Increased metastatic potential of tumor cells in von Willebrand factor-deficient mice

Abstract The role of von Willebrand factor (VWF) in thrombosis involves its binding to a number of ligands. To investigate the relative importance of these particular interactions in the thrombosis process, we have introduced mutations into murine VWF (mVWF) cDNA inhibiting VWF binding to glycoprotein (Gp) Ib, GPIIbIIIa, or to fibrillar collagen. These VWF mutants were expressed in VWF-deficient mice (VWF−/−) by using an hydrodynamic injection approach, and the mice were studied in the ferric chloride–induced injury model. Expression of the collagen and the GPIIbIIIa VWF-binding mutants in VWF−/− mice resulted in delayed thrombus growth and significantly increased vessel occlusion times compared with mice expressing wild-type (WT) mVWF (30 ± 3 minutes and 38 ± 4 minutes for the collagen and GPIIbIIIa mutants, respectively, vs 19 ± 3 minutes for WT mVWF). Interestingly, these mutants were able to correct bleeding time as efficiently as WT mVWF. In contrast, VWF−/− mice expressing the GPIb binding mutant failed to restore thrombus formation and were bleeding for as long as they were observed, confirming the critical importance of the VWF-GPIb interaction. Our observations suggest that targeting the VWF-collagen or VWF-GPIIbIIIa interactions could be an interesting alternative for new antithrombotic strategies.

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The Expression of von Willebrand Factor-Binding Protein Determines Joint-Invading Capacity of Staphylococcus aureus, a Core Mechanism of Septic Arthritis

mBio ◽

10.1128/mbio.02472-20 ◽

2020 ◽

Vol 11 (6) ◽

Author(s):

Manli Na ◽

Zhicheng Hu ◽

Majd Mohammad ◽

Mariana do Nascimento Stroparo ◽

Abukar Ali ◽

...

Keyword(s):

Septic Arthritis ◽

Von Willebrand Factor ◽

Binding Protein ◽

Joint Diseases ◽

Wild Type ◽

Content Type ◽

Factor Binding ◽

Von Willebrand ◽

Willebrand Factor ◽

Deficient Mice

ABSTRACT Septic arthritis, one of the most dangerous joint diseases, is predominantly caused by Staphylococcus aureus. In contrast, coagulase-negative staphylococci are rarely found in septic arthritis. We hypothesize that coagulases released by S. aureus, including coagulase (Coa) and von Willebrand factor-binding protein (vWbp), play potent roles in the induction of septic arthritis. Four isogenic S. aureus strains differing in expression of coagulases (wild-type [WT] Newman, Δcoa, Δvwb, and Δcoa Δvwb) were used to induce septic arthritis in both wild-type and von Willebrand factor (vWF)-deficient mice. Septic arthritis severity was greatly reduced when wild-type mice were infected with the Δcoa Δvwb and Δvwb variants compared to WT or Δcoa strains, suggesting that vWbp rather than Coa is a major virulence factor in S. aureus septic arthritis. vWF-deficient mice were more susceptible to bone damage in septic arthritis, especially when the Δvwb strain was used. Importantly, no difference in arthritis severity between the Δvwb and WT strains was observed in vWF-deficient mice. Collectively, we conclude that vWbp production by S. aureus enhances staphylococcal septic arthritis. IMPORTANCE Septic arthritis remains one of the most dangerous joint diseases with a rapidly progressive disease character. Despite advances in the use of antibiotics, permanent reductions in joint function due to joint deformation and deleterious contractures occur in up to 50% of patients with septic arthritis. So far, it is still largely unknown how S. aureus initiates and establishes joint infection. Here, we demonstrate that von Willebrand factor-binding protein expressed by S. aureus facilitates the initiation of septic arthritis. Such effect might be mediated through its interaction with a host factor (von Willebrand factor). Our finding contributes significantly to the full understanding of septic arthritis etiology and will pave the way for new therapeutic modalities for this devastating disease.

