Epidermal growth factor plays a crucial role in mitogenic regulation of human brain tumor stem cells.
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.
Soeda
Akio
A
Department of Neurosurgery, Tissue and Organ Development Regeneration and Advanced Medical Science, and Cell Signaling, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan. akio.soeda@gmail.com
Inagaki
Akihito
A
Oka
Naoki
N
Ikegame
Yuka
Y
Aoki
Hitomi
H
Yoshimura
Shin-Ichi
S
Nakashima
Shigeru
S
Kunisada
Takahiro
T
Iwama
Toru
T
D000071916:AC133 Antigen; D015703:Antigens, CD / Q000096:biosynthesis; D001932:Brain Neoplasms / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000502:physiology*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008954:Models, Biological; D010455:Peptides; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology
D000071916:AC133 Antigen; D015703:Antigens, CD; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib