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Int J Biol Sci 2011; 7(6):892-901. doi:10.7150/ijbs.7.892

Research Paper

Long-term Cultured Human Neural Stem Cells Undergo Spontaneous Transformation to Tumor-Initiating Cells

Weihua Wu1,2*, Qihua He2,3*, Xiaoxia Li2,4*, Xiaoyan Zhang1,2, Aili Lu1,2, Ruimin Ge1,2, HongYing Zhen1,2, Alfred E. Chang5, Qiao Li5✉, Li Shen1,2✉

1. Department of Cell Biology, Peking University Health Science Center; Beijing 100191, China;
2. Peking University Stem Cell Research Center, Beijing 100191, China;
3. Peking University Medical and Health Analysis Center; Beijing 100191, China;
4. Department of Physiology, Peking University Health Science Center; Beijing 100191, China;
5. Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0666, USA
* Weihua Wu, Qihua He and Xiaoxia Li contributed equally to this work.

Abstract

In this report, we describe the spontaneous malignant transformation of long-term cultured human fetal striatum neural stem cells (hsNSCs, passage 17). After subcutaneous transplantation of long-term cultured hsNSCs into immunodeficient nude mice, 2 out of 15 mice formed xenografts which expressed neuroendocrine tumor markers CgA and NSE. T1 cells, a cell line that we derived from one of the two subcutaneous xenografts, have undergone continuous expansion in vitro. These T1 cells showed stem cell-like features and expressed neural stem cell markers nestin and CD133. The T1 cells were involved in abnormal karyotype, genomic instability and fast proliferation. Importantly, after long-term in vitro culture, the T1 cells did not result in subcutaneous xenografts, but induced intracranial tumor formation, indicating that they adjusted themselves to the intracranial microenvironment. We further found that the T1 cells exhibited an overexpressed level of EGFR, and the CD133 positive T1 cells showed a truncation mutation in the exons 2-7 of the EGFR (EGFRvIII) gene. These results suggest that continuous expansion of neural stem cells in culture may lead to malignant spontaneous transformation. This phenomenon may be functionally related to EGFR by EGFRvIII gene mutation.

Keywords: tumorigenesis, malignant transformation, epidermal growth factor receptor (EGFR), xenograft

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How to cite this article:
Wu W, He Q, Li X, Zhang X, Lu A, Ge R, Zhen H, Chang AE, Li Q, Shen L. Long-term Cultured Human Neural Stem Cells Undergo Spontaneous Transformation to Tumor-Initiating Cells. Int J Biol Sci 2011; 7(6):892-901. doi:10.7150/ijbs.7.892. Available from http://www.ijbs.com/v07p0892.htm