This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bao, S. Articles by Rich, J. N. Search for Related Content PubMed PubMed Citation Articles by Bao, S. Articles by Rich, J. N.

Targeting Cancer Stem Cells through L1CAM Suppresses Glioma Growth

Departments of ¹ Surgery, ² Pathology, ³ Medicine, and ⁴ Pharmacology and Cancer Biology, and ⁵ Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina; and ⁶ Departments of Radiation Oncology and Neurosurgery, University of Colorado Denver School of Medicine, Aurora, Colorado

Requests for reprints: Jeremy N. Rich, Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, P.O. Box 2900, Durham, NC 27710. Phone: 919-681-1693; Fax: 919-684-6514; E-mail: rich0001{at}mc.duke.edu and Shideng Bao, Departments of Radiation Oncology and Neurosurgery, University of Colorado Denver School of Medicine, P.O. Box 6511, Mail Stop 8123, Aurora, CO 80045. Phone: 303-724-0166; Fax: 303-724-1554; E-mail: shideng.bao{at}uchsc.edu.

Key Words: Cancer Stem Cell • L1CAM • Olig2

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. [Cancer Res 2008;68(15):6043–8]

This article has been cited by other articles:

				Y. KODERA, H. NAKANISHI, S. ITO, K. MISAWA, Y. ITO, G. NAKAYAMA, M. KOIKE, M. FUJIWARA, Y. YAMAMURA, and A. NAKAO Expression of L1 Cell Adhesion Molecule Is a Significant Prognostic Factor in pT3-stage Gastric Cancer Anticancer Res, October 1, 2009; 29(10): 4033 - 4039. [Abstract] [Full Text] [PDF]

				W. Zhuang, Z. Qin, and Z. Liang The role of autophagy in sensitizing malignant glioma cells to radiation therapy Acta Biochim Biophys Sin, May 1, 2009; 41(5): 341 - 351. [Abstract] [Full Text] [PDF]

				J.N. Rich and C.E. Eyler Cancer Stem Cells in Brain Tumor Biology Cold Spring Harb Symp Quant Biol, March 27, 2009; (2009) sqb.2008.73.060v1. [Abstract] [PDF]