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Abstract

The growth of primary tumours beyond a critical mass is dependent on angiogenesis. The switch to the angiogenic phenotype involves changes in the local equilibrium of cytokines with either pro- or anti-angiogenic properties. Vascular Endothelial Growth Factor (VEGF) is one of the major positive regulators of tumour angiogenesis. Serum VEGF is, in cancer patients, correlated with worse prognosis. Recent evidence suggests that platelets are the main contributors of serum VEGF. We demonstrate, ultrastructurally and with immunofluorescence techniques, the alpha granule and membranous localisation of VEGF and provide further evidence for the role of platelets, both in healthy individuals as in patients with locally and advanced breast cancer, in the storage of circulating VEGF. We also demonstrate that, linear with tumoural progression, platelets accumulate more VEGF. Enhanced production in bone marrow platelet progenitors as well as endocytosis of circulating VEGF by platelets and/or megakaryocytes could explain the higher VEGF load in platelets from advanced cancer patients. This study provides further evidence for a role of platelets in transporting VEGF.

In Vivo Evidence for Platelet-Induced Physiological Angiogenesis by a COX Driven Mechanism

“…VEGF is considered a key mediator of both pathological and physiological angiogenesis, and is contained within platelet α-granules [15]. Thus, inhibition of capillary sprouting by platelet depletion or inhibition could result from the absence or impairment of local VEGF delivery.…”

“…Patients with cancers and inflammatory disorders that induce pathological angiogenesis demonstrate higher platelet levels of growth factors, including VEGF [13], [14]. It is known that the higher VEGF levels parallels tumour progression, and platelets are activated in the circulation of such individuals [15]. Lyst bg mice lacking dense granules and lysosomes demonstrate normal inflammatory angiogenesis [16], suggesting a role for α-granule release.…”

Vascular endothelial growth factor production in polymyalgia rheumatica

“…Thus, platelets can be considered carriers of a biologically active fraction of VEGF that is delivered and released at the site of tissue damage. Therefore, as suggested by Salgado et al (44), VEGF detected in serum, rather than in plasma, may reflect the total amount of biologically active protein that is potentially available at systemic levels. Besides platelets, another potential source of serum VEGF is PBMC.…”

Platelet secretion in inflammatory and infectious diseases

“…Platelets not only uptake, or endocytose, particles and solutes from the surrounding environment, but also retain and transport these substances for prolonged period of time[45]. Endocytosis is an important process in platelets and megakaryocytes for loading certain granule cargo, such as fibrinogen (Fg) and vascular endothelial growth factor (VEGF)[46–48]. While the mechanisms of platelet endocytosis remain incompletely understood, recent studies demonstrate that adenosine 5′-diphosphate–ribosylation factor 6 (Arf6), a small guanosine triphosphate-binding protein, regulates integrin α2bβ3 trafficking and fibrinogen uptake[49].…”