Artikel
Activation of multiple angiogenic signaling pathways in hemangiopericytoma
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Veröffentlicht: | 8. Juni 2016 |
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Gliederung
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Objective: Hemangiopericytoma (HPC) is a rare, highly cellular and vascularized mesenchymal tumor. Frequent local recurrence and distant metastasis are common features of HPC. Considering the remarkable hyper-vasculature phenotype of HPC, we assumed that dysregulated angiogenic signaling pathways were involved in this tumor.
Method: The key components of angiogenic signaling pathways including VEGF-VEGFR2, EphrinB2-EphB4 and DLL4-Notch were examined by real-time RT-PCR, Western blotting and immunostaining in 17 surgical specimens of 11 HPC patients and in 6 controls.
Results: A significant upregulation of VEGF and VEGFR2 associated with elevated levels of p-Akt and proliferating cell nuclear antigen (PCNA) was detected in HPC. Moreover, a dramatic increase in the mRNA and protein expression of EphB4 and its downstream factor p-Erk1/2, but not EphrinB2, was found in HPC, suggesting the activation of EphB4 forward signaling in this tumor. A massive activation of DLL4-Notch signaling was evidenced by detecting the upregulation of DLL4, Notch1, Notch4 and the targets Hey1, Hey2 and Hes1. Double-immunofluorescent staining confirmed the expression of these upregulated key factors in the endothelial cells of tumor vessels.
Conclusions: The present study identified the activation of multiple and crucial angiogenic signaling pathways, which could function individually and/or synergistically to stimulate angiogenesis in HPC and eventually contribute to tumor growth and progression. Furthermore, our findings suggest the importance of combinational targeting multiple angiogenic signaling pathways when considering an anti-angiogenic therapy for highly vascularized tumors.
Note: Daniela Pierscianek and Anna Michel contributed equally.