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Platelets and angiogenesis: novel aspects Expert. Rev. Hematol. 2(1), 1–2 (2009)
Jan Palmblad, MD, PhD Professor emeritus, Deptartment of Medicine and Hematology, The Karolinska Institutet and Karolinska University Hospital Huddinge, S141 86 Stockholm, Sweden Tel.: +46 5858 2693 Fax: +46 8711 7684
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“…our understanding of the platelet as a delivery system in hemostasis, tissue repair and angiogenesis, as well as being a watchdog for tumors, is remarkable.” Platelets are key elements in the regulation of hemostasis and thrombosis, and it is this function that many would say was their primary role. When passing by a wound in the vessel wall, platelets recognize inter alia, exposed collagen in the basal membrane and adhere to it and to each other. This releases various coagulation-regulating factors and forms the clot that prevents blood loss from injured vessels. Platelets can also be slightly overzealous, being involved in dangerous, even generalized, blood clotting, either as whole platelets or as ectosomes, often in cooperation with leukocytes and on the surface of endothelial cells.
“...platelets from tumor-bearing animals caused faster healing of wounds than platelets from healthy animals.” If we go back to the 1980s, another role for platelets emerged from research performed by several groups [1] . These investigators noted that, simultaneous with a release of coagulation-regulating factors, there was a release of growth factors for a number of cells in the vicinity of the injury, including endothelial cells and fibroblasts. This might be defined as the second role of a platelet – the healing function. This is still an interesting role, since local application of platelet preparations are advocated as a means to treat wounds and ulcers for faster healing [2,3] . A recent extension of this was the demonstration that platelets from tumor-bearing animals caused faster healing of wounds than platelets from healthy animals [4] . The third role for the platelet was outlined in the late 1990s, namely the release of angiogenic factors [5] . This might be www.expert-reviews.com
10.1586/17474086.2.1.1
regarded as an extension of the second role, that is, restoring the tissue infrastructure by providing pathways for delivery of oxygen and nutrients. However, this also demonstrated the possibility that increased platelet activity might be linked to angiogenesis necessary for tumor growth and, thus, tumor progression. Increased platelet counts were later found to be associated with tumor progression [6] . We recognize that as the thrombocythemia that occurs in some, often aggressive malignancies. The mechanisms for this have been further explored. In a series of elegant experiments, J Folkman and colleagues showed that the opposite (thrombocytopenia) reduced angiogenesis in experimental animals [7] . They further demonstrated that angiogenesisregulating proteins, including VEGF, were selectively pumped from a megakaryocyte in the bone marrow stroma through slim cytoplasmatic extensions that passed across the endothelial barrier into the blood vessels and then into the proplatelets [8] . Moreover, proa ngiogenic factors were localized in α-granules separate from those that harbored the antiangiogenic substances. These peptides were also differentially released. In beautiful in vivo video sequences, von Andrian and colleagues showed how these proplatelets detached from the megakaryocyte and followed the bloodstream [9] . Thus, the stage was set for delivery of angiogenic and angiostatic factors to various sites of the body, with the platelet as the delivery boy. The fourth role for a platelet has now been discovered. G Lakka Klement and colleagues have recently shown that platelets might also act as sponges and take up angiogenesis-regulating peptides. The first demonstration was the uptake of platelet factor-4 into platelets of tumor-bearing
© 2009 Expert Reviews Ltd
ISSN 1747-4086
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animals, representing a potential biomarker of early tumor progression [10] . Of note, platelet factor-4 levels were not elevated in plasma, only in platelets. It was then shown that platelets soaked up VEGF, PDGF, basic FGF and endostatin from various sources but, specifically, from not yet defined locations in tumor-bearing animals [11] . Again, this uptake was specific and plasma levels of these factors were not raised. Thus, the finetuned regulatory balance of the healthy host might be upset in tumors, which is consistent with H Dvorak’s notion that ‘tumors are wounds that do not heal’ [12] . The progress made in our understanding of the platelet as a delivery system in hemostasis, tissue repair and angiogenesis, References 1
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Möhle R, Green D, Moore MA, Nachman RL, Rafii S. Constitutive production and thrombin-induced release
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Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
of vascular endothelial growth factor by human megakaryocytes and platelets. Proc. Natl Acad. Sci. USA 94, 663–668 (1997).
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as well as being a watchdog for tumors, is remarkable. It is not known if we can use the latter ability for diagnostic purposes, but it could be intriguing.
Pinedo HM, Verheul HM, D’Amato RJ, Folkman J. Involvement of platelets in tumour angiogenesis? Lancet 352, 1775–1777 (1998). Kisucka J, Butterfield CE, Duda DG et al. Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage. Proc. Natl Acad. Sci. USA 103, 855–860 (2006).
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Italiano JE Jr, Richardson JL, Patel-Hett S et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet a-granules and differentially released. Blood 111, 1227–1233 (2008).
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Junt T, Schulze H, Chen Z et al. Dynamic visualization of thrombopoiesis within bone marrow. Science 317, 1767–1770 (2007).
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Cervi D, Yip TT, Bhattacharya N et al. Platelet-associated PF-4 as a biomarker of early tumor growth. Blood 111, 1201–1207 (2008).
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Klement GL, Yip TT, Cassiola F et al. Platelets actively sequester angiogenesis regulators. Blood DOI: blood-2008-06159541v1 (2008) (Epub ahead of print).
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Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).
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