Malignant progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma

Louis Chesler, David D. Goldenberg, Isha T. Seales, Ronit Satchi-Fainaro, Matt Grimmer, Rodney Collins, Chris Struett, Kim N. Nguyen, Grace Kim, Tarik Tihan, Yun Bao, Rolf A. Brekken, Gabriele Bergers, Judah Folkman, William A. Weiss

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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, 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 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.

Original languageEnglish (US)
Pages (from-to)9435-9442
Number of pages8
JournalCancer Research
Volume67
Issue number19
DOIs
StatePublished - Oct 1 2007

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Neuroblastoma
Tyrosine 3-Monooxygenase
Neoplasms
hydroxypropyl methacrylate
Matrix Metalloproteinases
Vascular Endothelial Growth Factor A
Transgenic Mice
Angiogenesis Inhibitors
Tumor Microenvironment
Neural Crest
Matrix Metalloproteinase 2
Weight Loss
O-(chloroacetylcarbamoyl)fumagillol
Pediatrics
Apoptosis
Ligands
Water
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Chesler, L., Goldenberg, D. D., Seales, I. T., Satchi-Fainaro, R., Grimmer, M., Collins, R., ... Weiss, W. A. (2007). Malignant progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma. Cancer Research, 67(19), 9435-9442. https://doi.org/10.1158/0008-5472.CAN-07-1316

Malignant progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma. / Chesler, Louis; Goldenberg, David D.; Seales, Isha T.; Satchi-Fainaro, Ronit; Grimmer, Matt; Collins, Rodney; Struett, Chris; Nguyen, Kim N.; Kim, Grace; Tihan, Tarik; Bao, Yun; Brekken, Rolf A.; Bergers, Gabriele; Folkman, Judah; Weiss, William A.

In: Cancer Research, Vol. 67, No. 19, 01.10.2007, p. 9435-9442.

Research output: Contribution to journalArticle

Chesler, L, Goldenberg, DD, Seales, IT, Satchi-Fainaro, R, Grimmer, M, Collins, R, Struett, C, Nguyen, KN, Kim, G, Tihan, T, Bao, Y, Brekken, RA, Bergers, G, Folkman, J & Weiss, WA 2007, 'Malignant progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma', Cancer Research, vol. 67, no. 19, pp. 9435-9442. https://doi.org/10.1158/0008-5472.CAN-07-1316
Chesler L, Goldenberg DD, Seales IT, Satchi-Fainaro R, Grimmer M, Collins R et al. Malignant progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma. Cancer Research. 2007 Oct 1;67(19):9435-9442. https://doi.org/10.1158/0008-5472.CAN-07-1316
Chesler, Louis ; Goldenberg, David D. ; Seales, Isha T. ; Satchi-Fainaro, Ronit ; Grimmer, Matt ; Collins, Rodney ; Struett, Chris ; Nguyen, Kim N. ; Kim, Grace ; Tihan, Tarik ; Bao, Yun ; Brekken, Rolf A. ; Bergers, Gabriele ; Folkman, Judah ; Weiss, William A. / Malignant progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma. In: Cancer Research. 2007 ; Vol. 67, No. 19. pp. 9435-9442.
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AU - Struett, Chris

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AU - Bao, Yun

AU - Brekken, Rolf A.

AU - Bergers, Gabriele

AU - Folkman, Judah

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