally evaluate tumor aggressiveness. A close association between cancer biology and coagulation disorders that has an impact on tumor progression has been reported (3). Hypercoagulability is more likely to occur in patients with pancreatic cancer than in those with other types of cancer (4). Patients with pancreatic cancer are predisposed to developing venous thromboembolic events (VTEs) (5). VTEs in patients with cancer are caused by hypercoagulable states and associated with a poor prognosis (6). Pancreatic resection is also associated with VTEs (7). In patients with hepatocellular carcinoma, coagulation disorders are associated with various complications and poor prognosis (8). Increased fibrinogen, fibrin split products, and D-dimer levels have been associated with worse survival outcomes in patients with breast and colorectal cancer (9-11). In patients with lung cancer, a prolonged prothrombin time-international normalized ratio (PT-INR) was found to be associated with worse survival outcomes (12). However, the clinical impact of coagulation disorders in PDAC is still unclear. Therefore, the purpose of this study was to ...

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“…On the other hand, several studies point out that blood coagulation proteins develop an important role in tumor progression [ 37 ]. These works discussed the impact of the activation of the blood clotting cascade on primary tumor growth [ 38 ], tumor metastasis and cancer-associated thrombosis [ 39 ] and antitumor therapies that target blood-coagulation-associated proteins [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Protein Corona Gold Nanoparticles Fingerprinting Reveals a Profile of Blood Coagulation Proteins in the Serum of HER2-Overexpressing Breast Cancer Patients

Chantada-Vázquez

López

García-Vence

et al. 2020

IJMS

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Breast cancer (BC) is a molecularly heterogeneous disease that encompasses five major molecular subtypes (luminal A (LA), luminal B HER2 negative (LB-), luminal B HER2 positive (LB+), HER2 positive (HER2+) and triple negative breast cancer (TNBC)). BC treatment mainly depends on the identification of the specific subtype. Despite the correct identification, therapies could fail in some patients. Thus, further insights into the genetic and molecular status of the different BC subtypes could be very useful to improve the response of BC patients to the range of available therapies. In this way, we used gold nanoparticles (AuNPs, 12.96 ± 0.72 nm) as a scavenging tool in combination with Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) to quantitatively analyze the serum proteome alterations in the different breast cancer intrinsic subtypes. The differentially regulated proteins specific of each subtype were further analyzed with the bioinformatic tools STRING and PANTHER to identify the major molecular function, biological processes, cellular origin, protein class and biological pathways altered due to the heterogeneity in proteome of the different BC subtypes. Importantly, a profile of blood coagulation proteins was identified in the serum of HER2-overexpressing BC patients.

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Targeting clotting proteins in cancer therapy – progress and challenges

Cited by 22 publications

References 117 publications

Vimentin prevents a miR-dependent negative regulation of tissue factor mRNA during epithelial–mesenchymal transitions and facilitates early metastasis

Vimentin prevents a miR-dependent negative regulation of tissue factor mRNA during epithelial–mesenchymal transitions and facilitates early metastasis

Prognostic Impact of Coagulation Activity in Patients Undergoing Curative Resection for Pancreatic Ductal Adenocarcinoma

Protein Corona Gold Nanoparticles Fingerprinting Reveals a Profile of Blood Coagulation Proteins in the Serum of HER2-Overexpressing Breast Cancer Patients

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