Malignant transformation in melanocytes is associated with increased production of procoagulant microvesicles

Luize G. Lima; Andreia S. Oliveira; Luiza C. Campos; Martin Bonamino; Roger Chammas; Claudio C. Werneck; Cristina P. Vicente; Marcello A. Barcinski; Lars C. Petersen; Robson Q. Monteiro

doi:10.1160/TH11-03-0143

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 106(04): 712-723
DOI: 10.1160/TH11-03-0143

Cellular Proteolysis and Oncology

Schattauer GmbH

Malignant transformation in melanocytes is associated with increased production of procoagulant microvesicles

Authors

Luize G. Lima

¹Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Andreia S. Oliveira

¹Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Luiza C. Campos

²Division of Experimental Medicine, National Cancer Institute, Rio de Janeiro, Brazil
Martin Bonamino

²Division of Experimental Medicine, National Cancer Institute, Rio de Janeiro, Brazil
Roger Chammas

³Laboratory of Experimental Oncology, School of Medicine, University of São Paulo, São Paulo, Brazil
Claudio C. Werneck

⁴Department of Anatomy, Cell Biology and Physiology and Biophysics, Institute of Biology, University of Campinas, São Paulo, Brazil
Cristina P. Vicente

⁵Department of Biochemistry, Institute of Biology, University of Campinas, São Paulo, Brazil
Marcello A. Barcinski

⁶Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
Lars C. Petersen

⁷Biopharmaceuticals Research Unit, Novo Nordisk A/S, Måløv, Denmark
Robson Q. Monteiro

¹Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Abstract

Summary

Shedding of microvesicles (MVs) by cancer cells is implicated in a variety of biological effects, including the establishment of cancer-associated hypercoagulable states. However, the mechanisms underlying malignant transformation and the acquisition of procoagulant properties by tumour-derived MVs are poorly understood. Here we investigated the procoagulant and prothrombotic properties of MVs produced by a melanocyte-derived cell line (melan-a) as compared to its tumourigenic melanoma counterpart Tm1. Tumour cells exhibit a two-fold higher rate of MVs production as compared to melan-a. Melanoma MVs display greater procoagulant activity and elevated levels of the clotting initiator protein tissue factor (TF). On the other hand, tumour- and melanocyte- derived MVs expose similar levels of the procoagulant lipid phosphatidylserine, displaying identical abilities to support thrombin generation by the prothrombinase complex. By using an arterial thrombosis model, we observed that melanoma- but not melanocyte-derived MVs strongly accelerate thrombus formation in a TF-dependent manner, and accumulate at the site of vascular injury. Analysis of plasma obtained from melanoma-bearing mice showed the presence of MVs with a similar procoagulant pattern as compared to Tm1 MVs produced in vitro. Remarkably, flow-cytometric analysis demonstrated that 60% of ex vivo MVs are TF-positive and carry the melanoma-associated antigen, demonstrating its tumour origin. Altogether our data suggest that malignant transformation in melanocytes increases the production of procoagulant MVs, which may contribute for a variety of coagulation- related protumoural responses.

Keywords

Microvesicles - cancer - melanocyte transformation - thrombosis

Full Text

References

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