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Chemotherapy-associated angiogenesis in neuroblastoma tumors.

Michaelis, Martin, Hinsch, Nora, Michaelis, U. Ruth, Rothweiler, Florian, Simon, Thorsten, Ilhelm Doerr, Hans W, Cinatl, Jaroslav, Cinatl, Jindrich (2012) Chemotherapy-associated angiogenesis in neuroblastoma tumors. American journal of pathology, 180 (4). pp. 1370-7. ISSN 1525-2191. (doi:10.1016/j.ajpath.2011.12.011) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided. (Contact us about this Publication)
Official URL
http://dx.doi.org/10.1016/j.ajpath.2011.12.011

Abstract

The influences of cytotoxic drugs on endothelial cells remain incompletely understood. Herein, we examined the effects of chemotherapeutic agents in experimental angiogenesis models and analyzed vessel densities in clinical neuroblastoma tumor samples. Cisplatin (20 to 500 ng/mL), doxorubicin (4 to 100 ng/mL), and vincristine (0.5 to 4 ng/mL), drugs commonly involved in neuroblastoma therapy protocols, induced pro-angiogenic effects in different angiogenesis models. They enhanced endothelial cell tube formation, endothelial cell sprouting from spheroids, formation of tip cells in the sprouting assay, expression of ?v?3 integrin, and vitronectin binding. All three drugs increased global cellular kinase phosphorylation levels, including the angiogenesis-relevant molecules protein kinase C? and Akt. Pharmacological inhibition of protein kinase C? or Akt upstream of phosphatidylinositol 3-kinase reduced chemotherapy-induced endothelial cell tube formation. Moreover, the investigated chemotherapeutics dose dependently induced vessel formation in the chick chorioallantoic membrane assay. Tumor samples from seven high-risk patients with neuroblastoma were analyzed for vessel density by IHC. Results revealed that neuroblastoma samples taken after chemotherapy consistently showed an enhanced microvessel density compared with the corresponding samples taken before chemotherapy. In conclusion, our data show that chemotherapy can activate endothelial cells by inducing multiple pro-angiogenic signaling pathways and exert pro-angiogenic effects in vitro and in vivo. Moreover, we report a previously unrecognized clinical phenomenon that might, in part, be explained by our experimental observations: chemotherapy-associated enhanced vessel formation in tumors from patients with neuroblastoma.

Item Type: Article
DOI/Identification number: 10.1016/j.ajpath.2011.12.011
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Martin Michaelis
Date Deposited: 05 Jun 2013 16:30 UTC
Last Modified: 29 May 2019 10:13 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/34051 (The current URI for this page, for reference purposes)
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