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: 3.23). 09/2011; 6(9):e24217. DOI: 10.1371/journal.pone.0024217
Source: PubMed


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.

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Available from: Ichiro Nakano
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    • "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. "
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    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.
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    • "Although it has been well characterised, there is some controversy regarding the specificity of CD44 to CSC as the full-length CD44 protein is widely expressed. However, recent studies have identified CSC-specific expres‐ sion of a particular splice variant of CD44 [10] [11]. Aldehyde dehydrogenase isoform 1 (ALDH1) is another commonly used marker of CSC from a range of cancer types [12] [13], however similarly to CD44, ALDH1 expression is also associated with normal haemato‐ poietic stem cells and therefore can be used as a marker of both normal and malignant stem cells [14]. "

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    • "Similarly, CD15 has literature both supporting the claim of it being a GBM stem-like cell marker [6] and refuting that claim [13]. Although CD44 has been shown to identify cancer stem cells in other pathologies [14], there is controversy about this association with GBM stem-like cells [7], [15]. The data on integrin α6 and L1CAM comes from populations first identified by expression of CD133 [8], [9]. "
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    ABSTRACT: Glioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor and is associated with poor survival. Recently, stem-like cell populations have been identified in numerous malignancies including GBM. To identify genes whose expression is changed with differentiation, we compared transcript profiles from a GBM oncosphere line before and after differentiation. Bioinformatic analysis of the gene expression profiles identified podocalyxin-like protein (PODXL), a protein highly expressed in human embryonic stem cells, as a potential marker of undifferentiated GBM stem-like cells. The loss of PODXL expression upon differentiation of GBM stem-like cell lines was confirmed by quantitative real-time PCR and flow cytometry. Analytical flow cytometry of numerous GBM oncosphere lines demonstrated PODXL expression in all lines examined. Knockdown studies and flow cytometric cell sorting experiments demonstrated that PODXL is involved in GBM stem-like cell proliferation and oncosphere formation. Compared to PODXL-negative cells, PODXL-positive cells had increased expression of the progenitor/stem cell markers Musashi1, SOX2, and BMI1. Finally, PODXL expression directly correlated with increasing glioma grade and was a marker for poor outcome in patients with GBM. In summary, we have demonstrated that PODXL is expressed in GBM stem-like cells and is involved in cell proliferation and oncosphere formation. Moreover, high PODXL expression correlates with increasing glioma grade and decreased overall survival in patients with GBM.
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