Preface - Ous-research.no

Vilhelm Magnus Laboratory for Neurosurgical Research
neural stem cells of the adult human brain. Håvard Ølstørn
demonstrated that stem cells isolated from tumors could
reproduce those tumors in immunodeficient mice, whereas
stem cells from normal human brain did not result in tumors
(Fig. 2) (Varghese M et al Neurosurgery, 2008).
Both normal and tumor stem cells showed a high proliferation
rate when cultured to do so. Interestingly, the
proliferation rate fell dramatically also in tumor stem cells
when they were induced to differentiate. Normal and tumor
stem cells showed a similar pattern of differentiation, i.e. in
neuronal and glial directions, although differentiated cells
from the tumor were clearly abnormal morphologically and
differentiation in itself progressed much faster. Einar Vik-Mo
has performed a number of experiments studying the effect
that in vitro culture of tumor stem cells has on the cells’
ability to form tumors, to differentiate and to undergo genotypic
and expressional changes (Vik-Mo et al, Neuro Oncol.
Fig.2a
Transplantation of normal progenitor cells from the adult human
brain (top panel, green) did not result in tumor formation, whereas
stem cells isolated from brain tumors (green, bottom panel)
reproduced a highly invasive tumor in the mouse brain. Blue
nuclear staining in both panels.
Fig.2b
2010 2010). He has also explored the cellular organization of
neuro- and tumorspheres, looking at the cellular heterogeneity
of such spheres (Vik-Mo et al, Exp Cell Res. 2011
2011). By sorting tumor cells based on surface antigens, we
hope to establish methods for better identification of the
progenitor population.
We have also used this technology and experience to establish
a clinical protocol. This protocol is designed to harness
the patients’ own immunity. The inclusion of patients into
the “Phase I/II trial of vaccine therapy with hTERT, survivin
and tumor stem cell derived mRNA- transfected dendritic
cells in patients receiving standard therapy for glioblastoma”
started in February 2009. So far 16 patients have been
recruited to the study. This clinical trial is backed up from
the collaboration through the Cancer Stem Cell Innovation
Center (SFI CAST) and is a collaboration with the Neurosurgical
department, Avd. for klinisk kreftforskning ,Avd. for
celleterapi, and Avd. for immunologi, Institutt for kreftforskning,
Radiumhospitalet and the Oncological department at
Oslo University Hospital.
Cecilie Sandberg has compared the global gene expression
in normal stem cells and tumor stem cells, in order
to identify possible targets for treatment and to better
understand the biology of the cell population that escapes
current treatment and causes recurrences. The results of
this comparison study show a significant upregulation in
tumour stem cells of genes connected to regulation of focal
adhesion, actin cytoskeleton, axon guidance as well as the
Wnt pathway. Putative target genes have been confirmed
at the protein level using immunohistochemistry and
Western blot. Currently, their role in gliomas is investigated
using siRNA-knockdown based technology and its effect
on proliferation, apoptosis and sphere-forming capacity.
The roles of the possible targets in the Wnt pathway are
investigated by Kirsten Strømme. Cecilie Sandberg is also,
in collaboration with Morten Moe, exploring the transcriptome
of single cells in neuro- and tumorspheres, looking at
the cellular hetereogeneity of such spheres.
Biljana Stangeland, identified a set of 20 genes that were
up-regulated in GBM tumour cultures using C. Sandberg’s
micro-array data. These results were confirmed by quantitative
RT-PCR (qPCR) comparing human adult neural stem
cells and tumours. In order to measure the relative expression
of genes, tumour and aNSCs cultures have to be grown
under identical conditions. B. Stangeland and Awais Mughal
tested different growth conditions and modified the current
procedure so that it could be used for qPCR. For some candidates
where the corresponding antibodies were available
immuno-labelling and Western-blot were applied. Genes
that are up-regulated in tumours are involved in cell-cycle/
division, epigenetic regulation, signalling or have unknown
functions. A few candidates seem to be inhibiting known
tumour-suppressors. The next goal is to down-regulate
(knock-down) the expression of the candidate genes using
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