Targeting cancer stem cells through L1CAM suppresses glioma growth.
Malignant gliomas are lethal cancers that display striking cellular heterogeneity. A highly tumorigenic glioma tumor subpopulation, termed cancer stem cells or tumor-initiating cells, promotes therapeutic resistance and tumor angiogenesis. Therefore, targeting cancer stem cells may improve patient survival. We interrogated the role of a neuronal cell adhesion molecule, L1CAM, in glioma stem cells as L1CAM regulates brain development and is expressed in gliomas. L1CAM(+) and CD133(+) cells cosegregated in gliomas, and levels of L1CAM were higher in CD133(+) glioma cells than normal neural progenitors. Targeting L1CAM using lentiviral-mediated short hairpin RNA (shRNA) interference in CD133(+) glioma cells potently disrupted neurosphere formation, induced apoptosis, and inhibited growth specifically in glioma stem cells. We identified a novel mechanism for L1CAM regulation of cell survival as L1CAM knockdown decreased expression of the basic helix-loop-helix transcription factor Olig2 and up-regulated the p21(WAF1/CIP1) tumor suppressor in CD133(+) glioma cells. To determine if targeting L1CAM was sufficient to reduce glioma stem cell tumor growth in vivo, we targeted L1CAM in glioma cells before injection into immunocompromised mice or directly in established tumors. In each glioma xenograft model, shRNA targeting of L1CAM expression in vivo suppressed tumor growth and increased the survival of tumor-bearing animals. Together, these data show that L1CAM is required for maintaining the growth and survival of CD133(+) glioma cells both in vitro and in vivo, and L1CAM may represent a cancer stem cell-specific therapeutic target for improving the treatment of malignant gliomas and other brain tumors.
Bao
Shideng
S
Department of Surgery, Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA. shideng.bao@uchsc.edu
Wu
Qiulian
Q
Li
Zhizhong
Z
Sathornsumetee
Sith
S
Wang
Hui
H
McLendon
Roger E
RE
Hjelmeland
Anita B
AB
Rich
Jeremy N
JN
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division; D002469:Cell Separation; D002470:Cell Survival; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000276:immunology; D016133:Polymerase Chain Reaction
D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D039842:Neural Cell Adhesion Molecule L1; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse