Brain Tumor Stem Cell Multipotency Correlates with Nanog Expression and Extent of Passaging in Human Glioblastoma Xenografts
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Dominique M. Higgins1,2, Ruisi Wang2, Brian Milligan3,*, Mark Schroeder4, Brett Carlson4, Jenny Pokorny4, Samuel H. Cheshier5,6, Fredric B. Meyer3, Irving L. Weissman6, Jann N. Sarkaria4, John R. Henley3
1 Medical Scientist Training Program, Mayo Clinic: College of Medicine, Rochester, Minnesota, USA.
2 Mayo Graduate School, Mayo Clinic: College of Medicine, Rochester, Minnesota, USA.
3 Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA.
4 Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
5 Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
6 Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Center, Stanford University Medical Center, Stanford, CA.
* Present address: Department of Neurosurgery, Saint Luke’s Neuroscience Institute, Kansas City, MO, USA.
John R. Henley, email:
Keywords: nanog, glioma, GBM, brain tumor stem cell, multipotency, xenograft, SDF-1
Received: May 29, 2013 Accepted: June 6, 2013 Published: June 8, 2013
Glioblastoma multiforme (GBM) is the most common primary brain tumor, with a median survival of only 15 months. A subpopulation of cells, the brain tumor stem cells (BTSCs), may be responsible for the malignancy of this disease. Xenografts have proven to be a robust model of human BTSCs, but the effects of long-term passaging have yet to be determined. Here we present a study detailing changes in BTSC multipotency, invasive migration, and proliferation after serial passaging of human GBM xenografts. Immunocytochemistry and tumorsphere formation assays demonstrated the presence of BTSCs in both early generation (EG-BTSCs; <15 passages) and late generation (LG-BTSCs; >24 passages) xenografts. The EG-BTSCs upregulated expression of lineage markers for neurons and oligodendrocytes upon differentiation, indicating multipotency. In contrast, the LG-BTSCs were restricted to an astrocytic differentiation. Quantitative migration and proliferation assays showed that EG-BTSCs are more migratory and proliferative than LG-BTSCs. However, both populations respond similarly to the chemokine SDF-1 by increasing invasive migration. These differences between the EG- and LG-BTSCs were correlated with a significant decrease in nanog expression as determined by qRT-PCR. Mice implanted intracranially with EG-BTSCs showed shorter survival when compared to LG-BTSCs. Moreover, differentiation prior to implantation of EG-BTSCs, but not LG-BTSCs, led to increased survival. Thus, nanog may identify multipotent BTSCs. Furthermore, limited passaging of xenografts preserves these multipotent BTSCs, which may be an essential underlying feature of GBM lethality.
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