Lysosomal Storage Diseases 795
The imino sugar miglustat has been shown to lead to partial glycosphingolipid
synthesis inhibition and modification of disease course in treated patients with
Gaucher disease (Pastores and Barnett, 2003). As miglustat can gain access to the
CNS and inhibit the formation of G
M2
-gangliosides, its potential use was explored in
patients with late-onset Tay–Sachs disease, Gaucher disease type III, and Niemann–
Pick type C. In patients with Niemann–Pick type C, miglustat has been shown
to improve saccadic eye movements and swallowing difficulties (Patterson et al.,
2007). Unfortunately, the miglustat trials in patients with late-onset Tay–Sachs dis-
ease and Gaucher disease type III failed to show any measurable benefit, perhaps
because of the advanced stage of disease suffered by the study subjects (Shapiro
Schiffmann et al., 2008; Shapiro et al., 2009). Surprisingly, there have been min-
imal side effects (e.g., diarrhea, weight loss) with the use of miglustat; although
long-term studies are required to ascertain safety and benefit of its use (Pastores and
Barnett, 2003).
Enzyme enhancement therapy involves the use of pharmacological chaperones,
which in cell culture and animal s tudies have been demonstrated to increase resid-
ual enzyme activity of the mutant enzyme by preventing its premature degradation
within the endoplasmic reticulum (Fan, 2008). Several studies have shown that defi-
cient lysosomal hydrolysis may in the majority of cases be due to mutations that
promote protein misfolding and failure of its delivery to the lysosome; as opposed
to mutations involving the catalytic site that inactivates enzyme activity altogether
(Steet et al., 2007; Sugawara et al., 2009). This approach is currently in clinical
trials; its effectiveness in substantially clearing tissue deposits and clinical effi-
cacy in modifying disease phenotype when used as a singular approach remains
to be established. As the drugs (isofogamine for Gaucher disease and the imino
sugar N-deoxygalactonojirimycin in Fabry disease) currently under study are also
inhibitors of enzyme activity, a particular challenge with the use of pharmacological
chaperones relates to determination of the appropriate dose and frequency of drug

administration, to ensure enzyme enhancement has the upper hand (Fan, 2008).
Gene therapy and stem cell therapies are other approaches that have been
explored, primarily in mouse models of various LSDs (Sands and Haskins, 2008).
Although results of various experiments have been promising, the application of
these techniques in human patients awaits further preclinical studies, ideally involv-
ing large animal models of disease (i.e., in dog, cats, and sheep), in which a larger
brain size and higher level of complexity may provide greater insights into the
challenge of these therapeutic strategies in humans (Haskins, 2009).
6 Summary
The clinical features of most LSDs likely have a multifactorial basis, and several
processes, such as inflammation and apoptosis, contribute to disease development.
However, the downstream events triggered by substrate storage in the lysosome are
796 G.M. Pastores
incompletely understood. Research in this area is motivated by the hope of discover-
ing markers that can serve as a surrogate for tissue substrate storage, and avoid the
need for invasive procedures. Furthermore, the discovery of disease mechanisms
may lead to the identification of putative therapeutic targets.
The LSD are defined by regulatory agencies as “orphan” disorders, that is, affect-
ing individuals numbering <200,000 in the United States, or no more than 5/10,000
in Europe (Graul, 2009). In the United States, therapeutic options for the LSDs
have and are being developed, pursuant to two pieces of landmark legislation: the
Bayh–Dole Act (BDA, 1980) and the Orphan Drug Act (ODA, 1983). Essentially,
these Acts of Congress enabled universities to patent their discoveries and license
them to private corporations (BDA); in turn, the biotech companies have received
several incentives (including the potential for fast-track approval and subsequent
marketing exclusivity) to stimulate development of medical drugs and devices for
rare disorders (ODA). Patient support and advocacy groups have played a major part
in upholding the enactment of these and related pieces of legislation, including the
more recent Genetic Information Nondiscrimination Act (GINA) of 2007–2008.
Several disease-based registries, sponsored by the drug manufacturers, have been