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Emerging Roles for von Willebrand Factor in Cancer Cell Biology

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0037-1607352 ◽

2017 ◽

Vol 44 (02) ◽

pp. 159-166 ◽

Cited By ~ 12

Author(s):

Roger Preston ◽

Tracy Robson ◽

James O'Donnell ◽

Jamie O'Sullivan

Keyword(s):

Tumor Cell ◽

Tumor Cells ◽

Cancer Cell ◽

Von Willebrand Factor ◽

Cell Biology ◽

Tumor Metastasis ◽

Human Tumor ◽

Advanced Tumor Stage ◽

Von Willebrand ◽

Willebrand Factor

Abstractvon Willebrand factor (VWF) is a complex multimeric plasma glycoprotein that plays critical roles in normal hemostasis. However, additional novel roles for VWF in modulating cancer cell biology, and in particular tumor metastasis, have recently been reported. Markedly elevated plasma VWF levels were associated with advanced tumor stage and metastatic disease. These observations have raised the question of whether VWF may be involved in regulating tumor progression. Interestingly, novel findings indicate that VWF is expressed by a variety of tumor cells of nonendothelial origin. Critically, tumor cells that exhibit de novo acquired VWF expression demonstrate enhanced binding to endothelial cells (EC) and platelets, and increased extravasation through EC barriers. Furthermore, in vitro studies have shown that VWF can bind a variety of different tumor cells mediated by specific receptors expressed on the tumor cell surface. The concept that VWF is important in modulating tumor metastasis is further supported by in vivo experiments demonstrating that antibody-mediated VWF inhibition significantly attenuated murine metastasis. Intriguingly, however, VWF binding to specific human tumor cell lines results in apoptosis. In this study, the authors provide an overview of recent advances supporting a role for VWF in regulating multiple aspects of cancer cell biology.

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von Willebrand Factor Deficient Mice.

Japanese Journal of Thrombosis and Hemostasis ◽

10.2491/jjsth.10.212 ◽

1999 ◽

Vol 10 (2/3) ◽

pp. 212-218 ◽

Cited By ~ 2

Author(s):

Hisashi YANO ◽

Kazuhiko TOMOKIYO ◽

Jun MIZUGUCHI

Keyword(s):

Von Willebrand Factor ◽

Von Willebrand ◽

Willebrand Factor ◽

Deficient Mice

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A Threshold Level of Von Willebrand Factor Is Required for Disease Pathogenesis in a Mouse Model of TTP.

Blood ◽

10.1182/blood.v108.11.177.177 ◽

2006 ◽

Vol 108 (11) ◽

pp. 177-177

Author(s):

David G. Motto ◽

Guojing Zhu ◽

Denisa D. Wagner ◽

David Ginsburg

Keyword(s):

Mouse Model ◽

Von Willebrand Factor ◽

Genetic Background ◽

Critical Role ◽

Threshold Level ◽

Bacterial Agent ◽

Absolute Requirement ◽

Von Willebrand ◽

Willebrand Factor ◽

Deficient Mice

Abstract Thrombotic Thrombocytopenic Purpura (TTP) is a life threatening systemic illness associated with inherited or acquired deficiency of the ADAMTS13 metalloprotease. ADAMTS13 deficiency results in the appearance of ultra-large multimers of von Willebrand Factor (UL-VWF) in the circulation, which are thought to play a central role in the formation of the platelet-rich thrombi which are the pathological hallmark of this disease. Despite the critical role postulated for VWF in TTP pathogenesis, direct experimental evidence in support of this hypothesis is lacking. Recently we demonstrated that a TTP-like syndrome can be induced in ADAMTS13-deficient mice of a mixed CASA/Rk genetic background (Adamts13CASA−/−) by the bacterial agent shigatoxin. As pure CASA/Rk mice exhibit VWF levels 5 to 10-fold higher than most of the common strains of laboratory mice, we hypothesized that increased plasma VWF levels in the Adamts13CASA−/− mice (which ranged from 200–600% of C57BL/6) were responsible for their increased TTP susceptibility. Surprisingly however, plasma VWF levels did not correlate with the degree of thrombocytopenia or hemolytic anemia induced in Adamts13CASA−/− mice by shigatoxin challenge, with mice inheriting the lowest VWF levels having TTP pathology equal to those inheriting the highest levels. To further examine the requirement for VWF in TTP pathogenesis, we generated ADAMTS13-deficient mice on a susceptible CASA/Rk genetic background that were also either haploinsufficient (Vwf+/−) or completely deficient (Vwf−/−) in VWF. Absolute deficiency of VWF resulted in complete protection from shigatoxin-induced thrombocytopenia. However, thrombocytopenia was consistently observed in Vwf+/− mice similar to that previously reported in Adamts13CASA−/− mice with wild-type VWF. Importantly, again no correlation was observed between VWF level and degree of thrombocytopenia among the ADAMTS13-deficient mice that were Vwf haploinsufficient (Vwf+/−), confirming our previous observation. In summary, we now have demonstrated an absolute requirement for VWF in the pathogenesis of TTP in this mouse model system. Together with the observations that increasing VWF levels do not correlate with increasing TTP pathology, these results suggest that a threshold level of VWF is required for induction of TTP, but that further increases of VWF level do not result in worsening disease. Though these findings remain to be confirmed in humans, our data suggest that the wide variation in plasma VWF levels in the human population will not be a significant determinant of TTP susceptibility or disease severity.

