ABSTRACT
Increasing evidence suggests that brain tumors arise from the transformation of neural stem/precursor/progenitor cells. Much current research on human brain tumors is focused on the stem-like properties of glioblastoma. Here we show that anaplastic lymphoma kinase (ALK) and its ligand pleiotrophin are required for the self-renewal and tumorigenicity of glioblastoma stem cells (GSCs). Furthermore, we demonstrate that pleiotrophin is transactivated directly by SOX2, a transcription factor essential for the maintenance of both neural stem cells and GSCs. We speculate that the pleiotrophin-ALK axis may be a promising target for the therapy of glioblastoma.
Subject(s)
Brain Neoplasms/metabolism , Carcinogenesis/metabolism , Carrier Proteins/genetics , Cytokines/genetics , Glioblastoma/metabolism , Neoplastic Stem Cells/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Anaplastic Lymphoma Kinase , Animals , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Carrier Proteins/metabolism , Cell Proliferation , Cytokines/metabolism , Gene Expression Regulation, Neoplastic , Glioblastoma/genetics , Glioblastoma/pathology , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Neoplastic Stem Cells/pathology , Neoplastic Stem Cells/physiology , SOXB1 Transcription Factors/metabolism , Transcriptional Activation , Tumor Cells, CulturedABSTRACT
Cancer stem cells are believed to be responsible for tumor initiation and development. Much current research on human brain tumors is focused on the stem-like properties of glioblastoma stem cells (GSCs). However, little is known about the molecular mechanisms of cell cycle regulation that discriminate between GSCs and differentiated glioblastoma cells. Here we show that cyclin D2 is the cyclin that is predominantly expressed in GSCs and suppression of its expression by RNA interference causes G1 arrest in vitro and growth retardation of GSCs xenografted into immunocompromised mice in vivo. We also demonstrate that the expression of cyclin D2 is suppressed upon serum-induced differentiation similar to what was observed for the cancer stem cell marker CD133. Taken together, our results demonstrate that cyclin D2 has a critical role in cell cycle progression and the tumorigenicity of GSCs.
Subject(s)
Cell Cycle/physiology , Cyclin D2/metabolism , Glioblastoma/metabolism , Neoplastic Stem Cells/metabolism , Animals , Cell Line, Tumor , Flow Cytometry , Glioblastoma/pathology , Humans , Immunoblotting , Immunohistochemistry , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplastic Stem Cells/pathology , Oligonucleotide Array Sequence Analysis , RNA Interference , RNA, Small Interfering , Reverse Transcriptase Polymerase Chain Reaction , Transplantation, HeterologousABSTRACT
Cellular prion protein (PrP(C)), a cell-surface glycoprotein normally associated with neurons, is also expressed in other cell types such as glia and lymphocytes. To further elucidate these roles of PrP(C), wild-type prion protein gene (Prnp(+/+)) mice and Prnp-deficient (Prnp(-/-)) mice were infected with encephalomyocarditis virus B variant (EMCV-B) via an intracranial route. EMCV-B causes encephalitis and apoptotic cell death in vivo. Histopathological studies revealed that Prnp(+/+) mice infected with 600 pfu of EMCV-B showed more severe infiltration of inflammatory cells, accompanied by higher activation of microglia cells around the hippocampus, than Prnp(-/-) mice; viz., no differences in the brain virus titer between these two lines of mice. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP, nick end-labeling (TUNEL) staining of the brain specimens revealed that the CA1 hippocampal pyramidal cells showed a larger number of apoptotic neurons in Prnp(-/-) than Prnp(+/+) mice. Based on all these findings, PrP(C) may play certain roles in the induction of inflammation and inhibition of apoptosis in vivo.