established; primarily for disorders in which there is commercially available treat-
ment. Guidelines for the monitoring and treatment of the affected individual are
being formulated under the auspices of various experts involved in these surveillance
efforts (Martin et al., 2008; Muenzer et al., 2009).
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Genetic Signaling in Glioblastoma
Multiforme (GBM): A Current Overview
Walter J. Lukiw and Frank Culicchia
Abstract Cancers of the brain comprise a genetically and morphologically hetero-
geneous class of proliferating neural cells derived from incompletely differentiated
brain tumor stem cells (BTSCs). The molecular and genetic mechanisms that con-
tribute to their development and propagation are incompletely understood, however,

current research is expanding our knowledge as to what specific gene activation
and deactivation mechanisms are triggered during the onset of brain cell neoplasia.
Apparently, only relatively small populations of BTSCs are capable of driving the
proliferative and invasive nature of these cancers, and the intrinsic ability to reiniti-
ate and propagate aberrant cell growth at any metabolic cost. This chapter provides
a current overview of gene expression patterns in glioma and glioblastoma multi-
forme (GBM), with special emphasis on messenger RNA (mRNA) and micro RNA
(miRNA) speciation and abundance, and how our recent understanding of specific
mRNA–miRNA interactions have increased our comprehension of this insidious
neoplastic process.
Keywords Amyloid beta peptides · Brain tumor stem cells · Caspase-3 · Cyclin-
dependent kinase · Glioblastoma · Micro RNA · Pentraxin
Abbreviations
Aβ peptides amyloid beta peptides
ATCC American tissue culture collection
Bapp beta amyloid precursor protein
BDC brain differentiated cell
BTSC brain tumor stem cell
CD133 neuronal precursor cell surface marker prominin-1
CDKN2A cyclin-dependent kinase inhibitor 2A
CRL-1690 an experimental glioblastoma (GBM) cell line; also known as
T98G (ATCC)
W.J. Lukiw (B)
LSU Neuroscience Center of Excellence, Louisiana State University Health Science Center, New
Orleans, LA 70112, USA
e-mail:
799
J.P. Blass (ed.), Neurochemical Mechanisms in Disease,
Advances in Neurobiology 1, DOI 10.1007/978-1-4419-7104-3_24,
C


Springer Science+Business Media, LLC 2011
800 W.J. Lukiw and F. Culicchia
EGFR epidermal growth factor receptor
NBSCs normal brain stem cells
GBM glioblastoma multiforme
HTB-138 an experimental glioma cell line; also known as Hs683 (ATCC)
LOH loss of heterozygosity
MBAD metal-based anticancer drugs
miRNA micro RNA
mRNA messenger RNA
NHA normal human astrocytes
NPX2 neuronal pentraxin-2
NSC neural stem cell
NV neovascularization
PDGFα platelet-derived growth factor-alpha
PDGFR platelet-derived growth factor receptor
Rb retinoblastoma
SAP serum amyloid P component
TMZ temozolomide
VEGF vascular endothelial growth factor
WHO World Health Organization
Contents
1 Introduction 800
2 Brain Cancer Etiology—Glioma and GBM
802
3 Brain Tumors—Subpopulations of Brain Tumor Stem Cells
804
4 Gene Expression in the Human Brain
805

5 Gene Expression in Brain Cancers
805
5.1 Beta-Amyloid Precursor Protein (βAPP)
807
5.2 Caspase-3
808
5.3 Pentraxin-2 (NP2; NPTX2)
809
5.4 Vascular Endothelial Growth Factor (VEGF)
809
6 Specific Alterations in the Expression of Brain-Enriched Genes
810
7 Micro RNAs (miRNAs): Specific miRNA and mRNA Alterations in Human
Brain Cancer
811
8 Therapeutic Strategies for the Clinical Management of Glioma and GBM
813
9 Summary
815
References
816
1 Introduction
Brain cancers constitute a genetically and phenotypically diverse class of prolif-
erative neoplasms derived from incompletely differentiated neuroglial stem cells,
sometimes referred to as brain tumor stem cells (BTSCs). Early pathogenetic events
Genetic Signaling in GBM 801
appear to differ between glioma and glioblastoma multiforme (GBM), and whether
the glioma-to-GBM transition is a developmental attribute or is related to brain
tumor progression, is not well understood. The molecular–genetic mechanisms and
pathological neurobiology of glioma and GBM remain unclear, however, current

