1. Systemic miRNA-7 delivery inhibits tumor angiogenesis and growth in murine xenograft glioblastoma
- Author
-
Maaike van Berkel, Francesco Cerisoli, Raymond M. Schiffelers, Paula I. van Noort, Mark Verheul, Judy R. van Beijnum, Yijia Liu, Rick Jan van Haastert, Gert Storm, Martin C. Woodle, Grégoire Pierre André Prevost, Roel Q.J. Schaapveld, Enrico Mastrobattista, Ebel H. E. Pieters, Arjan W. Griffioen, Puthupparampil V. Scaria, Meriem Bourajjaj, Afrouz Yousefi, Eugene Berezikov, Negar Babae, Edwin Cuppen, Hubrecht Institute for Developmental Biology and Stem Cell Research, Biomaterials Science and Technology, Faculty of Science and Technology, Medical oncology laboratory, and CCA - Innovative therapy
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Mice, Inbred A ,Angiogenesis ,Mice, Nude ,Chick Embryo ,Biology ,Transfection ,Research Support ,IR-95146 ,Neovascularization ,Mice ,Random Allocation ,In vivo ,Human Umbilical Vein Endothelial Cells ,Journal Article ,medicine ,Animals ,Humans ,Viability assay ,Non-U.S. Gov't ,Cell Proliferation ,Medicine(all) ,Tube formation ,Neovascularization, Pathologic ,METIS-309475 ,Cell growth ,Research Support, Non-U.S. Gov't ,miR-7 ,MicroRNA ,Genetic Therapy ,Xenograft Model Antitumor Assays ,MicroRNAs ,Oncology ,Cancer research ,Systemic administration ,Female ,Therapy ,medicine.symptom ,Glioblastoma ,Delivery ,Research Paper - Abstract
Tumor-angiogenesis is the multi-factorial process of sprouting of endothelial cells (EC) into micro-vessels to provide tumor cells with nutrients and oxygen. To explore miRNAs as therapeutic angiogenesis-inhibitors, we performed a functional screen to identify miRNAs that are able to decrease EC viability. We identified miRNA-7 (miR-7) as a potent negative regulator of angiogenesis. Introduction of miR-7 in EC resulted in strongly reduced cell viability, tube formation, sprouting and migration. Application of miR-7 in the chick chorioallantoic membrane assay led to a profound reduction of vascularization, similar to anti-angiogenic drug sunitinib. Local administration of miR-7 in an in vivo murine neuroblastoma tumor model significantly inhibited angiogenesis and tumor growth. Finally, systemic administration of miR-7 using a novel integrin-targeted biodegradable polymeric nanoparticles that targets both EC and tumor cells, strongly reduced angiogenesis and tumor proliferation in mice with human glioblastoma xenografts. Transcriptome analysis of miR-7 transfected EC in combination with in silico target prediction resulted in the identification of OGT as novel target gene of miR-7. Our study provides a comprehensive validation of miR-7 as novel anti-angiogenic therapeutic miRNA that can be systemically delivered to both EC and tumor cells and offers promise for miR-7 as novel anti-tumor therapeutic.
- Full Text
- View/download PDF