Glioma Signaling (Advances in Experimental Medicine and Biology, 1202)

Preface
Contents
Contributors
Chapter 1: Introduction to Purinergic Signalling in the Brain
	1.1 Introduction
	1.2 Purinergic Signalling in the CNS
		1.2.1 Cotransmission
		1.2.2 Glial Cells
		1.2.3 Neuron-Glial Interactions
	1.3 Purinergic Signalling in Normal Behaviour
	1.4 Purinergic Pathophysiology in the CNS, Including Gliomas
	References
Chapter 2: Adenosine Signaling in Glioma Cells
	2.1 Introduction
	2.2 Adenosine Metabolism and P1 Adenosine Receptors
	2.3 A Role for Ecto-5′-Nucleotidases CD39 and CD73 in Gliomas?
	2.4 Receptor-Mediated Effects of Adenosine on Glioma Cell Growth and Survival
		2.4.1 A1AR-, A2AAR-, and A2BAR-Mediated Effects on Glioma Cells
		2.4.2 The A3 Receptor Subtype as a New Pharmacological Target for Innovative Chemotherapy Approaches to Gliomas
	2.5 Receptor-Independent Effects of Adenosine Analogues in Glioma Cell Growth and Survival
	2.6 Conclusions and Future Perspectives
	References
Chapter 3: Cross-Talk in Nucleotide Signaling in Glioma C6 Cells
	3.1 Introduction
	3.2 Properties of P2 Receptors
		3.2.1 P2X Receptors
		3.2.2 P2Y Receptors
	3.3 P2Y1, P2Y2 and P2Y12 Receptor Expression and Functionality in Glioma C6 Cells
	3.4 Serum Withdrawal
		3.4.1 Effect on P2Y1 and P2Y12 Receptor Expression
		3.4.2 Effect on C6 Cell Morphology, Growth and Differentiation
		3.4.3 Effect on the P2Y14 Receptor
	3.5 Cyclic AMP Effect on Cell Proliferation, Growth and Differentiation
	3.6 Effect of Extracellular Nucleotides on ERK1/2 and PI3K/Akt Activity: P2Y1/P2Y12 Cross-Talk
	3.7 The P2X7 Receptor
	3.8 Concluding Remarks
	References
Chapter 4: Calcium Signaling in Glioma Cells: The Role of Nucleotide Receptors
	4.1 Origin of the Calcium Signaling
	4.2 Sources of the Calcium Signal
		4.2.1 Extracellular Calcium Signal
		4.2.2 Signal Generated by Calcium Stores
			4.2.2.1 Store-Operated Calcium Signaling
			4.2.2.2 Calcium-Induced Calcium Signaling
	4.3 Calcium Signaling in Non-excitable Glial Cells
		4.3.1 Astrocytes
		4.3.2 Microglia
	4.4 Nucleotide Receptor-Evoked Calcium Signaling in Glial Cells
		4.4.1 P2X7 Receptors Downstream Signaling in Glioma
	4.5 Glioma C6: A Case Study
		4.5.1 The Nature of the Signal: The Role of Nucleotide Receptors in Glioma C6 Cells
	4.6 Gliomas: The Motile Tumors, Calcium Signaling and Chemotaxis
		4.6.1 The Calcium Signal in Glioma C6 Is Strongly Dependent on Actin Cytoskeleton
	4.7 Concluding Remarks
	References
Chapter 5: Purinergic Signaling in Glioma Progression
	5.1 Introduction
		5.1.1 Molecular and Cellular Origins of Gliomas
		5.1.2 Glioma Cancer Stem Cells (CSCs)
		5.1.3 Tumor Microenvironment – Key for Understanding and Targeting Gliomas
	5.2 Purinergic Signaling in Gliomas
	5.3 Ectonucleotidases
		5.3.1 Ectonucleoside Triphosphate Diphosphohydrolases (E-NTPDases)
		5.3.2 Ectonucleotide Pyrophosphatase/Phosphodiesterases (E-NPPs)
		5.3.3 Ecto-Alkaline Phosphatases (ALP)
		5.3.4 Ecto-5ʹ-Nucleotidase (Ecto-5ʹ-NT/CD73)
	5.4 Ecto-Adenosine Deaminase (Ecto-ADA)
	5.5 Other Ecto-Nucleotide Metabolizing Enzymes
	5.6 Ectonucleotidases in Gliomas
	5.7 The Purinergic Hypothesis of Glioma Invasion
	References
Chapter 6: Cytoskeleton and Nucleotide Signaling in Glioma C6 Cells
	6.1 Introduction
	6.2 The Role of the P2Y2 Receptor in Actin Cytoskeleton Organization
		6.2.1 Regulation by PIP2
