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 CD44high 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 CD44high GBM but not from CD44low 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 CD44high GBM, but not in CD44low 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/AKTpathway.
Highlights
Glioblastoma multiforme (GBM) is one of the most lethal types of human cancers, with a median patient survival of 12–15 months [1,2]
Small GBM samples were dissociated with a firepolished glass pipette and resuspended at 50,000 cells/ml in neurosphere medium, containing Dulbecco’s modified Eagle medium (DMEM)/F12 medium (GIBCO, Invitrogen, Carlsbad, CA) supplemented with B27, basic fibroblast growth factor (20 ng/ml, Peprotech, Rocky Hill, NJ), epidermal growth factor (EGF) (50 ng/ml, Peprotech), penicillin/streptomycin (1%, GIBCO, Invitrogen, Carlsbad, CA), and heparin
Overall CD44 expression is elevated in GBM To investigate the roles of the CD44 pathway in GBM, we first examined the expression of pan-CD44 in GBM surgical specimens
Summary
Glioblastoma multiforme (GBM) is one of the most lethal types of human cancers, with a median patient survival of 12–15 months [1,2]. Current therapy, including surgery followed by chemotherapy and radiation, is generally only palliative and does not result in marked improvement in patient survival [2,3]. The initial treatment regimen generally shrinks the tumor mass, recurrence of the tumor is virtually inevitable, suggesting that at least a subset of tumor cells is resistant to therapy [2]. The development of therapies directed against BTSC is complicated partly due to the fact that they are heterogeneous, lacking a definitive marker set, even within tumors of the same histopathological types [6,7,8]
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