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Desch, A.* ; Strozyk, E.A. ; Bauer, A.T.* ; Huck, V.* ; Niemeyer, V.* ; Wieland, T.* ; Schneider, S.W.*

Highly invasive melanoma cells activate the vascular endothelium via an MMP-2/Integrin αvβ5-induced secretion of VEGF-A.

Am. J. Pathol. 181, 693-705 (2012)
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Tumor cell extravasation is a critical step in the metastatic cascade and requires interaction between the tumor cell and the endothelium. Although cancer progression depends on a complex network of mechanisms, including inflammation and coagulation, the involvement of tumor-induced endothelium activation and the subsequent release of procoagulatory factors in this process are not well understood. Using tissue sections from patients with malignant melanoma, immunofluorescence studies for the presence of von Willebrand factor (VWF) clearly demonstrated endothelium activation and the formation of ultra-large VWF fibers in these patients. In vitro analyses revealed that supernatants from highly invasive melanoma cells induced an acute endothelium activation measured by VWF, P-selectin, and angiopoietin-2 release. Proteome profiling identified vascular endothelial growth factor A (VEGF-A) as the main mediator of endothelium activation. Inhibition and knock-down of VEGF-A in melanoma cells led to a rigorous decrease in VWF exocytosis. Selective small-interfering RNA to matrix metalloproteinase-2 (MMP-2) inhibited endothelium activation, and this effect correlated with reduced VEGF-A content in the supernatants of melanoma cells. Further experiments showed that active MMP-2 regulates VEGF-A in melanoma cells on a transcriptional level via an integrin alpha v beta 5/phosphoinositide-3-kinase dependent pathway. In conclusion, these results indicate an important role of VEGF-A in acute endothelium activation and provide clear evidence that MMP-2 plays a pivotal role in the autocrine regulation of VEGF-A expression in melanoma cells. (Ani J Pathol 2012, 181: 693-705,- http://dx.doi.org/10.1016/j.ajpath.2012.04.012)
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Publication type Article: Journal article
Document type Scientific Article
Keywords Molecular-Weight Heparin; Von-Willebrand-Factor; Nude-Mice; Tumor Progression; Growth-Factor; Cancer-Cells; P-Selectin; Venous Thromboembolism; Advanced Malignancy; Metastasis
Language english
Publication Year 2012
HGF-reported in Year 2012
ISSN (print) / ISBN 0002-9440
e-ISSN 1525-2191
Journal American Journal of Pathology, The
Quellenangaben Volume: 181, Issue: 2, Pages: 693-705 Article Number: , Supplement: ,
Publisher Elsevier
Reviewing status Peer reviewed
Institute(s) CCG Tumor Therapy with Hyperthermia (IMI-KTH)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Immune Response and Infection
PSP Element(s) G-521100-001
PubMed ID 22659470
DOI 10.1016/j.ajpath.2012.04.012
WOS ID WOS:000307141800033
Scopus ID 84864123612
Erfassungsdatum 2012-08-30
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