Heparan sulfate dependent binding of plasmatic von Willebrand factor to blood circulating melanoma cells attenuates metastasis.

Heparan sulfate (HS), a highly negatively charged glycosaminoglycan, is ubiquitously present in all tissues and also exposed on the surface of mammalian cells. A plethora of molecules such as growth factors, cytokines or coagulation factors bear HS binding sites. Accordingly, HS controls the communication of cells with their environment and therefore numerous physiological and pathophysiological processes such as cell adhesion, migration, and cancer cell metastasis. In the present work, we found that HS exposed by blood circulating melanoma cells recruited considerable amounts of plasmatic von Willebrand factor (vWF) to the cellular surface. Analyses assisted by super-resolution microscopy indicated that HS and vWF formed a tight molecular complex. Enzymatic removal of HS or genetic engineering of the HS biosynthesis showed that a reduced length of the HS chains or complete lack of HS was associated with significantly reduced vWF encapsulation. In microfluidic experiments, mimicking a tumor-activated vascular system, we found that vWF-HS complexes prevented vascular adhesion. In line with this, single molecular force spectroscopy suggested that the vWF-HS complex promoted the repulsion of circulating cancer cells from the blood vessel wall to counteract metastasis. Experiments in wild type and vWF knockout mice confirmed that the HS-vWF complex at the melanoma cell surface attenuated hematogenous metastasis, whereas melanoma cells lacking HS evade the anti-metastatic recognition by vWF. Analysis of tissue samples obtained from melanoma patients validated that metastatic melanoma cells produce less HS. Transcriptome data further suggest that attenuated expression of HS-related genes correlate with metastases and reduced patients' survival. In conclusion, we showed that HS-mediated binding of plasmatic vWF to the cellular surface can reduce the hematogenous spread of melanoma. Cancer cells with low HS levels evade vWF recognition and are thus prone to form metastases. Therefore, therapeutic expansion of the cancer cell exposed HS may prevent tumor progression.

Clinical outcomes of cryoballoon ablation for pulmonary vein isolation: Impact of intraprocedural heart rhythm.

BACKGROUND: The current study sought to assess the impact of the intraprocedural heart rhythm (sinus rhythm [SR] vs. atrial fibrillation [AF]) on acute procedural characteristics, durability of pulmonary vein isolation (PVI) and long-term clinical outcomes of cryoballoon (CB) ablation. METHODS: A total of 195 patients with symptomatic paroxysmal (n = 136) or persistent AF (n = 59) underwent CB-based PVI. Ablation procedures were either performed in SR (SR group; n = 147) or during AF (AF group; n = 48). Persistent AF was more frequent in the AF group than in the SR group (62% vs. 20%). All other patient baseline characteristics did not differ between the two groups. RESULTS: The nadir temperature during the CB applications was significantly lower in the AF group than in patients in the SR group (-49 [interquartile range, -44; -54]°C vs. -47 [-42; -52]°C, p = 0.002). Median procedure and fluoroscopy times as well as the rate of real-time recordings were not different between the two groups. Repeat ablation for the treatment of atrial arrhythmia recurrence was performed in 60 patients (SR: 44 [30%] patients; AF: 16 [33%] patients), with a trend towards a lower rate of pulmonary vein reconnections in the AF group (p = 0.07). There was no difference in 3-year arrhythmia-free survival (p = 0.8). CONCLUSIONS: Cryoballoon-based PVI during AF results in lower nadir balloon temperatures and a trend towards a higher durability of PVI as compared to procedures performed in SR. The rate of real-time PVI recordings was not affected by the intraprocedural heart rhythm.