Deepak Bhere1,2,3, Kaoru Tamura1,2, Hiroaki Wakimoto1,2,4,3, Sung Hugh Choi1,2,3, Benjamin Purow5, Jeremy Debatisse1,2, Khalid Shah1,2,6,7,3. 1. Center for Stem Cell Therapeutics and Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. 2. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. 3. Center for Stem Cell Therapeutics and Imaging, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 4. Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. 5. Department of Neurology, University of Virginia, Charlottesville, Virginia. 6. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. 7. Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts.
Abstract
Background: MicroRNAs (miRs) are known to play a pivotal role in tumorigenesis, controlling cell proliferation and apoptosis. In this study, we investigated the potential of miR-7 to prime resistant tumor cells to apoptosis in glioblastoma (GBM). Methods: We created constitutive and regulatable miR-7 expression vectors and utilized pharmacological inhibition of caspases and genetic loss of function to study the effect of forced expression of miR-7 on death receptor (DR) pathways in a cohort of GBM with established resistance to tumor necrosis factor apoptosis inducing ligand (TRAIL) and in patient-derived primary GBM stem cell (GSC) lines. We engineered adeno-associated virus (AAV)-miR-7 and stem cell (SC) releasing secretable (S)-TRAIL and utilized real time in vivo imaging and neuropathology to understand the effect of the combined treatment of AAV-miR-7 and SC-S-TRAIL in vitro and in mouse models of GBM from TRAIL-resistant GSC. Results: We show that expression of miR-7 in GBM cells results in downregulation of epidermal growth factor receptor and phosphorylated Akt and activation of nuclear factor-kappaB signaling. This leads to an upregulation of DR5, ultimately priming resistant GBM cells to DR-ligand, TRAIL-induced apoptotic cell death. In vivo, a single administration of AAV-miR-7 significantly decreases tumor volumes, upregulates DR5, and enables SC-delivered S-TRAIL to eradicate GBM xenografts generated from patient-derived TRAIL-resistant GSC, significantly improving survival of mice. Conclusions: This study identifies the unique role of miR-7 in linking cell proliferation to death pathways that can be targeted simultaneously to effectively eliminate GBM, thus presenting a promising strategy for treating GBM.
Background: MicroRNAs (miRs) are known to play a pivotal role in tumorigenesis, controlling cell proliferation and apoptosis. In this study, we investigated the potential of miR-7 to prime resistant tumor cells to apoptosis in glioblastoma (GBM). Methods: We created constitutive and regulatable miR-7 expression vectors and utilized pharmacological inhibition of caspases and genetic loss of function to study the effect of forced expression of miR-7 on death receptor (DR) pathways in a cohort of GBM with established resistance to tumor necrosis factor apoptosis inducing ligand (TRAIL) and in patient-derived primary GBM stem cell (GSC) lines. We engineered adeno-associated virus (AAV)-miR-7 and stem cell (SC) releasing secretable (S)-TRAIL and utilized real time in vivo imaging and neuropathology to understand the effect of the combined treatment of AAV-miR-7 and SC-S-TRAIL in vitro and in mouse models of GBM from TRAIL-resistant GSC. Results: We show that expression of miR-7 in GBM cells results in downregulation of epidermal growth factor receptor and phosphorylated Akt and activation of nuclear factor-kappaB signaling. This leads to an upregulation of DR5, ultimately priming resistant GBM cells to DR-ligand, TRAIL-induced apoptotic cell death. In vivo, a single administration of AAV-miR-7 significantly decreases tumor volumes, upregulates DR5, and enables SC-delivered S-TRAIL to eradicate GBM xenografts generated from patient-derived TRAIL-resistant GSC, significantly improving survival of mice. Conclusions: This study identifies the unique role of miR-7 in linking cell proliferation to death pathways that can be targeted simultaneously to effectively eliminate GBM, thus presenting a promising strategy for treating GBM.
Authors: X Chen; H Thakkar; F Tyan; S Gim; H Robinson; C Lee; S K Pandey; C Nwokorie; N Onwudiwe; R K Srivastava Journal: Oncogene Date: 2001-09-20 Impact factor: 9.867
Authors: Hiroaki Wakimoto; Santosh Kesari; Christopher J Farrell; William T Curry; Cecile Zaupa; Manish Aghi; Toshihiko Kuroda; Anat Stemmer-Rachamimov; Khalid Shah; Ta-Chiang Liu; Deva S Jeyaretna; Jason Debasitis; Jan Pruszak; Robert L Martuza; Samuel D Rabkin Journal: Cancer Res Date: 2009-04-07 Impact factor: 12.701
Authors: Leslie L Muldoon; Carole Soussain; Kristoph Jahnke; Conrad Johanson; Tali Siegal; Quentin R Smith; Walter A Hall; Kullervo Hynynen; Peter D Senter; David M Peereboom; Edward A Neuwelt Journal: J Clin Oncol Date: 2007-06-01 Impact factor: 44.544
Authors: Amanda Tivnan; Wayne Shannon Orr; Vladimir Gubala; Robert Nooney; David E Williams; Colette McDonagh; Suzanne Prenter; Harry Harvey; Raquel Domingo-Fernández; Isabella M Bray; Olga Piskareva; Catherine Y Ng; Holger N Lode; Andrew M Davidoff; Raymond L Stallings Journal: PLoS One Date: 2012-05-25 Impact factor: 3.240