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Tumor Growth: A Putative Role for Platelets?

Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands

Tumors do not grow without inducing new vessel formation. The postulation of Dr. Folkman in 1971—that tumor growth is angiogenesis-dependent [1]—has been widely accepted, more than two decades later. The question now becomes, "Is it possible to treat cancer by attacking its blood supply?"

Many pharmaceutical companies directed their research to antiangiogenic therapy in the past years. Despite increasing knowledge of tumor-induced angiogenesis, the mechanism as to how antiantiogenic agents inhibit new vessel formation remains unknown. Even the mechanisms of two of the most potent preclinical antiangiogenic drugs, angiostatin and endostatin, are still unknown. Many factors are involved in new vessel formation and experimental models are not sophisticated enough to take into account all factors that play a role in spontaneously occurring tumors. Translational research from the clinic to the laboratory is warranted for the discovery of new potent antiangiogenic agents.

Our translational angiogenesis research started two years ago, when we hypothesized that circulating concentrations of vascular endothelial growth factor (VEGF), an important angiogenic factor, if initially elevated, would decrease during therapy in cancer patients. Until then, several investigators tried to correlate serum concentrations of VEGF with the prognosis of cancer patients. Fascinatingly, we found a specific pattern of VEGF concentrations that correlated exactly with the platelet counts of these patients during therapy. No relationship with tumor burden was detected, indicating that circulating levels of VEGF are not influenced by tumor cells, but are mainly dependent on platelet contents [2]. In addition, it was shown by others that thrombin activation of platelets causes VEGF release [3].

What then is the role of circulating VEGF carried by platelets? VEGF has been shown to induce permeability, has mitogenic and chemotactic activity on endothelial cells, and also has procoagulatory activity. Platelets play a critical role in wound healing and, if they are activated, they release upon activation, in addition to VEGF, other growth factors that are involved in angiogenesis (e.g., platelet-derived endothelial cell growth factor, thrombospondin, and platelet factor 4). On the other hand, in the clinic it was found that platelet counts have prognostic significance for cancer patients and that coagulation abnormalities are regularly found in cancer patients [4]. In preclinical studies the tumor-platelet interactions have been studied extensively and a relationship between metastasis formation and platelet-tumor interaction has been reported. We are currently investigating whether a specific tumor endothelium-platelet interaction can contribute to tumor-induced angiogenesis.

Although these translational studies have no direct impact on clinical cancer therapy, oncologists should be aware of a potential role for platelets in cancer growth. For example, bone marrow-supportive agents, currently used in high-dose chemotherapy, contribute to platelet production and thereby may influence response to therapy. At this time we investigate in our hospital the pretreatment platelet counts in cancer patients, and we are studying how bone marrow-supportive agents during chemotherapy affect these counts in relation to the response to therapy. We would be pleased to learn of your observations.

View larger version (249K): [in this window] [in a new window]   H.M.W. Verheul and H.M. Pinedo Department of Medical Oncology Free University Hospital Amsterdam, The Netherlands

1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-1186.
2. Verheul HMW, Hoekman K, Luykx-de Bakker et al. Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 1977;3:2187-2190.[Abstract/Free Full Text]
3. Möhle R, Green D, Moore MA et al. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci USA 1997;94:663-668.[Abstract/Free Full Text]
4. Dvorak HF. Abnormalities of hemostasis in malignancy. In: Colman RW, Hirsch J, Marder VJ et al, eds. Hemostasis and Thrombosis. Basic Principles and Clinical Practice, Third edition. Philadelphia: JB Lippincott 1994:1238-1254.

This Article Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article link to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Verheul, H.M.W. Articles by Pinedo, H.M. Search for Related Content PubMed Articles by Verheul, H.M.W. Articles by Pinedo, H.M.