Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, Aigner L, Brawanski A, Bogdahn U, Beier CPCD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67: 4010-4015

Laboratory of Neurooncology, University of Regensburg, Regensburg, Germany.
Cancer Research (Impact Factor: 9.33). 06/2007; 67(9):4010-5. DOI: 10.1158/0008-5472.CAN-06-4180
Source: PubMed


Although glioblastomas show the same histologic phenotype, biological hallmarks such as growth and differentiation properties vary considerably between individual cases. To investigate whether different subtypes of glioblastomas might originate from different cells of origin, we cultured tumor cells from 22 glioblastomas under medium conditions favoring the growth of neural and cancer stem cells (CSC). Secondary glioblastoma (n = 7)-derived cells did not show any growth in the medium used, suggesting the absence of neural stem cell-like tumor cells. In contrast, 11/15 primary glioblastomas contained a significant CD133(+) subpopulation that displayed neurosphere-like, nonadherent growth and asymmetrical cell divisions yielding cells expressing markers characteristic for all three neural lineages. Four of 15 cell lines derived from primary glioblastomas grew adherently in vitro and were driven by CD133(-) tumor cells that fulfilled stem cell criteria. Both subtypes were similarly tumorigenic in nude mice in vivo. Clinically, CD133(-) glioblastomas were characterized by a lower proliferation index, whereas glial fibrillary acidic protein staining was similar. GeneArray analysis revealed 117 genes to be differentially expressed by these two subtypes. Together, our data provide first evidence that CD133(+) CSC maintain only a subset of primary glioblastomas. The remainder stems from previously unknown CD133(-) tumor cells with apparent stem cell-like properties but distinct molecular profiles and growth characteristics in vitro and in vivo.

Download full-text


Available from: Alexander Brawanski,
  • Source
    • "An expanding body of literature indicates that glioma stem cells (GSCs) identified as the CD133+ subpopulation of cells within the GBM tumor mass is actually responsible for the initiation and growth of the malignancy. As these GSCs have been implicated as the underlying cause of radioresistance (Bao et al., 2006; Beier et al., 2007), it would be of great interest to target this type of cells to enhance the efficacy of radiotherapy. One study reported that CD133+ GSCs induced autophagy after radiation and these cells could be radiosensitized by inhibiting autophagy (Lomonaco et al., 2009). "
    [Show description] [Hide description]
    DESCRIPTION: Autophagy is a natural self-degradative process by which cells eliminate misfolded proteins and damaged organelles. Autophagy has been shown to have multiple functions in tumor cells that may be dependent on the tumor type and the treatment conditions. Autophagy can have a cytoprotective role and be thought of as a survival mechanism or be cytotoxic in nature and mediate cell death. Radiation, one of the primary treatments for many different types of cancer, almost uniformly promotes autophagy in tumor cells. While autophagy produced in response to radiation is often considered to be cytoprotective, radiation-induced autophagy has also been shown to mediate susceptibility to radiation. This review addresses the complexity of autophagy in response to radiation treatment in three different cancer models, specifically lung cancer, breast cancer and glioblastoma. A deeper understanding of the different roles played by autophagy in response to radiation should facilitate the development of approaches for enhancing the therapeutic utility of radiation by providing strategies for combination treatment with unique radiosensitizers as well as preventing the initiation of strategies which are likely to attenuate the effectiveness of radiation therapy.
  • Source
    • "For gliomas, these CSCs are called glioma stem cells (GSCs) or glioma initiating cells (GICs). GSCs express nestin and CD133, factors associated with neural stem cells, although there are some GSCs that are CD133-negative [23] [24]. GSCs also share with normal neural stem cells the ability to form neurospheres in serumfree culture condition, self-renew, and differentiate into different neural cells [25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Glioblastoma (GBM) is the most aggressive, deadliest, and most common brain malignancy in adults. Despite the advances made in surgical techniques, radiotherapy and chemotherapy, the median survival for GBM patients has remained at a mere 14 months. GBM poses several unique challenges to currently available treatments for the disease. For example, GBM cells have the propensity to aggressively infiltrate/invade into the normal brain tissues and along the vascular tracks, which prevents complete resection of all malignant cells and limits the effect of localized radiotherapy while sparing normal tissue. Although anti-angiogenic treatment exerts anti-edematic effect in GBM, unfortunately, tumors progress with acquired increased invasiveness. Therefore, it is an important task to gain a deeper understanding of the intrinsic and post-treatment invasive phenotypes of GBM in hopes that the gained knowledge would lead to novel GBM treatments that are more effective and less toxic. This review will give an overview of some of the signaling pathways that have been shown to positively and negatively regulate GBM invasion, including, the PI3K/Akt, Wnt, sonic hedgehog-GLI1, and microRNAs. The review will also discuss several approaches to cancer therapies potentially altering GBM invasiveness. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Cancer letters 03/2015; 362(1). DOI:10.1016/j.canlet.2015.03.015 · 5.62 Impact Factor
  • Source
    • "However, independent of its stem cell associations, PROM1 seems to be associated with clinically relevant biology in GBM. Multiple studies have shown neurosphere formation or CD133 antigen expression to be associated with shorter survival in patients and mice transplanted with such cells [16], [46], [47]. Our work with PROM1 RNA and protein as biomarkers agrees with these findings. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prominin-1 (CD133) is a commonly used cancer stem cell marker in central nervous system (CNS) tumors including glioblastoma (GBM). Expression of Prom1 in cancer is thought to parallel expression and function in normal stem cells. Using RNA in situ hybridization and antibody tools capable of detecting multiple isoforms of Prom1, we find evidence for two distinct Prom1 cell populations in mouse brain. Prom1 RNA is first expressed in stem/progenitor cells of the ventricular zone in embryonic brain. Conversely, in adult mouse brain Prom1 RNA is low in SVZ/SGZ stem cell zones but high in a rare but widely distributed cell population (Prom1hi). Lineage marker analysis reveals Prom1hi cells are Olig2+Sox2+ glia but Olig1/2 knockout mice lacking oligodendroglia retain Prom1hi cells. Bromodeoxyuridine labeling identifies Prom1hi as slow-dividing distributed progenitors distinct from NG2+Olig2+ oligodendrocyte progenitors. In adult human brain, PROM1 cells are rarely positive for OLIG2, but express astroglial markers GFAP and SOX2. Variability of PROM1 expression levels in human GBM and patient-derived xenografts (PDX) - from no expression to strong, uniform expression - highlights that PROM1 may not always be associated with or restricted to cancer stem cells. TCGA and PDX data show that high expression of PROM1 correlates with poor overall survival. Within proneural subclass tumors, high PROM1 expression correlates inversely with IDH1 (R132H) mutation. These findings support PROM1 as a tumor cell-intrinsic marker related to GBM survival, independent of its stem cell properties, and highlight potentially divergent roles for this protein in normal mouse and human glia.
    PLoS ONE 09/2014; 9(9):e106694. DOI:10.1371/journal.pone.0106694 · 3.23 Impact Factor
Show more