		6.2.2 Regulation by the Small GTP-Binding Proteins: Rho, Rac and Cdc42
	6.3 Compensation of ROCK Inhibition by P2Y2R Activated Signaling Pathways
		6.3.1 ROCK Inhibition in Glioma C6 Cells
		6.3.2 Effect of P2Y2 Receptor Stimulation on MLC Phosphorylation: The Role of MLCK
		6.3.3 Effect of P2Y2 Receptor Stimulation on Cofilin Phosphorylation: The Role of Rac1 Protein
		6.3.4 Effect of Integrin on Glioma C6 Cell Recovery from ROCK: Essential Role of Rac1 Protein
	6.4 Summary
	References
Chapter 7: Signaling Determinants of Glioma Cell Invasion
	7.1 Invasiveness of Glioma Cells
	7.2 Factors That Control Glioma Invasion
		7.2.1 Autocrine Factors
		7.2.2 Paracrine Factors
	7.3 Signaling Mechanisms That Control Glioma Invasion
		7.3.1 Integrins
		7.3.2 Rho GTPases
		7.3.3 PI3K and Phospholipid Signaling
		7.3.4 Akt Kinase
	7.4 Proteases
	7.5 Conclusions and Future Directions
	References
Chapter 8: Receptor Tyrosine Kinases: Principles and Functions in Glioma Invasion
	8.1 Introduction
	8.2 EGFR/EGF
	8.3 PDGFR/PDGF
	8.4 ERBB2
	8.5 c-Met/HGF
	8.6 Tie/Ang
	8.7 Axl/Gas6
	8.8 DDR1/Collagen
	8.9 Eph/Ephrin
	8.10 TrkA
	8.11 Cross-Talk
	8.12 Targeting Receptor Type Tyrosine Kinases
		8.12.1 Targeting EGFR
			8.12.1.1 Gefitinib
			8.12.1.2 Erlotinib
			8.12.1.3 125I-mAb 425
			8.12.1.4 Nimotuzumab
			8.12.1.5 Cetuximab
			8.12.1.6 Lapatinib
		8.12.2 Targeting PDGFR
			8.12.2.1 Imatinib
			8.12.2.2 Sunitinib
			8.12.2.3 Dasatinib
		8.12.3 Multi-Kinase Inhibitors
			8.12.3.1 Cediranib
			8.12.3.2 Sorafenib
			8.12.3.3 Vandetanib
			8.12.3.4 Cabozantinib (XL-184)
	8.13 Prospective
	References
Chapter 9: Recent Advances in Understanding Mechanisms of TGF Beta Signaling and Its Role in Glioma Pathogenesis
	9.1 Introduction
	9.2 A Brief Summary of Mechanisms of TGF-β Signaling in Normal and Malignant Cells
		9.2.1 Components and Mechanisms of TGF-β Signaling
		9.2.2 Negative Regulators of TGF-β Signaling
		9.2.3 Transcriptional Responses Induced by TGF-β Signaling
	9.3 Deregulation of TGF-β Signaling in Gliomas
	9.4 Functions of TGF-β Signaling in Glioma Biology
		9.4.1 TGF-β Signaling in Controlling Cell Proliferation
		9.4.2 TGF-β Signaling in the Regulation of Invasion
		9.4.3 TGF-β1 as Pro-angiogenic Factor
		9.4.4 A Role of TGF-β Signaling in Glioma Cancer Initiating Cells
		9.4.5 TGF-β Signaling in Tumor-Mediated Immunosuppression
	9.5 Molecular and Pharmacological Strategies to Interfere with TGF-β Signaling for Potential Therapeutic Intervention in Gliomas
		9.5.1 Antibodies Inhibiting TGF-β Signaling
		9.5.2 Antisense Oligodeoxynucleotides and Short Interfering RNAs Inhibiting TGF-β Signaling
		9.5.3 Small Molecules Inhibitors of the Catalytic Activity of TGF-β Receptor Kinase
	References
Chapter 10: STAT Signaling in Glioma Cells
	10.1 Introduction
	10.2 A Brief Summary of Mechanisms of STAT Activation in Normal and Malignant Signaling
		10.2.1 Mechanisms of STAT Activation
		10.2.2 Negative Regulators of STAT Signaling
		10.2.3 Transcriptional Targets of STATs
	10.3 Dysfunction of STAT Signaling in Gliomas
		10.3.1 Constitutive Activation of STAT3 in Gliomas
		10.3.2 STAT Activation in Gliomas Results from Dysfunction in Control Mechanisms
	10.4 Functions of STAT3 in Gliomas
		10.4.1 STAT3 as Oncogene
		10.4.2 STAT3 as a Tumor Suppressor in Gliomas
		10.4.3 STAT3 in Glioma Cancer Initiating Cells
