Laura A Genovesi1,2, Simon Puttick3, Amanda Millar1, Marija Kojic1, Pengxiang Ji1, Anne K Lagendijk2, Caterina Brighi4,5, Claudine S Bonder6,7, Christelle Adolphe1, Brandon J Wainwright1,2. 1. The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia. 2. Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia. 3. Probing Biosystems Future Science Platform, Commonwealth Scientific and Industrial Research Organization, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. 4. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia. 5. ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Queensland, St Lucia, Queensland, Australia. 6. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia. 7. Adelaide Medical School, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia.
Abstract
BACKGROUND: Novel targeted therapies for children diagnosed with medulloblastoma (MB), the most common malignant pediatric brain tumor, are urgently required. A major hurdle in the development of effective therapies is the impaired delivery of systemic therapies to tumor cells due to a specialized endothelial blood-brain barrier (BBB). Accordingly, the integrity of the BBB is an essential consideration in any preclinical model used for assessing novel therapeutics. This study sought to assess the functional integrity of the BBB in several preclinical mouse models of MB. METHODS: Dynamic contrast enhancement magnetic resonance imaging (MRI) was used to evaluate blood-brain-tumor barrier (BBTB) permeability in a murine genetically engineered mouse model (GEMM) of Sonic Hedgehog (SHH) MB, patient-derived orthotopic xenograft models of MB (SHH and Gp3), and orthotopic transplantation of GEMM tumor cells, enabling a comparison of the direct effects of transplantation on the integrity of the BBTB. Immunofluorescence analysis was performed to compare the structural and subcellular features of tumor-associated vasculature in all models. RESULTS: Contrast enhancement was observed in all transplantation models of MB. No contrast enhancement was observed in the GEMM despite significant tumor burden. Cellular analysis of BBTB integrity revealed aberrancies in all transplantation models, correlating to the varying levels of BBTB permeability observed by MRI in these models. CONCLUSIONS: These results highlight functional differences in the integrity of the BBTB and tumor vessel phenotype between commonly utilized preclinical models of MB, with important implications for the preclinical evaluation of novel therapeutic agents for MB.
BACKGROUND: Novel targeted therapies for children diagnosed with medulloblastoma (MB), the most common malignant pediatric brain tumor, are urgently required. A major hurdle in the development of effective therapies is the impaired delivery of systemic therapies to tumor cells due to a specialized endothelial blood-brain barrier (BBB). Accordingly, the integrity of the BBB is an essential consideration in any preclinical model used for assessing novel therapeutics. This study sought to assess the functional integrity of the BBB in several preclinical mouse models of MB. METHODS: Dynamic contrast enhancement magnetic resonance imaging (MRI) was used to evaluate blood-brain-tumor barrier (BBTB) permeability in a murine genetically engineered mouse model (GEMM) of Sonic Hedgehog (SHH) MB, patient-derived orthotopic xenograft models of MB (SHH and Gp3), and orthotopic transplantation of GEMM tumor cells, enabling a comparison of the direct effects of transplantation on the integrity of the BBTB. Immunofluorescence analysis was performed to compare the structural and subcellular features of tumor-associated vasculature in all models. RESULTS: Contrast enhancement was observed in all transplantation models of MB. No contrast enhancement was observed in the GEMM despite significant tumor burden. Cellular analysis of BBTB integrity revealed aberrancies in all transplantation models, correlating to the varying levels of BBTB permeability observed by MRI in these models. CONCLUSIONS: These results highlight functional differences in the integrity of the BBTB and tumor vessel phenotype between commonly utilized preclinical models of MB, with important implications for the preclinical evaluation of novel therapeutic agents for MB.
