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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    • "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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    • "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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