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). References Alroy J, Ucci AA (2006) Skin biopsy: a useful tool in the diagnosis of lysosomal storage diseases. Ultrastruct Pathol 30(6):489–503 Ausseil J, Desmaris N, Bigou S, Attali R, Corbineau S, et al. (2008) Early neurodegenera- tion progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice. PLoS ONE 3(5):e2296 Ballabio A, Gieselmann V (2009) Lysosomal disorders: from storage to cellular damage. 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Expert Rev Mol Diagn 4(5):677–691 Muenzer J, Wraith JE, Clarke LA International Consensus Panel on Management and Treatment of Mucopolysaccharidosis I (2009) Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics123(1):19–29 Ostrer H (2001) A genetic profile of contemporary Jewish populations. Nat Rev Genet 2(11): 891–898 Pacheco CD, Lieberman AP (2008) The pathogenesis of Niemann-Pick type C disease: a role for autophagy? Expert Rev Mol Med 10:e26 Pastores GM (2003) Enzyme therapy for the lysosomal storage disorders: principles, patents, practice and prospects. Expert Opin Ther Patents 13(8):1157–1172 Pastores GM, Barnett NL (2003) Substrate reduction therapy: miglustat as a remedy for symp- tomatic patients with Gaucher disease type 1. Expert Opin Investig Drugs 12(2):273–281 Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE (2007) Miglustat for treatment of Niemann- Pick C disease: a randomised controlled study. Lancet Neurol 6(9):765–772 Pierret C, Morrison JA, Kirk MD (2008) Treatment of lysosomal storage disorders: focus on t he neuronal ceroid-lipofuscinoses. Acta Neurobiol Exp (Wars) 68(3):429–442 Platt FM, Jeyakumar M (2008) Substrate reduction therapy. Acta Paediatr Suppl 97(457):88–93 Prasad VK, Kurtzberg J (2008) Emerging trends in transplantation of inherited metabolic diseases. Bone Marrow Transplant 41(2):99–108 Raben N, Hill V, Shea L, Takikita S, Baum R, et al. (2008) Suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in Pompe disease. Hum Mol Genet 17(24):3897–3908 Reuser AJ, Drost MR (2006) Lysosomal dysfunction, cellular pathology and clinical symptoms: basic principles. Acta Paediatr Suppl 95(451):77–82 Sands MS, Haskins ME (2008) CNS-directed gene therapy for lysosomal storage diseases. Acta Paediatr Suppl 97(457):22–27 Schiffmann R, Fitzgibbon EJ, Harris C, DeVile C, Davies EH, et al. (2008) Randomized, controlled trial of miglustat in Gaucher’s disease type 3. Ann Neurol 64(5):514–522 Settembre C, Fraldi A, Jahreiss L, Spampanato C, Venturi C, et al. (2008) A block of autophagy in lysosomal storage disorders. Hum Mol Genet 17(1):119–129 Shapiro BE, Pastores GM, Gianutsos J, Luzy C, Kolodny EH (2009) Miglustat in late-onset Tay- Sachs disease: a 12-month, randomized, controlled clinical study with 24 months of extended treatment. Genet Med [Epub ahead of print] Steet R, Chung S, Lee WS, Pine CW, Do H, Kornfeld S (2007) Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-beta-glucosidase. Biochem Pharmacol 73(9):1376–1383 Sugawara K, Tajima Y, Kawashima I, Tsukimura T, Saito S, et al. (2009) Molecular inter- action of imino sugars with human alpha-galactosidase: insight into the mechanism of complex formation and pharmacological chaperone action in Fabry disease. Mol Genet Metab 96(4):233–238 Suzuki K (1998) Twenty five years of the “psychosine hypothesis”: a personal perspective of its history and present status. Neurochem Res 23(3):251–259 Walkley SU (2009) Pathogenic cascades in lysosomal disease-Why so complex? J Inherit Metab Dis 32(2):181–189 Yang Z, Vatta M (2007) Danon disease as a cause of autophagic vacuolar myopathy. Congenit Heart Dis 2(6):404–409 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: wlukiw@lsuhsc.edu 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 . 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. 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. 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