title: Malignant progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma.
abstract: Targeted expression of MYCN to the neural crest [under control of the rat tyrosine hydroxylase (TH) promoter] causes neuroblastoma in transgenic mice (TH-MYCN) and is a well-established model for this disease. Because high levels of MYCN are associated with enhanced tumor angiogenesis and poor clinical outcome in neuroblastoma, we serially characterized malignant progression, angiogenesis, and sensitivity to angiogenic blockade in tumors from these animals. Tumor cells were proliferative, secreted high levels of the angiogenic ligand vascular endothelial growth factor (VEGF), and recruited a complex vasculature expressing the angiogenic markers VEGF-R2, alpha-SMA, and matrix metalloproteinases MMP-2 and MMP-9, all of which are also expressed in human disease. Treatment of established murine tumors with the angiogenesis inhibitor TNP-470 caused near-complete ablation, with reduced proliferation, enhanced apoptosis, and vasculature disruption. Because TNP-470 has been associated with neurotoxicity, we tested the recently described water-soluble HPMA copolymer-TNP-470 conjugate (caplostatin), which showed comparable efficacy and was well tolerated without weight loss or neurotoxicity as measured by rotarod testing. This study highlights the importance of angiogenesis inhibition in a spontaneous murine tumor with native tumor-microenvironment interactions, validates the use of mice transgenic for TH-MYCN as a model for therapy in this common pediatric tumor, and supports further clinical development of caplostatin as an antiangiogenic therapy in childhood neuroblastoma.
authors.affiliation: Department of Pediatrics, Neurology, University of California-San Francisco Medical School, San Francisco, California 94143, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Chesler
authors.forename: David D
authors.initials: DD
authors.lastname: Goldenberg
authors.forename: Isha T
authors.initials: IT
authors.lastname: Seales
authors.forename: Ronit
authors.initials: R
authors.lastname: Satchi-Fainaro
authors.forename: Matt
authors.initials: M
authors.lastname: Grimmer
authors.forename: Rodney
authors.initials: R
authors.lastname: Collins
authors.forename: Chris
authors.initials: C
authors.lastname: Struett
authors.forename: Kim N
authors.initials: KN
authors.lastname: Nguyen
authors.forename: Grace
authors.initials: G
authors.lastname: Kim
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Yun
authors.initials: Y
authors.lastname: Bao
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.forename: Gabriele
authors.initials: G
authors.lastname: Bergers
authors.forename: Judah
authors.initials: J
authors.lastname: Folkman
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D016259:Genes, myc; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009447:Neuroblastoma / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D051381:Rats; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol