Oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells transformed with c-myc and H-ras form high-grade glioma after stereotactic injection into the rat brain

Abstract

The oligodendrocyte-type-2 astrocyte lineage (O-2A) comprises a progenitor cell that is able to differentiate into an oligodendrocyte or astrocyte in vitro. The lineage was originally identified in the neonatal rat central nervous system but evidence suggests that the equivalent O-2A lineage also exists in humans. Apart from its putative and widely studied role in glial repair, this cell type could potentially be involved in malignant glioma formation. In this study we demonstrate that a rat O-2A progenitor cell line carrying the bacterial beta-galactosidase reporter gene and transformed with the c-myc and H-ras oncogenes which has lost its differentiation capacity in vitro generates glioma-like growth after stereotactic injection into the adult rat brain. Tumour pathology was similar to human glioblastoma, suggesting that one of the pathways in the generation of human glioblastomas may be the transformation of adult O-2A progenitor cells. Parallel studies demonstrated the presence of a DNA-binding protein complex, termed APprog, in a panel of human glioma cell lines. This protein was initially identified in O-2A progenitor cells and not their differentiated progeny. These data lead us to propose that APprog could be used as an indicator of the lineage origin of gliomas.

Candidate genes for sensitivity and resistance of human glioblastoma multiforme cell lines to erlotinib

“…The expression of FGFR4, to begin with, has been shown to correlate with histopathological grading of astrocytomas; 30 similarly, FOSL1 is known to modulate the malignant features of glioma cells. 8,17 While MYC is well known to play a critical role in glioma cell proliferation, 4,6 RAC1 is a key contributor to glioma cell survival, probably via multiple signaling pathways including JNK. 24 Interestingly, overexpression of EGFR variant III, a naturally occurring, truncated, and constitutively (ligand-independently) active receptor mutation found in a large subgroup of human GBMs, results in an increase in basal JNK activity.…”

“…scribed, 14 4 were selected to represent the erlotinib-sensitive (G-599GM), somewhat responsive (G-210GM and G-750GM), and erlotinib-resistant (G-1163GM) phenotypes. An additional cell line derived from a secondary GBM (H-199GM) was obtained from Dr. C. Herold-Mende of the University of Heidelberg, Germany.…”

Cancer stem cells – old concepts, new insights

“…For example when ras and c-myc are introduced into oligodendrocyte progenitors, tumors with a glioma multiforme phenotype arise upon in vivo transplantation. 78 This indicates that also for solid malignancies to occur there is no absolute prerequisite for genetic mutation of normal stem cells. It is important to note that the term cancer stem cell, therefore, does not necessarily refer to a stem cell origin.…”

Cancer stem cells with genetic instability: the best vehicle with the best engine for cancer

“…In the first, neoplastic transformations may arise in stem cells and their expansion results in cancerous stem cells. 47 In the second, neoplastic transformations may activate self-renewing genes in transit amplifying progenitor cells, 53,54 allowing further mutations to accumulate in what have now become cancer stem cells. Thus, different target cells may be mutated during normal developmental pathways and would be present at the formation of cancer stem cells, driving tumor growth and tumor heterogeneity and even metastases.…”