	10.5 Molecular and Pharmacological Strategies to Interfere with STAT Signaling for Potential Therapeutic Intervention in Gliomas
	References
Chapter 11: Cannabinoid Signaling in Glioma Cells
	11.1 Introduction
	11.2 Cannabinoids and Their Receptors
	11.3 Cannabinoid System in Gliomas
	11.4 Action of Cannabinoids in Glioma Cells
		11.4.1 Mechanism of Cannabinoids Pro-apoptotic Action – Inhibition of Pro-survival Pathways
		11.4.2 The Role of ER Stress and Autophagy in Cannabinoid-Induced Cell Death
		11.4.3 Proapoptotic Actions Beyond the Cannabinoid Receptors
		11.4.4 Effects of Cannabinoids on The Tumor Microenvironment in Malignant Gliomas
	11.5 Therapeutic Potential of Targeting Cannabinoid Signaling in Gliomas
	References
Chapter 12: Effects of Arginine and Its Deprivation on Human Glioblastoma Physiology and Signaling
	12.1 Introduction
	12.2 Involvement of L-Arginine in Cellular Processes
	12.3 Arginine Metabolism
	12.4 Defects in Arginine Synthesis in Cancer Cells, Including Glioblastomas
	12.5 Arginine Deprivation in Human Glioblastoma Cell Lines
		12.5.1 Effects of Arginine Deprivation on Glioblastoma Cell Growth and Viability
		12.5.2 Effects of Arginine Deprivation on Glioblastoma Cell Morphology
		12.5.3 Effects of Arginine Deprivation on Glioblastoma Cell Adhesion
		12.5.4 Effects of Arginine Deprivation on Glioblastoma Cell Migration and Invasiveness
		12.5.5 Effects of Arginine Deprivation on Cytoskeleton Organization in Glioblastoma Cells
		12.5.6 Arginine and Actin Arginylation
	12.6 Arginine Deprivation-Based Anticancer Strategies for Glioblastoma
	12.7 Concluding Remarks
	References
Chapter 13: Histone Modifying Enzymes and Chromatin Modifiers in Glioma Pathobiology and Therapy Responses
	13.1 Chromatin as a Dynamic Platform for Signal Integration and Information Storage
	13.2 Mutations in Epigenetics-Related Genes or Their Aberrant Expression Contribute to the Dysregulated Epigenetic Landscape in Gliomas
	13.3 Histone Acetylases and Deacetylases as Therapeutic Targets in Malignant Gliomas
	13.4 Role of G9a: A Histone Methyltransferase in Glioma Pathobiology
		13.4.1 Functions of G9a as a Histone Methyltransferase
		13.4.2 Role of G9a in Glioma Biology
		13.4.3 Inhibitors of Histone Methyltransefase G9a/GLP
			13.4.3.1 Quinazoline Derivatives
			13.4.3.2 Selective Inhibitors for GLP
			13.4.3.3 Substrate-Competitive Inhibitors
			13.4.3.4 SAM-Competitive G9a Inhibitors
			13.4.3.5 Dual Inhibitors of G9a and Other Epigenetic Enzymes
			13.4.3.6 Inhibition of G9a as a New Therapeutic Approach in Gliomas
	13.5 Functions of SWI/SNF Family Members SMARCA2 and SMARCA4 in Gliomas
		13.5.1 Genetic Alterations or SNPs in Genes Coding for SWI/SNF Family Members in Gliomas
		13.5.2 Targeting SWI/SNF Family Members in Cancer Cells
		13.5.3 SMARCA4 and SMARCA2 Show a Synthetic Lethality
	References
Chapter 14: Role of Infiltrating Microglia/Macrophages in Glioma
	14.1 Introduction
	14.2 Glioma-Associated Microglia/Macrophages (GAMs) in Brain Tumors
		14.2.1 Microglia and Other Myeloid Cells in the Healthy Brain
		14.2.2 Microglia Activities
	14.3 Mechanism of Bidirectional Communication Between Tumor and Parenchymal Cells
		14.3.1 How GAMs Support the Tumor Growth
		14.3.2 How Glioma Modifies Microglia/Macrophages Phenotype and Activity
	14.4 Modulators of Tumor-Parenchyma Cross-Talk
		14.4.1 K+ Channels
		14.4.2 Environmental Stimuli/NK Cells
	14.5 Concluding Remarks
	References
Index