Download The Importance of Platelet Counts and Their Contents in Cancer

Vol. 9, 3219 –3221, August 15, 2003
Clinical Cancer Research 3219
Editorial
The Importance of Platelet Counts and Their Contents in Cancer
Henk M. W. Verheul and Herbert M. Pinedo1
Department of Internal Medicine, University Medical Center Utrecht,
3508 GA Utrecht [H. M. W. V.], and VU Medical Center-Cancer
Center-Amsterdam, Amsterdam 1007 MB [H. M. P.], the Netherlands
VEGF,2 a potent angiogenic growth factor, plays an important role in several pathophysiological processes including
tumorigenesis. It is presumably involved in the angiogenic
switch from the initial avascular phase of a microscopic tumor
into a progressively, rapidly growing and metastasizing tumor
by stimulation of new vessel formation. Because of this important role, many investigators have been studying whether circulating VEGF can be used as a prognostic marker in patients with
different cancer types, including breast cancer. These kind of
studies have been performed since the beginning of the 90s,
reviewed by Hormbrey et al. (1). In this review, the differences
between the methods that were used for obtaining and measuring plasma and serum VEGF in these studies were compared,
and they proposed a standardized way to collect and measure
VEGF in blood samples of cancer patients.
After initial reports that serum VEGF is increased in cancer
patients, we published in this journal in 1997 that serum VEGF
concentrations in breast cancer patients were determined by
platelet counts and not by tumor burden (Fig. 1). We found that
platelets release VEGF on activation. Therefore, we predicted
that plasma VEGF instead of serum VEGF concentrations
should be studied as a marker for tumor progression (2). In
addition, we found evidence that platelets may be involved in
tumor-induced angiogenesis because of their release of angiogenic growth factors on activation by angiogenic endothelium
(3). Apart from VEGF, platelets contain several other angiogenic growth factors and inhibitors that are released on activation, including platelet-derived endothelial cell growth factor,
transforming growth factor-␤, hepatocyte growth factor, thrombospondin, and even endostatin (4).
In addition, other studies report an increased VEGF content
of platelets from cancer patients compared with healthy volunteers (5, 6).
Now, 6 years later, the dispute is still ongoing whether
serum VEGF or plasma VEGF should be used as a marker of
tumor progression or prognosis. Some studies show that platelet-poor plasma reflect more accurate tumor progression (7),
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1
To whom requests for reprints should be addressed, at VUMC-Cancer
Center-Amsterdam, P. O. Box 7057, 1007 MB Amsterdam, the Netherlands. E-mail: [email protected].
2
The abbreviations used are: VEGF, vascular endothelial growth factor;
TPO, thrombopoietin.
whereas others found that serum VEGF gives a better indication
of tumor progression (6).
Heer et al. (8) published earlier in this journal that serum
VEGF detects breast cancer preoperatively with a sensitivity of
62.1%. In addition, they show a relation with the estrogen
positivity of the tumors and VEGF levels. In this issue of
Clinical Cancer Research, Murphy et al. (9) question again
whether these measurements of serum-VEGF are meaningful,
because they published earlier that plasma VEGF but not serum
VEGF is elevated in breast cancer patients when these levels
were compared with healthy volunteers (10; see Letters to the
Editor in this issue). Taken the different studies together, the
question remains whether serum-VEGF or plasma-VEGF
should be determined.
When taking these different opinions and findings together,
what do they tell us about tumor biology? Is it possible that
tumors stimulate the megakaryocytes in the bone marrow to
generate increasing amounts of platelets that contain more
VEGF? If so, which tumor-released factor is responsible for
this, and secondly, what is the effect on tumor progression?
It is well known that tumors can stimulate the bone marrow; for example, it has been shown that tumors promote the
mobilization of progenitor endothelial cells from the bone marrow, and presumably VEGF plays an important role in this
pathway (11). In addition, it has been shown that tumors initiate
intratumoral activation of the coagulation cascade including
platelet activation (disseminated intravascular coagulation; Ref.
12). Furthermore, platelets have been shown to contain TPO and
release it on activation. TPO is the specific cytokine that stimulates megakaryocytes in the bone marrow to generate platelets.
Folman et al. (13) suggested a self-regulatory vicious circle of
platelet counts and the bone marrow controlled by TPO. In
response to an injury of the vessel wall or any other local
thrombogenic process, platelets attach to the vessel wall and
subsequently become activated and release their contents, including TPO. On its turn, this platelet-released TPO stimulates
the bone marrow to generate new platelets into the circulation.
We hypothesize that activated platelets in the tumor vasculature release TPO, and thereby stimulate bone marrow generation of platelets (Fig. 2). As a consequence of our hypothesis,
an increased number of platelets will reach the circulation as we
often see in cancer patients. On the basis of this hypothesis both
plasma VEGF and serum VEGF may be important to indicate
tumor activity. Plasma VEGF may be increased because of
direct tumor release of VEGF, and by tumor-induced intravascular platelet activation and subsequent VEGF release. On the
other hand, elevated serum VEGF may be the consequence of
increased platelet numbers in cancer patients caused by intratumoral platelet activation and subsequent release of TPO.
In conclusion, as mentioned before, we strongly recommend in any study regarding circulating VEGF to include
plasma and serum levels, and platelet counts. Hopefully we will
come to a better understanding of what role circulating growth
factors and platelets play in tumor biology. In the end, it might
well be that just a simple platelet count is a better prognostic
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3220 Platelet Counts and Their Contents in Cancer
Fig. 1 VEGF concentrations and platelet counts
during treatment with chemotherapy plus granulocyte macrophage colony-stimulating factor in
breast cancer patients. The chemotherapy administration is given every 3 weeks.
Fig. 2 In the tumor vasculature, tumor produced growth factors (GF), including VEGF,
activate the endothelium into a prothrombotic
state causing subsequent platelet activation
with TPO and VEGF release. This release of
growth factors and cytokines by platelets on
its turn stimulate bone marrow generation of
platelets and progenitor endothelial cells
(CECs). Subsequently, these bone marrowderived cells are thought to play an important
role in the angiogenic process in the tumor.
factor compared with plasma or serum VEGF concentrations in
cancer patients (14, 15).
References
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Clinical Cancer Research 3221
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The Importance of Platelet Counts and Their Contents in
Cancer
Henk M. W. Verheul and Herbert M. Pinedo
Clin Cancer Res 2003;9:3219-3221.
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