Heparins that block VEGF-A-mediated von Willebrand factor fiber generation are potent inhibitors of hematogenous but not lymphatic metastasis

Goertz, Lukas; Schneider, Stefan W.; Desch, Anna; Mayer, Frank Thomas; Koett, Julian; Nowak, Kai; Karampinis, Ioannis; Bohlmann, Michael K.; Umansky, Viktor; Bauer, Alexander

doi:10.18632/oncotarget.11832

Cited by 37 publications

(58 citation statements)

References 67 publications

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“…Besides the antithrombotic impact of LMWHs, accumulating clinical evidence suggests that LMWH significantly improve disease progression and OS directly by its antitumor effect. Indeed, in vitro and in vivo studies also from our group have shown that LMWHs could influence angiogenesis, cancer cell adhesion, tumor cell proliferation, local tumor growth and metastases through a number of coagulation‐independent mechanisms …”

Section: Discussionmentioning

confidence: 98%

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D‐dimers in malignant melanoma: Association with prognosis and dynamic variation in disease progress

Desch

Gebhardt

Utikal

et al. 2016

Intl Journal of Cancer

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Malignant cells elicit a chronic hemostatic activation in disease progress. This procoagulant activity does not only bear a risk for thromboembolism but also facilitates tumor growth and dissemination. An elevated plasma D-dimer level indicates an activated coagulation and fibrinolysis. In this study, the association of D-dimer levels with clinicopathological parameters and patients outcome in melanoma was investigated analyzing in total 533 melanoma patients retrospectively. Using the cut-off point of 0.6 mg/L D-dimer 145 of the total 533 patients (27.2%) were identified with elevated plasma D-dimer levels. This increased D-dimer level positively correlated with tumor thickness (p = 0.0003), lymph node invasion (p = 0.0004) and metastatic state (p <0.0001). To assess the association of D-dimer levels with progression-free survival (PFS) and overall survival (OS), long-rank test and the Cox proportional hazard model was performed. Univariate analyses revealed that elevated D-dimer levels were significantly associated with decreased PFS (HR:2.89, 95% CI (2.07-7.56), p < 0.0001) and OS (HR:2.22, 95% CI (1.06-4.57), p = 0.035). Moreover, multivariate analyses identified elevated D-dimer levels being associated with poor disease outcome (PFS:HR:2.47, 95% CI (1.23-4.98), p = 0.012; OS:HR:2.01, 95% CI (0.09-4.45), p = 0.087). Additionally, D-dimer levels were significantly increased in terminal stage patients when comparing plasma levels 0-8 versus 24-48 weeks before death (p = 0.0003). In summary, this study presents multiple evidence that elevated D-dimer levels in melanoma patients associate with poor prognosis and therefore plasma levels of D-dimers could reveal a more aggressive phenotype of melanoma and may guide the management of anti-melanoma treatment including the concept of an anti-coagulatory therapy in tumor patients.

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Section: Discussionmentioning

confidence: 98%

“…In order to address the problem of activated coagulation in cancer patients several studies have focused on the effect of heparin on tumor progression . Recent clinical studies have demonstrated an inhibitory effect of low molecular weight heparins (LMWH) on tumor growth and metastasis, resulting in a beneficial effect on the survival of cancer patients …”

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confidence: 99%

D‐dimers in malignant melanoma: Association with prognosis and dynamic variation in disease progress

Desch

Gebhardt

Utikal

et al. 2016

Intl Journal of Cancer

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“…41 We generated primary melanomas characterized by well-defined disease progression and active luminal VWF secretion from the endothelium. 4,42 Our previous studies already suggested potential cross talk between VWF and the endothelial glycocalyx because therapy with the low molecular-weight heparin tinzaparin blocked the formation of VWF fiber networks in tumor-bearing mice. Suppressed fiber formation was associated with a reduced tumor-cell progression, underlining the potential biological relevance of an endothelial glycocalyx-mediated anchorage of VWF.…”