oncological research into molecular alterations observed in tumors over time are
expanding our understanding as to what brain-enriched genes and induction mech-
anisms are specifically activated during the onset and propagation of the neoplastic
process. Although brain cancer cells are pathologically heterogeneous, only a small
population of BTSCs appears to drive the invasive neoplastic phenotype, and the
intrinsic ability repeatedly to reinitiate and propagate cancer cell growth at any
metabolic cost (Fig. 1 and 2). Several interrelated alterations in gene expression
are common among different tumor cell types, especially those that target cell-cycle
regulation and growth-promoting pathways, resulting, ultimately, in angiogenesis,
apoptosis, necrosis, and deregulated mitotic proliferation. The molecular, genetic,
and cellular heterogeneity of glioma and GBM may well underlie the basis for
each type of brain cancer’s highly variable resistance to current pharmacotherapeu-
tic treatment strategies. The scope of this chapter is to provide a current overview
concerning gene expression patterns in glioma and GBM with special emphasis on
specific messenger RNA (mRNA), micro RNA (miRNA) interactions, and the con-
tribution of altered miRNA-mRNA-directed signaling pathways to this currently
incurable neoplastic process.
Fig. 1 Cultured human neurons and glia can be differentially viewed or stained to study the con-
tribution of each cell type to brain cell morphology, growth, cell type, drug interaction, and gene
expression (see e.g., Lukiw et al., 2005) Control (normal) human neuronal-glial (HNG) cells in
primary co-culture exhibit complex, small diameter neuritic extensions and extensive (a); cultured
HTB-138 glioma cells (American Type Tissue Collection, Bethesda, MD) (b); cultured CRL-1690
glioblastoma cells (c); all cultured brain cells are about 15–20% confluent, photographed using
phase contrast light microscopy (Lukiw et al., 2009); note cell-contact avoidance in the HTB-138
glioma culture, lack of small diameter extensions and altered, flattened, and diverse morphologies
of glioma, and especially of GBM cells (b),(c) when compared to control (a); 1 week of culture;
bar = 25 μm
802 W.J. Lukiw and F. Culicchia
Fig. 2 Highly schematicized representation of normal neural stem cell (NSC), brain differenti-
ated cell (BDC), and brain tumor stem cell (BTSC) development into glioma and gliobalstoma

