Artikel
SU11248 therapy inhibits cluster formation and vascular network formation of endothelial progenitor cells in the treatment of malignant glioma
SU11248 Therapie inhibiert den Prozess der Cluster-Formation und der vaskulären Netzwerkbildung endothelialer Vorläuferzellen in der Behandlung des malignen Glioms
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Veröffentlicht: | 30. Mai 2008 |
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Objective: The recruitment of endothelial progenitor cells (EPCs) to tumor neovasculature has been characterized as a multi-step process contributing to tumor angiogenesis. However, the role of EPCs during anti-angiogenic therapy remains unknown. It was the aim of our study to investigate and characterize the recruitment process during anti-angiogenic therapy using the multi-kinase inhibitor SU11248.
Methods: C6 glioma cells were implanted into dorsal skinfold chambers (N=6 per group). Animals in the treatment group received SU11248 (40mg/kg BW) i.p. for five days prior to EPC application. Controls received NaCl i.p. instead. EPCs (6*106 cells / animal) were injected intraarterially after placement of a common carotid artery catheter. Intravital microscopy was performed during injection, 1h and 48h after injection. Analysis included total (TVD) and functional (FVD) vessel densities, perfusion index (PI) and blood flow rate (Q). First interaction with tumor microvessels (during injection), firm adhesion (1h later), transmigration and cluster formation/network formation (48h later) were analyzed by intravital microscopy.
Results: SU 11248 therapy resulted in significant reduction of TVD (365±47cm/cm2 vs. 183±37cm/cm2) and FVD (227±65cm/cm2 vs. 147±25cm/cm2) while increasing PI (63±19% vs. 81±8%) and Q (19,7±4,9nl/sec vs. 59,0±11,7nl/sec). Initial interaction (1,69±1,12 cells/cm vs. 2,18±0,90cells/cm) and firm adhesion were unaffected by therapy (3,94±1,16 cells/cm vs. 2,65±1,17cells/cm). Transmigration was comparable between both groups (98,4±2% vs. 96,0±4%). Cluster and network formation was significantly diminished in Sutent treated tumors (53,7±8% vs. 24,0±17%).
Conclusions: SU 11248 therapy inhibits cluster and network formation of EPCs and therefore interferes with EPC-induced neovascularization in glioma angiogenesis. Initial adhesion and firm adhesion of EPCs are unaffected by SU 11248 therapy despite significantly improved tumor perfusion and tumor microhemodynamics in response to anti-angiogenic therapy. The transmigration process of EPCs remains unchanged.