title: CD44v6 regulates growth of brain tumor stem cells partially through the AKT-mediated pathway.
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.
authors.affiliation: Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Jijiwa
authors.forename: Habibe
authors.initials: H
authors.lastname: Demir
authors.forename: Snehalata
authors.initials: S
authors.lastname: Gupta
authors.forename: Crystal
authors.initials: C
authors.lastname: Leung
authors.forename: Kaushal
authors.initials: K
authors.lastname: Joshi
authors.forename: Nicholas
authors.initials: N
authors.lastname: Orozco
authors.forename: Tiffany
authors.initials: T
authors.lastname: Huang
authors.forename: Vedat O
authors.initials: VO
authors.lastname: Yildiz
authors.forename: Ichiyo
authors.initials: I
authors.lastname: Shibahara
authors.forename: Jason A
authors.initials: JA
authors.lastname: de Jesus
authors.forename: William H
authors.initials: WH
authors.lastname: Yong
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
authors.forename: Soledad
authors.initials: S
authors.lastname: Fernandez
authors.forename: Harley I
authors.initials: HI
authors.lastname: Kornblum
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005434:Flow Cytometry; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
chemical_list: D018960:Hyaluronan Receptors; D034741:RNA, Small Interfering; D053495:Osteopontin; D051057:Proto-Oncogene Proteins c-akt