HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 16, 10958-10966, April 18, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/16/10958    most recent M704205200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Soeda, A. Articles by Iwama, T. Search for Related Content PubMed PubMed Citation Articles by Soeda, A. Articles by Iwama, T. Social Bookmarking                      What's this?

Epidermal Growth Factor Plays a Crucial Role in Mitogenic Regulation of Human Brain Tumor Stem Cells^*

Akio Soeda¹, Akihito Inagaki, Naoki Oka, Yuka Ikegame, Hitomi Aoki, Shin-ichi Yoshimura, Shigeru Nakashima^¶, Takahiro Kunisada, and Toru Iwama

From the Departments of Neurosurgery, Tissue and Organ Development Regeneration and Advanced Medical Science, and ^¶Cell Signaling, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan

A cancer stem cell population in malignant brain tumors takes an essential part in brain tumor initiation, growth, and recurrence. Growth factors, such as epidermal growth factor, fibroblast growth factor-2, vascular endothelial growth factor, platelet-derived growth factor, and hepatocyte growth factor, are shown to support the proliferation of neural stem cells and also may play key roles in gliomagenesis. However, the responsible growth factor(s), which controls maintenance of brain tumor stem cells, is not yet uncovered. We have established three cancer stem cell lines from human gliomas. These cells were immunoreactive with the neuronal progenitor markers, nestin and CD133, and established tumors that closely resembled the features of original tumor upon transplantation into mouse brain. Three cell lines retained their self-renewal ability and proliferation only in the presence of epidermal growth factor (>2.5 ng/ml). In sharp contrast, other growth factors, including fibroblast growth factor-2, failed to support maintenance of these cells. The tyrosine kinase inhibitors of epidermal growth factor signaling (AG1478 and gefitinib) suppressed the proliferation and self-renewal of these cells. Gefitinib inhibited phosphorylation of epidermal growth factor receptor as well as Akt kinase and extracellular signal-regulated kinase 1/2. Flow cytometric analysis revealed that epidermal growth factor concentration-dependently increased the population of CD133-positive cells. Gefitinib significantly reduced CD133-positive fractions and also induced their apoptosis. These results indicate that maintenance of human brain tumor stem cells absolutely requires epidermal growth factor and that tyrosine kinase inhibitors of epidermal growth factor signaling potentially inhibit proliferation and induce apoptosis of these cells.

Received for publication, May 22, 2007 , and in revised form, February 20, 2008.

^* This work was supported by in part by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2.

¹ To whom correspondence should be addressed: Dept. of Medicine, Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Research Pavilion at the Hillman Cancer Center, Suite G.1, 5150 Centre Ave., Pittsburgh, PA 15232. Tel.: 412-623-3270; Fax: 412-623-4747; E-mail: akio.soeda{at}gmail.com.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Arita, T. Wakita, and H. Shimizu Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in viral protein 3A similar to that of enviroxime J. Gen. Virol., August 1, 2009; 90(8): 1869 - 1879. [Abstract] [Full Text] [PDF]

				Z. Li, H. Wang, C. E. Eyler, A. B. Hjelmeland, and J. N. Rich Turning Cancer Stem Cells Inside Out: An Exploration of Glioma Stem Cell Signaling Pathways J. Biol. Chem., June 19, 2009; 284(25): 16705 - 16709. [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]

				F. Griffero, A. Daga, D. Marubbi, M. C. Capra, A. Melotti, A. Pattarozzi, M. Gatti, A. Bajetto, C. Porcile, F. Barbieri, et al. Different Response of Human Glioma Tumor-initiating Cells to Epidermal Growth Factor Receptor Kinase Inhibitors J. Biol. Chem., March 13, 2009; 284(11): 7138 - 7148. [Abstract] [Full Text] [PDF]