muliforme (GBM) tumor cells. NSCs have an intrinsic property for long-term self-renewal and
are pluripotent, that is, have an intrinsic capability to give rise to multiple types of differentiated
progeny. In the normal condition (left), NSCs differentiate into BDCs such as neurons, glia, and
neuroglial subspecies. In contrast, in glioma and GBM, genetic mutations, environmental factors,
and alterations in miRNA signaling and pathogenic gene expression trigger the development of
BTSCs from both NSCs and BDCs. BTSCs, that make up only a relatively small fraction of the
entire heterogeneous tumor cell mass, give rise to a series of genotypically and phenotypically het-
erogeneous tumor cells and a proliferating and invasive tumor cell mass (see Singh et al., 2004;Xie
and Chin, 2008; Godlewski et al., 2008; Hide et al., 2008; Yadirgi and Marino, 2009). Recent evi-
dence suggests the participation of the polytopic membrane protein beta-amyloid precursor protein
(βAPP), the apoptosis effector protein caspase-3, the cell contact and synaptic remodeling protein
pentraxin-2, and vascular endothelial growth factor (VEGF), the most potent vascular substance
known in driving brain oncogenesis. More recently, specific micro RNA (miRNA; miRNA-124
and miRNA-137) downregulation has been shown to affect cellular proliferation and/or induce
unscheduled differentiation of BTSCs (Gurdon and Melton, 2008; Silber et al., 2008). GBM is
further associated with an upregulation in miRNA-125b and miRNA-221. miRNA-125b is upreg-
ulated in IL-6-stressed normal human astrocytes (NHA), a treatment known to induce astrogliosis,
and in vitro, anti-miRNA-125b added exogenously to IL-6-stressed NHA cultures attenuated both
glial cell proliferation and increased the expression of CDKN2A, a predicted miRNA-125b target
and negative regulator of cell growth (Pogue et al., 2010). GBM-up-regulated miRNA-221 appears
to target the cell growth suppressive cyclin-dependent kinase inhibitors p27 and p57, linking the
cell cycle checkpoint at S phase initiation with growth factors, which may be another trigger for
tumor cell proliferation (Li et al., 1999;leSageetal.,2007; Mellai et al., 2008;Medinaetal.,
2008; Lukiw et al., 2009)
2 Brain Cancer Etiology—Glioma and GBM
Tumors are classified by their tissue of origin. Astrocytomas fall into the largest
category of tumors of neuroepithelial tissue. Neoplastic neuroepithelial tumors of
the central nervous system (CNS) are categorized by the World Health Organization
Genetic Signaling in GBM 803
(WHO) rating as being pilocytic, and having circumscribed growth that tends to

respect anatomic boundaries because they do not invade (WHO grade I). The more
diffuse (WHO grade II) tumors demonstrate slow growth, moderate hypercellularity,
occasional nuclear atypia, and diffuse infiltration of neighboring brain cell struc-
tures. These lesions have a tendency for malignant transformation, possibly dediffer-
entiating all the way to glioblastoma multiforme (GBM) and included in this group
are protoplasmic, gemistocytic, fibrillary, and mixed variants. Anaplastic (WHO
grade III) tumors demonstrate hypercellularity, moderate nuclear atypia, prominent
mitotic activity, and diffuse infiltration. These tumors are most often the result of
dedifferentiation of a grade II astrocytoma. Glioblastoma multiforme (WHO grade
IV) demonstrate marked nuclear atypia, high mitotic activity, microvascular pro-
liferation, and areas of coagulative necrosis. This group includes GBM and two
variants: giant-cell glioblastoma and gliosarcoma. Although a glioblastoma may
represent a dedifferentiated grade II or III astrocytoma, most are primary glioblas-
tomas and do not derive from a less malignant precursor. Primary GBMs often
manifest de novo; without clinical or histopathological evidence of a pre-existing,
less-malignant precursor lesion. These tumors are identified in patients after a short
clinical history of usually less than three months. Primary GBM accounts for the
vast majority of cases (60%) in adults older than 50 years of age and secondary
GBMs (40%) typically develop in younger patients (<45 years) through malignant
progression from a low-grade astrocytoma (WHO grade II) or anaplastic astrocy-
toma (WHO grade III). The time required for this progression varies considerably,
ranging from less than 1 year to more than 10 years, the mean interval being 4–5
years. These classifications provide the standard for communication between differ-
ent medical institutions in the United States and around the world, and are based
on the premise that each type of tumor results from the abnormal growth from a
specific CNS cell class (Lopes et al., 1993; Louis, 2006; Rosell et al., 2008; Rueger
et al., 2008; Tatter, 2005; Fuller et al., 2002).
Of the estimated 17,000 primary brain tumors diagnosed in the United States
each year, gliomas account for more than 75% of all brain tumors and are the
most common supratentorial tumor in all age groups. These tumors comprise

