CD44v6 Regulates Growth of Brain Tumor Stem Cells Partially through the AKT-Mediated Pathway

Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, United States of America.
PLoS ONE (Impact Factor: 3.53). 09/2011; 6(9):e24217. DOI: 10.1371/journal.pone.0024217
Source: PubMed

ABSTRACT Identification of stem cell-like brain tumor cells (brain tumor stem-like cells; BTSC) has gained substantial attention by scientists and physicians. However, the mechanism of tumor initiation and proliferation is still poorly understood. CD44 is a cell surface protein linked to tumorigenesis in various cancers. In particular, one of its variant isoforms, CD44v6, is associated with several cancer types. To date its expression and function in BTSC is yet to be identified. Here, we demonstrate the presence and function of the variant form 6 of CD44 (CD44v6) in BTSC of a subset of glioblastoma multiforme (GBM). Patients with CD44(high) GBM exhibited significantly poorer prognoses. Among various variant forms, CD44v6 was the only isoform that was detected in BTSC and its knockdown inhibited in vitro growth of BTSC from CD44(high) GBM but not from CD44(low) GBM. In contrast, this siRNA-mediated growth inhibition was not apparent in the matched GBM sample that does not possess stem-like properties. Stimulation with a CD44v6 ligand, osteopontin (OPN), increased expression of phosphorylated AKT in CD44(high) GBM, but not in CD44(low) GBM. Lastly, in a mouse spontaneous intracranial tumor model, CD44v6 was abundantly expressed by tumor precursors, in contrast to no detectable CD44v6 expression in normal neural precursors. Furthermore, overexpression of mouse CD44v6 or OPN, but not its dominant negative form, resulted in enhanced growth of the mouse tumor stem-like cells in vitro. Collectively, these data indicate that a subset of GBM expresses high CD44 in BTSC, and its growth may depend on CD44v6/AKT pathway.

Download full-text


Available from: Ichiro Nakano, Jul 23, 2015
  • Source
    • "Although there is no perfect model to recapitulate human HGG tumors completely, both patient-derived orthotopic and murine genetic models have recently been shown to reproduce, at least partially , the pathophysiology of these cancers. Human GSC cultures, derived from HGG patients and cultured as neurospheres , recapitulate at least some part of human HGG histopathology upon orthotopic transplantation in mice (Lee et al., 2006; Nakano et al., 2008, 2011; Jijiwa et al., 2011; Visnyei et al., 2011; Miyazaki et al., 2012). However , it is essential to avoid cellular transformation resulting from in vitro expansion, especially when the cells are on culture dishes for a long time. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neural oncogenesis is currently incurable and invariably lethal. The development of innovative treatments for this devastating cancer will require a deeper molecular understanding of how cancer cells survive, proliferate, and escape from current therapies. In high-grade gliomas (HGGs), glioma stem cells (GSCs) may causally contribute to tumor initiation and propagation, therapeutic resistance, and subsequent recurrence of tumors. Within a tumor mass, GSCs are enriched in a hypoxic niche in which the oxidative stress levels are substantially elevated. Paradoxically, however, recent studies suggest that GSCs appear to generate less reactive oxygen species (ROS), a chemical component responsible for elevation of oxidative stress levels. To date, molecular mechanisms for how GSCs reduce oxidative stress to allow preferential survival in hypoxic areas in tumors remains elusive. This review article summarizes recent studies on the role of ROS-reducing enzymes, including peroxiredoxin 4, in detoxifying oxidative stress preferentially for GSCs in HGGs. In addition, the therapeutic potential of some of the recently identified antioxidant chemotherapeutic agents and avenues for future research in this area are discussed. © 2014 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 11/2014; 92(11). DOI:10.1002/jnr.23431 · 2.73 Impact Factor
  • Source
    • "The human glioma cell lines LN229, A172, A1207, and U87MG were purchased from American Type Culture Collection (ATCC) and were grown in Dulbecco's Modified Eagle's Medium (DMEM, Lonza) supplemented with 10% FBS. Several glioma stem cell lines (X01, X02, X03 [16], GSC4 [17] and 528NS, AC17, AC20 [18] [19]) were established from human brain tumors. Primary human neural stem cells (HNSCs) were provided by Department of Neurosurgery, Sungkyunkwan University School of Medicine. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aberrant epidermal growth factor receptor (EGFR) signaling is a typical oncogenic signature in glioblastoma. Here, we show that EGFR inhibition in primary glioma stem cells (GSCs) with oncogenic EGFRvIII and EGFRvIII-transduced glioma stem-like cells promotes invasion by decreasing ID3 levels. ID3 suppresses GSC invasiveness by inhibiting p27KIP1-RhoA-dependent migration and MMP3 expression. Xenograft and human glioblastoma specimens show that ID3 localizes within glioblastoma cores, whereas p27KIP1 and MMP3 are predominantly expressed in glioma cells in invasive fronts. Together, our findings show that EGFR inhibition induces GSC invasiveness by abolishing ID3-mediated inhibition of p27KIP1 and MMP3 expression.
    Cancer letters 01/2013; 328(2):235–242. DOI:10.1016/j.canlet.2012.09.005 · 5.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Primary and secondary malignant central nervous system (CNS) tumors are devastating invasive tumors able to give rise to many kinds of differentiated tumor cells. Glioblastoma multiform (GBM), is the most malignant brain tumor, in which its growth and persistence depend on cancer stem cells with enhanced DNA damage repair program that also induces recurrence and resists current chemo- and radiotherapies. Unlike non-tumor stem cells, tumor stem cells lack the normal mechanisms that regulate proliferation and differentiation, resulting in uncontrolled production and incomplete differentiation of tumor cells. In current paper recent developments and new researches in the field of brain tumor stem cells have been reviewed.
    Medical journal of the Islamic Republic of Iran 02/2012; 26(1):31-40.
Show more