Section: Discussionmentioning

confidence: 98%

The endothelial glycocalyx anchors von Willebrand factor fibers to the vascular endothelium

et al. 2018

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The dynamic change from a globular conformation to an elongated fiber determines the ability of von Willebrand factor (VWF) to trap platelets. Fiber formation is favored by the anchorage of VWF to the endothelial cell surface, and VWF-platelet aggregates on the endothelium contribute to inflammation, infection, and tumor progression. Although P-selectin and ανβ3-integrins may bind VWF, their precise role is unclear, and additional binding partners have been proposed. In the present study, we evaluated whether the endothelial glycocalyx anchors VWF fibers to the endothelium. Using microfluidic experiments, we showed that stabilization of the endothelial glycocalyx by chitosan oligosaccharides or overexpression of syndecan-1 (SDC-1) significantly supports the binding of VWF fibers to endothelial cells. Heparinase-mediated degradation or impaired synthesis of heparan sulfate (HS), a major component of the endothelial glycocalyx, reduces VWF fiber–dependent platelet recruitment. Molecular interaction studies using flow cytometry and live-cell fluorescence microscopy provided further evidence that VWF binds to HS linked to SDC-1. In a murine melanoma model, we found that protection of the endothelial glycocalyx through the silencing of heparanase increases the number of VWF fibers attached to the wall of tumor blood vessels. In conclusion, we identified HS chains as a relevant binding factor for VWF fibers at the endothelial cell surface in vitro and in vivo.

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“…As a mechanistic explanation of this association it was hypothesized that cancer‐related VTE may be based on VWF‐mediated platelet aggregation . Bauer et al recently demonstrated in vitro that melanoma cells can activate vascular endothelial cells and prompt them to release ULVWF which is followed by platelet aggregation.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, in this study both VWF−/− and ADAMTS‐13−/− mice showed more metastatic lung foci. The authors hypothesize that VWF‐deficient mice come with further alteration of endothelial cell physiology (like missing Weibel palade bodies and dysregulated secretion of pro‐metastatic factors), which may be responsible for the increased metastatic potential …”

Section: Discussionmentioning

confidence: 99%

The role of ADAMTS‐13 and von Willebrand factor in cancer patients: Results from the Vienna Cancer and Thrombosis Study

Obermeier

Riedl

et al. 2019

Research and Practice in Thrombosis and Haemostasis

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Cancer is associated with increased risk of developing venous thrombosis. Cancer patients were studied for ADAMTS‐13 and VWF levels and occurrence of venous thrombosis. Increased VWF in cancer patients is associated with a higher risk of venous thrombosis. Low levels of ADAMTS‐13 and/or increased VWF in cancer patients are associated with worse survival. Background Cancer‐associated venous thromboembolism (VTE) is an important complication in the course of a malignant disease. Low ADAMTS‐13 (a disintegrin‐like and metalloproteinase with thrombospondin type 1 motif 13) and increased von Willebrand Factor (VWF) levels in cancer patients have been described numerously. Objectives Investigation of the influence of ADAMTS‐13 and VWF on the probability of VTE and survival in malignancy. Patients/Methods In the framework of the ongoing prospective Cancer and Thrombosis Study (CATS) ADAMTS‐13 activity and VWF antigen levels were investigated in cancer patients. Results In total, 795 patients with various tumor types (364 female/431 male, median age 62 years) were included; of those, 56 developed VTE and 359 patients died during a median follow‐up time of 730 days. The hazard ratio (HR) of VTE per doubling of VWF level was 1.56 (95% confidence interval [CI] 1.13‐2.16) in multivariable competing risk analysis. ADAMTS‐13 levels showed no correlation with the incidence of VTE in univariate competing risk analysis. The HR of mortality per doubling of VWF level was 1.46 (95% CI 1.28‐1.66) and per SD increment of ADAMTS‐13was 0.90 (95% CI 0.81‐1.00) in multivariable Cox regression analysis. Patients with VWF >75th percentile and concomitant low (<25th percentile) or medium (25‐75th percentile) ADAMTS‐13 values had the highest probability of mortality (HR 4.31 and 4.75, respectively). Conclusions High VWF levels were significantly associated with the risk of developing VTE in cancer patients, whereas ADAMTS‐13 was not. Low ADAMTS‐13 and increased VWF levels were independently associated with worse overall survival.

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Heparins that block VEGF-A-mediated von Willebrand factor fiber generation are potent inhibitors of hematogenous but not lymphatic metastasis

Cited by 37 publications

References 67 publications

D‐dimers in malignant melanoma: Association with prognosis and dynamic variation in disease progress

D‐dimers in malignant melanoma: Association with prognosis and dynamic variation in disease progress

The endothelial glycocalyx anchors von Willebrand factor fibers to the vascular endothelium

The role of ADAMTS‐13 and von Willebrand factor in cancer patients: Results from the Vienna Cancer and Thrombosis Study

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