a heterogeneous group of neoplasms that differ in location within the CNS, in
age and sex distribution, in growth potential, in extent of invasiveness, in mor-
phological features, in tendency for progression, and in response to treatments.
WHO grade IV GBMs are the most frequent and malignant histological brain
tumor cell type (Ohgaki and Kleihues, 2005; Ohgaki, 2009). There is a tendency
toward a higher incidence of gliomas in Caucasians of the more highly developed,
industrialized societies (Ohgaki and Kleihues, 2005; Fisher et al., 2007; Ohgaki,
2009). The epidemiology of GBM as a spontaneously occurring malignant neo-
plasm remains largely unknown. Familial gliomas account for about 5% or less
of all malignant gliomas, and less than 1% of gliomas are associated with known
genetic syndromes such as tuberous sclerosis, neurofibromatosis, Turcot syndrome,
Li–Fraumeni, von Hippel–Lindau, or related neurological syndromes (Fisher et al.,
2007; Farrell and Plotkin, 2007). About 95% of all brain cancers are of idiopathic,
sporadic, or unknown origin (Louis, 2006; Fisher et al., 2007; Ohgaki, 2009).
804 W.J. Lukiw and F. Culicchia
Recent concerns regarding the association between GBM and head injury, labile
nitrogenated and nitroso-compounds, exogenous or endogenous genomic alkylat-
ing factors, occupational hazards, and electromagnetic field exposure including cell
phone use have been inconclusive and to date no hard and fast rules apply (Fisher
et al., 2007; Ohgaki, 2009). GBM most often occurs in the subcortical white mat-
ter of the cerebral hemispheres, and in one recent epidemiological study of 987
cases of GBM, the most frequently affected sites were the temporal (31%), pari-
etal (24%), frontal (23%), and occipital (16%) lobes (Ohgaki and Kleihues, 2005;
Ohgaki, 2009). The prognosis of patients diagnosed with GBM remains dismal,
and the median survival time of patients with this most common form of malignant
glioma currently averages less than one year. Some of the newer treatment strategies
and novel pharmacological approaches are further described in the sections below.
3 Brain Tumors—Subpopulations of Brain Tumor Stem Cells
An evolving concept in the neuro-oncological mechanism driving glioma and GBM
is that brain tumor stem cells, which represent a relatively minor population of the

entire tumor mass, constitute the essential “functional core” of the tumor that drives
neoplastic proliferation. As do normal brain stem cells (NBSCs), BTSCs exhibit two
defining properties including the capability for long-term self-renewal, and pluripo-
tency, that is, the capability to give rise to multiple types of differentiated progeny.
In normal brain stem cells the balanced coordination of these two defining proper-
ties is essential for brain development and functional homeostasis, yet these same
two parameters are fundamentally altered in brain tumor development (Gurdon and
Melton, 2008; Yadirgi and Marino, 2009). In brain cancers, variable populations
of BTSCs have been detected in glioblastoma, medulloblastoma, and ependymoma
(Singh et al., 2003, 2004; Xie et al., 2008). In the framework of this brain can-
cer stem cell hypothesis, genes important for normal neural stem cell homeostatic
function appear also to be essential to support their pathological development into
BTSCs. This concept of nuclear reprogramming, describing a switch in gene expres-
sion from one kind of cell to that of another unrelated cell type, may be central to
oncogenesis (Fig. 2; Gurdon and Melton, 2008). BTSCs appear to incompletely dif-
ferentiate in vivo, and their neoplastic potential depends on the balance between
their replicative index and the degree of terminal differentiation that these minority
brain cell populations achieve.
A specific oncogenic family of genes may be involved in triggering BTSC
development, proliferation, and pathogenic functions, including polytopic sur-
face sensor proteins such as the neural precursor cell surface marker prominin-1
(CD133), beta-amyloid precursor protein (βAPP), several neural-enriched pentraxin
species, vascular endothelial growth factor (VEGF), caspase-3 and other potentially
oncogenic genes associated with growth rate, cell cycle regulation, angiogenesis,
apoptosis and/or necrosis, and deregulated mitotic proliferation (Singh et al., 2004;
Xie et al., 2008; Bauer et al., 2008; Culicchia et al., 2008). Uncovering the molec-
ular mechanism of how these individual genes are activated, if their expression is