Authors: Eleanor B Carson-Walter; Jessica Hampton; Eveline Shue; Daniel M Geynisman; Pramod Kumar Pillai; Ramasri Sathanoori; Stephen L Madden; Ronald L Hamilton; Kevin A Walter Journal: Clin Cancer Res Date: 2005-11-01 Impact factor: 12.531
Authors: M A Warso; A J Maniotis; X Chen; D Majumdar; M K Patel; A Shilkaitis; T K Gupta; R Folberg Journal: Clin Cancer Res Date: 2001-03 Impact factor: 12.531
Authors: Rajneet K Oberoi; Karen E Parrish; Terence T Sio; Rajendar K Mittapalli; William F Elmquist; Jann N Sarkaria Journal: Neuro Oncol Date: 2015-09-10 Impact factor: 12.300
Authors: Florence M G Cavalli; Marc Remke; Ladislav Rampasek; John Peacock; David J H Shih; Betty Luu; Livia Garzia; Jonathon Torchia; Carolina Nor; A Sorana Morrissy; Sameer Agnihotri; Yuan Yao Thompson; Claudia M Kuzan-Fischer; Hamza Farooq; Keren Isaev; Craig Daniels; Byung-Kyu Cho; Seung-Ki Kim; Kyu-Chang Wang; Ji Yeoun Lee; Wieslawa A Grajkowska; Marta Perek-Polnik; Alexandre Vasiljevic; Cecile Faure-Conter; Anne Jouvet; Caterina Giannini; Amulya A Nageswara Rao; Kay Ka Wai Li; Ho-Keung Ng; Charles G Eberhart; Ian F Pollack; Ronald L Hamilton; G Yancey Gillespie; James M Olson; Sarah Leary; William A Weiss; Boleslaw Lach; Lola B Chambless; Reid C Thompson; Michael K Cooper; Rajeev Vibhakar; Peter Hauser; Marie-Lise C van Veelen; Johan M Kros; Pim J French; Young Shin Ra; Toshihiro Kumabe; Enrique López-Aguilar; Karel Zitterbart; Jaroslav Sterba; Gaetano Finocchiaro; Maura Massimino; Erwin G Van Meir; Satoru Osuka; Tomoko Shofuda; Almos Klekner; Massimo Zollo; Jeffrey R Leonard; Joshua B Rubin; Nada Jabado; Steffen Albrecht; Jaume Mora; Timothy E Van Meter; Shin Jung; Andrew S Moore; Andrew R Hallahan; Jennifer A Chan; Daniela P C Tirapelli; Carlos G Carlotti; Maryam Fouladi; José Pimentel; Claudia C Faria; Ali G Saad; Luca Massimi; Linda M Liau; Helen Wheeler; Hideo Nakamura; Samer K Elbabaa; Mario Perezpeña-Diazconti; Fernando Chico Ponce de León; Shenandoah Robinson; Michal Zapotocky; Alvaro Lassaletta; Annie Huang; Cynthia E Hawkins; Uri Tabori; Eric Bouffet; Ute Bartels; Peter B Dirks; James T Rutka; Gary D Bader; Jüri Reimand; Anna Goldenberg; Vijay Ramaswamy; Michael D Taylor Journal: Cancer Cell Date: 2017-06-12 Impact factor: 31.743
Authors: Elisabeth A Seftor; Paul S Meltzer; Gina C Schatteman; Lynn M Gruman; Angela R Hess; Dawn A Kirschmann; Richard E B Seftor; Mary J C Hendrix Journal: Crit Rev Oncol Hematol Date: 2002-10 Impact factor: 6.312
Authors: S Perreault; V Ramaswamy; A S Achrol; K Chao; T T Liu; D Shih; M Remke; S Schubert; E Bouffet; P G Fisher; S Partap; H Vogel; M D Taylor; Y J Cho; K W Yeom Journal: AJNR Am J Neuroradiol Date: 2014-05-15 Impact factor: 3.825
Authors: P S Tofts; G Brix; D L Buckley; J L Evelhoch; E Henderson; M V Knopp; H B Larsson; T Y Lee; N A Mayr; G J Parker; R E Port; J Taylor; R M Weisskoff Journal: J Magn Reson Imaging Date: 1999-09 Impact factor: 4.813