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First published online March 1, 2007
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2006-0585v1
25/6/1478    most recent
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Submitted on September 21, 2006
Accepted on February 22, 2007

Cancer Stem Cells

Spontaneous transformation of human adult non-tumorigenic stem cells to cancer stem cells is driven by Genomic Instability in a human model of Glioblastoma

Anjali Shiras 1*, Sivarajan Chettiar 1, Varsha Shepal 1, Ganeshkumar Rajendran 1, Rajendra Prasad 1, Padma Shastry 1

1 National Centre for Cell Science (NCCS), NCCS Complex, University of Pune Campus, Ganeshkhind, Pune, Maharashtra, India

* To whom correspondence should be addressed. E-mail: anjalishiras{at}nccs.res.in.


  Abstract

The presence of a CD133+/nestin+ population in brain tumors suggests that a normal Neural stem cell (NSC) may be the cell of origin for gliomas. We have identified human CD133 positive NSCs from adult glioma tissue and established them as long term in vitro cultures HNGC-1 (Human Neuro Glial Culture). Replicative senescence in HNGC-1 led to high level of genomic instability and emergence of a spontaneously immortalized clone that developed into a cell-line HNGC-2 with features of cancer stem cells (CSCs) that includes ability for self-renewal, capacity to form CD133 positive Neurospheres and develop intracranial tumors. The data from our study specifies an important role of genomic instability in initiation of transformed state as well as its progression in to highly tumorigenic CSCs. The activated froms of Notch and Hes isoforms were expressed in both non-neoplastic neural stem cells and brain tumor stem cells derived from it. Importantly, a significant over-expression of these molecules were found in the brain tumor stem cells. These findings suggest that this model comprising of HNGC-1 and HNGC-2 cells would be a useful system for studying pathways involved in self-renewal of stem cells and their transformation to cancer stem cells.

Key Words. Neural Stem cells, Cancer stem cells, Glioblastoma, Genomic Instability, adult stem cell transformation, Spontaneous immortalization




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