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

Author(s)

Lima, Luize G. ^[1] ; Oliveira, Andreia S. ^[1] ; Campos, Luiza C. ^[2] ; Bonamino, Martin ^[2] ; Chammas, Roger ^[3] ; Werneck, Claudio C. ^[4] ; Vicente, Cristina P. ^[5] ; Barcinski, Marcello A. ^[6] ; Petersen, Lars C. ^[7] ; Monteiro, Robson Q. ^[1]

Affiliation

^[1] Univ Fed Rio de Janeiro, Inst Med Biochem, Rio De Janeiro - Brazil

^[2] Natl Canc Inst, Div Expt Med, Rio De Janeiro - Brazil

^[3] Univ Sao Paulo, Sch Med, Expt Oncol Lab, Sao Paulo - Brazil

^[4] Univ Estadual Campinas, Dept Anat Cell Biol & Physiol & Biophys, Inst Biol, Sao Paulo - Brazil

^[5] Univ Estadual Campinas, Dept Biochem, Inst Biol, Sao Paulo - Brazil

^[6] Univ Sao Paulo, Dept Parasitol, Inst Biomed Sci, Sao Paulo - Brazil

^[7] Novo Nordisk AS, Biopharmaceut Res Unit, Malov - Denmark

• Document type: Journal article
• Source: THROMBOSIS AND HAEMOSTASIS; v. 106, n. 4, p. 712-723, OCT 2011.
• Web of Science Citations: 32

Abstract

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 IF-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 IF-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. (AU)

• FAPESP's process: 09/00950-3 - Evaluation of fibrillin-1's role in arterial thrombogenesis
• Grantee: Claudio Chrysostomo Werneck
• Support Opportunities: Regular Research Grants