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 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.

Podoplanin-mediated cell adhesion through extracellular matrix in oral squamous cell carcinoma

“…In the present study, we have demonstrated for the first time that the most fundamental function of PDPN in oral SCC cells is mediating cell adhesion through the crosstalk between CD44 and hyaluronic acid, although its functions had been mainly correlated to cell proliferation 30,31 and migration 32,33 in the literature. The PDPN contribution to cell proliferation has now been shown to be a secondary event to cell adhesion, and the present PDPN inhibition by siRNA did not affect cell migration, as shown in either scratch-wound or transwell migration assays.…”

Thrombin-cleaved Fragments of Osteopontin Are Overexpressed in Malignant Glial Tumors and Provide a Molecular Niche with Survival Advantage

“…Glioma stem cells share significant similarities with normal neural SCs, including the expression of stem cell markers (CD133, Nestin, Musashi, and Sox2) and the capacity to differentiate into the three CNS lineages, neurons, oligodendrocytes, and astrocytes. More recently, the CD44v6-OPN axis has been reported to regulate growth of brain tumor stem cells through Akt activation (41). These reports led us to investigate the effect on OPN and its cleaved forms on the behavior of cancer stem cell-like U-87 MG (U-87 SC).…”

Prognostic Value of CD44 Variant exon 6 Expression in Non-Small Cell Lung Cancer: a Meta-analysis

“…In the early 1990s, it was found that the CD44 variant exon 6 (CD44v6) was the chief variant isoform to regulate tumor invasion, progression, and metastasis in rat carcinoma cells (Gunthert et al, 1991). Meanwhile, CD44v6 is also expressed in both fetal and mature lung, being associated with epithelial stem cells (Jijiwa et al, 2011). Nowadays, several studies have demonstrated that CD44v6 was correlated with the prognosis of ovarian cancer (Shi et al, 2013), colorectal cancer (Wielenga et al, 1993), gastric carcinoma (Mayer et al, 1993), osteosarcoma (Deng et al, 2013), breast cancer (Kaufmann et al, 1995), bladder cancer (Omran et al, 2012) and liver cancer (Coradini et al, 2004).…”