A mouse model of human primitive neuroectodermal tumors resulting from microenvironmentally-driven malignant transformation of orthotopically transplanted radial glial cells.

PLoS One

Cancer Biology and Epigenomics Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States of America; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America; Division of Hematology/Oncology, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.

Published: March 2016

AI Article Synopsis

  • Research shows that most pediatric brain tumors likely arise from stem cells, particularly radial glial cells, which play a role in brain development.
  • Injections of human radial glial cells into a specific brain area of immunocompromised mice lead to tumors that mimic primitive neuroectodermal tumors (PNETs) and show features of aggressive cancer behavior, including invasiveness and recruitment of blood vessels.
  • This study indicates that radial glial cells can transform into tumors without specific genetic changes, suggesting that their fate depends on the surrounding brain environment, and highlights the potential for using this mouse model for drug development and understanding cancer at a molecular level.

Article Abstract

There is growing evidence and a consensus in the field that most pediatric brain tumors originate from stem cells, of which radial glial cells constitute a subtype. Here we show that orthotopic transplantation of human radial glial (RG) cells to the subventricular zone of the 3rd ventricle--but not to other transplantation sites--of the brain in immunocompromised NOD-SCID mice, gives rise to tumors that have the hallmarks of CNS primitive neuroectodermal tumors (PNETs). The resulting mouse model strikingly recapitulates the phenotype of PNETs. Importantly, the observed tumorigenic transformation was accompanied by aspects of an epithelial to mesenchymal transition (EMT)-like process. It is also noteworthy that the tumors are highly invasive, and that they effectively recruit mouse endothelial cells for angiogenesis. These results are significant for several reasons. First, they show that malignant transformation of radial glial cells can occur in the absence of specific mutations or inherited genomic alterations. Second, they demonstrate that the same radial glial cells may either give rise to brain tumors or differentiate normally depending upon the microenvironment of the specific region of the brain to which the cells are transplanted. In addition to providing a prospect for drug screening and development of new therapeutic strategies, the resulting mouse model of PNETs offers an unprecedented opportunity to identify the cancer driving molecular alterations and the microenvironmental factors that are responsible for committing otherwise normal radial glial cells to a malignant phenotype.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380339PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121707PLOS

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