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Von Willebrand Factor (VWF) Regulates Angiogenesis: Studies in Blood-Derived Endothelial Progenitor Cells From Von Willebrand's Disease Patients and VWF-Deficient Mice

Blood ◽

10.1182/blood.v118.21.5311.5311 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5311-5311

Author(s):

Richard D Starke ◽

Koralia Paschalaki ◽

Francesco Ferraro ◽

Thomas A J McKinnon ◽

Nicola H Dryden ◽

...

Keyword(s):

Endothelial Cells ◽

Von Willebrand Factor ◽

Vascular Network ◽

Vascular Density ◽

Type I ◽

Von Willebrand ◽

Willebrand Factor ◽

In Vitro Angiogenesis ◽

Deficient Mice

Abstract Abstract 5311 Dysregulation of angiogenesis is implicated in many diseases. Von Willebrand factor (VWF), a large plasma glycoprotein essential for normal haemostasis is synthesized by endothelial cells (EC) and megakaryocytes. Raised VWF plasma levels are a risk factor for arterial thrombosis, whilst deficiency of VWF causes Von Willebrand disease (VWD), the most common congenital bleeding disorder in man. VWD can be associated with angiodysplasia, vascular malformations linked to defective angiogenesis which are responsible for intractable bleeding. We recently showed that VWF is involved in angiogenesis. Inhibition of VWF expression in human umbilical vein EC (HUVEC) with specific siRNA resulted in increased in vitro angiogenesis on Matrigel, proliferation and migration. Mechanism studies implicated the endothelial VWF receptor, integrin αvβ3 and the angiogenesis regulator angiopoietin-2. The findings were confirmed in EC from VWD patients and in VWF-deficient mice. Blood outgrowth endothelial cells (BOEC) isolated from peripheral blood of patients with VWD showed decreased VWF release, compared to control BOEC, and increased in vitro angiogenesis, migration and proliferation, similar to what observed with VWF siRNA-treated HUVEC. In vivo studies using the matrigel model and imaging of blood vessels in the ear showed increased angiogenesis and vascular network in VWF-deficient mice compared to controls. Recent studies in patients BOEC and in VWF deficient mice provide new insight into the complexity of this phenotype. We have used the mouse model of post-natal angiogenesis in the retina to carry out detailed analysis of angiogenic networks in the VWF-deficient mouse, and found increased vascular density and defective vascular network. Moreover, using BOEC from patients with type I and type II VWD, we have studied VWF intracellular distribution by immunofluorescence confocal analysis and found patterns of expression that point to a variety of defects in synthesis, storage and secretion. These studies define a new function for VWF, which may have clinical implications for VWD and for patients at risk of CV disease. Moreover, studies with BOEC from VWF patients provide a novel understanding of the physiopathology of this disease. Disclosures: No relevant conflicts of interest to declare.

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Defect in regulated secretion of P-selectin affects leukocyte recruitment in von Willebrand factor-deficient mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.061307098 ◽

2001 ◽

Vol 98 (7) ◽

pp. 4072-4077 ◽

Cited By ~ 109

Author(s):

C. V. Denis ◽

P. Andre ◽

S. Saffaripour ◽

D. D. Wagner

Keyword(s):

Von Willebrand Factor ◽

Leukocyte Recruitment ◽

Regulated Secretion ◽

Von Willebrand ◽

Willebrand Factor ◽

Deficient Mice

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Platelet mediated TRAIL delivery for efficiently targeting circulating tumor cells

Nanoscale Advances ◽

10.1039/d0na00271b ◽

2020 ◽

Vol 2 (9) ◽

pp. 3942-3953 ◽

Cited By ~ 1

Author(s):

Nerymar Ortiz-Otero ◽

Jocelyn R. Marshall ◽

Bradley W. Lash ◽

Michael R. King

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Von Willebrand Factor ◽

Cancer Metastasis ◽

Liposomal Formulation ◽

Von Willebrand ◽

Willebrand Factor

Liposomal formulation to deliver TNF-related apoptosis-inducing ligand (TRAIL) to platelets via von Willebrand Factor (vWF) interaction. TRAIL-coated platelets killed circulating tumor cells (CTCs) in the bloodstream to reduce cancer metastasis.

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