We measured normal neural stem cell–associated intracellular markers that have also been implicated in GSC proliferation, migration, and tumorigenesis, e.g., Sox2 ( 19– 21), Musashi ( 22– 24), Nanog ( 25), and Nestin ( 26) ( 7, 8, 12). We used mass cytometry to evaluate the intracellular states associated with 4 commonly used GSC surface markers, CD15, CD44, CD133, and α 6 integrin. As such, mass cytometry theoretically enables the use of up to 100 analysis channels, with over 50 currently available heavy metal isotopes to study ( 17, 18). This largely overcomes the spectral overlap typical of standard flow cytometry, which limits the number of observations possible on a given cell. Mass cytometry is a quantitative analytical technique whereby single cells labeled with antibodies tagged with rare earth metals are ionized and analyzed by time-of-flight mass spectrometry. These issues are important for how we study GBM in vitro and in animal models and understand intratumor and intertumor heterogeneity and treatment resistance. More broadly, it remains unknown whether all GSCs are alike or have their own hierarchy of function. It remains unknown how GSC populations defined by single-surface markers compare with each other, in terms of intracellular signaling and function and whether expression of different combinations of these markers is associated with differences in the probability of tumor-forming capacity. GSCs tend to be enriched in serum-free media conditions, often referred to as stem cell media conditions. We use it here as synonymous with a stem cell marker–bearing GBM cell. The literature has used the term GSC with varying definitions. Alternative single-surface markers such as CD15 (SSEA-1), CD44, α 6 integrin, and A2B5 may also enrich for the GSC state ( 12– 16). Although sorting by CD133 enriches for GSC function, CD133 lo cells can also exhibit clonogenic self-renewal and asymmetric cell division, albeit less efficiently ( 10, 11). CD133 hi cells have clonogenic self-renewal capacity and efficiently engraft and form intracranial tumors in immunocompromised mice ( 8, 9). GSCs were first isolated using an antibody against the cell-surface protein CD133 (Prominin-1) ( 7). GBM stem cells (GSCs), also known as tumor-propagating cells or tumor-initiating cells ( 3), may be one reason for inevitable recurrence, as they are highly resistant to radiation and chemotherapy ( 4– 6). Recurrence, on average, occurs 6 months after maximal therapy ( 2). Standard therapy includes surgery, radiation, temozolomide chemotherapy, and, more recently, tumor-treating fields ( 1). Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Larger patient sample sizes and antibody panels are required to confirm these findings. This work highlights the potential signaling and phenotypic diversity of GSCs. GSCs that highly expressed all 4 surface markers had the greatest self-renewal capacity, WNT inhibitor sensitivity, and in vivo tumorigenicity. Once in culture, some subpopulations were lost and previously undetectable ones materialized. Using mass cytometry and fresh operating room specimens, we found 15 distinct GSC subpopulations in patients, and they differed in their MEK/ERK, WNT, and AKT pathway activation status. It remains unknown how these single-surface marker–defined GSC populations compare with each other in terms of signaling and function and whether expression of different combinations of these markers is associated with different functional capacity. Since their discovery in 2003, GSCs have been isolated using single-surface markers, such as CD15, CD44, CD133, and α 6 integrin. A major therapeutic goal is to target GBM stem cells (GSCs), a subpopulation of cells that contribute to treatment resistance and recurrence. Most patients with glioblastoma (GBM) die within 2 years. Chheda, 660 South Euclid, Campus Box 8069, St. Louis, Missouri, USA.Īddress correspondence to: Milan G. Louis, Missouri, USA.ħDepartment of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.ĨBrain Tumor Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.ĩDepartment of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.ĦSiteman Cancer Center, Washington University in St. Louis, Missouri, USA.ĥDivision of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA.ĤBiomedical Engineering and Center for Biological Systems Engineering, Washington University in St. 2Center for Human Immunology and Immunotherapy Programs, andģDepartment of Neurosurgery, Washington University School of Medicine, St.
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