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

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.

Recurrent genomic instability of chromosome 1q in neural derivatives of human embryonic stem cells

“…In contrast, it is expected that derivatives of hESCs should enter senescence after a finite number of doublings, as do any somatic cells (10). However, somatic cells maintained in culture occasionally acquire mutations that allow them to escape senescence (11). Loss of evolution toward senescence observed in hESCs derivatives may therefore reflect the presence of chromosomal changes.…”

Chromosomal Abnormalities in Embryonic and Somatic Stem Cells

“…NSCs display high variability in the chromosome complement when cultured. For example, neither numerical nor structural chromosome abnormalities were detected in both rat and human NSC samples, cultivated up to 70 passages and analyzed with G-banding [Bai et al, 2004;Jiang et al, 2008;Sareen et al, 2009]; on the contrary, using the same technique, other samples (human NSCs derived from the striatum fetal) displayed different numerical (from 60-70 chromosomes per metaphase) and structural chromosome aberrations [Wu et al, 2011]. Also, the analysis of more than 70 other human NSC samples identified trisomy of chromosomes 7, 10, 18, or 19 [Sareen et al, 2009;Ben-David et al, 2011] and monosomy of chromosome 18 [Ben-David et al, 2011] in longterm cultures ( table 2 ).…”

Human Pluripotent Stem Cell Therapy for Huntington's Disease: Technical, Immunological, and Safety Challenges

“…In vitro, this possibility is welldocumented for undifferentiated hPSC [116-118, 132, 133] and for fetal-derived human neural progenitor cell culture in which emerging dominance of trisomic cells (chromosome 7 or 19) is correlated with increased proliferation, neurogenesis, and expression of the epidermal growth factor receptor [134,135]. These reports advocate for careful and systematic QC of the karyotype of the hPSC derivatives using the most sensitive techniques and not just relying on usual G-banding.…”