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 wellestablished 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, A-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 watersoluble 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 tumormicroenvironment 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. [Cancer Res 2007;67(19):9435-42]

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

“…We and others have reported prolonged survival of these animals using novel treatments (8)(9)(10). However, once the tumors are established, it is difficult to achieve tolerable therapeutic effects, due to the known short treatment window and rapid disease progression (7,11,12).…”

In Vivo/Ex Vivo and In Situ Assays Used in Cancer Research: A Brief Review

“…TNP-470 continues to be explored preclinically in a variety of tumor models, including orthotopic anaplastic thyroid cancer, orthotopic prostate cancer, and endometriosis (Becker et al 2007;Kosharskyy et al 2006;Nahari et al 2007). A promising new direction has been conjugation of TNP-470 to a HPMA copolymer (Chesler et al 2007;Rihova et al 2007;Satchi-Fainaro et al 2004;Satchi-Fainaro et al 2005). A water-soluble copolymer based on N-(2-hydroxypropyl)methacrylamide (HPMA)-TNP-470 conjugate (caplostatin) may overcome the limitations of the TNP-470 small molecule.…”

Licorice isoliquiritigenin dampens angiogenic activity via inhibition of MAPK-responsive signaling pathways leading to induction of matrix metalloproteinases

“…It was assumed in this study that the ISL blockade of the MMP production and activation hampered endothelial cell motility. MMP was involved in the angiogenic and metastatic cascades of knockout or transgenic animals and tumor cell lines overexpressing or down-regulating a specific MMP [26][27][28]. One of the earliest events in cancer metastasis and angiogenesis is a proteolytic degradation of the ECM proteins including the basement membrane [26].…”