Abstract
Although extensive angiogenesis takes place in glial tumors, antiangiogenic therapies have remained without the expected success. In the peripheral circulation of glioma patients, increased numbers of endothelial precursor cells (EPCs) are present, potentially offering targets for antiangiogenic therapy. However, for an antiangiogenic therapy to be successful, the therapy should specifically target glioma-related EPC subsets and secreted factors only. Here, we compared the EPC subsets and plasma factors in the peripheral circulation of patients with gliomas to acute myocardial infarctions. We investigated the five most important EPC subsets and 21 angiogenesis-related plasma factors in peripheral blood samples of 29 patients with glioma, 14 patients with myocardial infarction, and 20 healthy people as controls, by FACS and Luminex assay. In GBM patients, all EPC subsets were elevated as compared to healthy subjects. In addition, HPC and KDR+ cell fractions were higher than in MI, while CD133+ and KDR+CD133+ cell fractions were lower. There were differences in relative EPC fractions between the groups: KDR+ cells were the largest fraction in GBM, while CD133+ cells were the largest fraction in MI. An increase in glioma malignancy grade coincided with an increase in the KDR+ fraction, while the CD133+ cell fraction decreased relatively. Most plasma angiogenic factors were higher in GBM than in MI patients. In both MI and GBM, the ratio of CD133+ HPCs correlated significantly with elevated levels of MMP9. In the GBM patients, MMP9 correlated strongly with levels of all HPCs. In conclusion, the data demonstrate that EPC traffic in patients with glioma, representing neoplasia, is different from that in myocardial infarction, representing tissue regeneration. Glioma patients may benefit from therapies aimed at lowering KDR+ cells and HPCs.
Highlights
Gliomas are among the most vascularized tumors, results of antiangiogenic therapies have been disappointing [1]
We investigated the frequencies of HPCs (CD34+CD133+/−CD45dim), KDR+ cells (KDR+CD34−CD133−), CD133+ cells (CD133+CD34−KDR−), KDR+CD133+ cells (KDR+CD133+CD34−), and circulating endothelial cells (CECs; CD34brightKDR+CD45−CD133−)
Out of 38 patients with radiologically suspect malignant intracranial tumors included for FACS analysis, 20 patients received a definitive diagnosis of glioblastoma (GBM), 5 patients of astrocytoma grade II/III (AII/III)
Summary
Gliomas are among the most vascularized tumors, results of antiangiogenic therapies have been disappointing [1]. One reason is that these drugs act against a single step in the complex process of neovascularization that can be compensated for by employing alternative routes of vessel formation [2] Targeting these alternative routes may result in more successful antiangiogenic therapeutic strategies. Apart from sprouting angiogenesis, circulating endothelial progenitor cells (EPCs) stimulate neovascularization by vasculogenesis, i.e., de novo formation of blood vessels [3,4,5,6]. These circulating cells are interesting targets for antiangiogenic strategies, there are only scarce data on their frequencies in glioma patients [7]. A subset of EPCs differentiates into endothelial cells and becomes part of the vessel wall [9]
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