title: Chemotherapy-associated angiogenesis in neuroblastoma tumors.
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 αvβ3 integrin, and vitronectin binding. All three drugs increased global cellular kinase phosphorylation levels, including the angiogenesis-relevant molecules protein kinase Cβ and Akt. Pharmacological inhibition of protein kinase Cβ 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.
authors.affiliation: Institute for Medical Virology, Clinics of Goethe-University, Frankfurt am Main, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Michaelis
authors.forename: Nora
authors.initials: N
authors.lastname: Hinsch
authors.forename: U Ruth
authors.initials: UR
authors.lastname: Michaelis
authors.forename: Florian
authors.initials: F
authors.lastname: Rothweiler
authors.forename: Thorsten
authors.initials: T
authors.lastname: Simon
authors.forename: Hans W
authors.initials: HW
authors.lastname: ilhelm Doerr
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Cinatl
authors.forename: Jindrich
authors.initials: J
authors.lastname: Cinatl
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology; D004317:Doxorubicin / Q000009:adverse effects / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000473:pathology; D009447:Neuroblastoma / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D014750:Vincristine; D004317:Doxorubicin; D002945:Cisplatin