Glioma Signaling

<p>1. INTRODUCTION TO PURINERGIC SIGNALING IN THE BRAIN</p><p>Geoffrey Burnstock</p><p>Abstract</p><p>1.1 Introduction</p><p>1.2 Purinergic Signalling in the CNS</p><p>1.2.1 Cotransmission</p><p>1.2.2 Glial Cells</p><p>1.2.3 Neuron-Glial Interactions</p><p>1.3 Purinergic Signalling in Normal Behaviour</p><p>1.4 Purinergic Pathophysiology in the CNS, including Gliomas</p><p>References</p><p>2. ADENOSINE SIGNALING IN GLIOMA CELLS</p><p>Stefania Ceruti and Maria P. Abbracchio</p><p>Abstract</p><p>2.1 Introduction</p><p>2.2 Adenosine Metabolism and P1 Adenosine Receptors</p><p>2.3 A Role for Ecto-5’-Nucleotidases CD39 and CD73 in Gliomas?</p><p>2.4 Receptor-Mediated Effects of Adenosine on Glioma Cell Growth and Survival</p><p>2.4.1 A₁-, A_2A-, and A_2B-Mediated Effects on Glioma Cells</p><p>2.4.2 The A₃ Receptor Subtype as a New Pharmacological Ttarget for Innovative Chemotherapic Approaches to Gliomas</p><p>2.5 Receptor-Idependent Effects of Adenosine Analogues on Glioma Cell Growth and Survival</p><p>2.6 Conclusions and Future Perspectives</p><p>References</p><p>3. CROSS-TALK IN NUCLEOTIDE SIGNALING IN GLIOMA C6 CELLS</p><p>Dorota Wypych and Jolanta Barańska </p><p>Abstract</p><p>3.1 Introduction</p><p>3.2 Properties of P2 Receptors</p><p>3.2.1 P2X Receptors</p><p>3.2.2 P2Y Receptors</p><p>3.3 P2Y₁, P2Y₂ and P2Y₁₂ Rreceptor Expression and Functionality in Rat Glioma C6 cells</p><p>3.4 Serum Withdrawal</p><p>3.4.1 Effect on P2Y₁ and P2Y₁₂ Receptor Expression</p><p>3.4.2 Effect on C6 cell Morphology, Growth and Differentiation</p><p>3.4.3 Effect on the P2Y₁₄ Receptor</p><p>3.5 Cyclic AMP Effect on Cell Proliferation, Growth and Differentiation</p><p>3.6 Effect of Extracellular Nucleotides on ERK1/2 and PI3K/Akt Activity: P2Y₁ and P2Y₁₂ Cross-Talk.</p><p>3.7 The P2X₇ Receptor</p><p>3.8 Concluding Remarks</p><p>References</p><p>4. CALCIUM SIGNALING IN GLIOMA CELLS – THE ROLE OF NUCLEOTIDE RECEPTORS</p><p>Dorota Wypych and Pawel Pomorski </p><p>Abstract</p><p>4.1 Origin of the Calcium Signaling</p><p>4.2 Sources of the Calcium Signal</p><p>4.2.1 Extracellular Calcium Signal</p><p>4.2.2 Signal Generated by Calcium Stores</p><p>4.2.2.1 Store Operated Calcium Signaling</p><p>4.2.2.2 Calcium-Induced Calcium Signaling</p><p>4.3 Calcium Signaling in Non-Excitable Glial Cells</p><p>4.3.1 Astrocytes</p><p>4.3.2 Microglia</p><p>4.4 Nucleotide Receptors-Evoked Calcium Signaling in Glial Cells</p><p>4.5 Glioma C6: a Case Study</p><p>4.5.1 The Nature of the Signal – the Role of Nucleotide Receptors in Glioma C6 Cells</p><p>4.6 Gliomas: The Motile Tumors, Calcium Signaling and Chemotaxis</p><p>4.6.1 The Calcium Signal in Glioma C6 is Strongly Dependent on Actin Cytoskeleton</p><p>4.7 Concluding Remarks</p><p>References</p><p>5. PURINERGIC SIGNALING IN GLIOMA PROGRESSION</p><p>Elizandra Braganhol, Márcia Rosângela Wink, Guido Lenz and Ana Maria Oliveira Battastini</p><p>Abstract</p><p>5.1 Introduction</p><p>5.1.1 Molecular and Cellular Origins of Gliomas</p><p>5.1.2 Glioma Cancer Stem Cells (CSCs)</p><p>5.1.3 Tumor Microenvironment – Key for Understanding and Targeting Gliomas</p><p>5.2 Purinergic Signaling in Gliomas</p><p>5.3 Ectonucleotidases</p><p>5.3.1 Ectonucleoside Triphosphate Diphosphohydrolases (E-NTPDases)</p><p>5.3.2 Ectonucleotide Pyrophosphatase/Phosphodiesterases (E-NPPs)</p><p>5.3.3 Ecto-Alkaline Phosphatases (ALP)</p><p>5.3.4 Ecto-5’-Nucleotidase (ecto-5’-NT/CD73)</p><p>5.4 Ecto-adenosine Deaminase (ecto-ADA)</p><p>5.5 Other Ecto-Nucleotide Metabolizing Enzymes</p><p>5.6 Ectonucleotidases in Gliomas</p><p>5.7 The Purinergic Hypothesis of Glioma Invasion</p><p>References</p><p>6. CYTOSKELETON AND NUCLEOTIDE SIGNALING IN GLIOMA CELLS</p><p>Wanda Kłopocka, Jarosław Korczyński and Pawel Pomorski </p><p>Abstract</p><p>6.1 Introduction</p><p>6.2 The Role of P2Y₂ Receptor in Actin Cytoskeleton Organization</p><p>6.2.1 Regulation by PIP₂</p><p>6.2.2 Regulation by the Small GTP-binding Proteins: Rho, Rac and Cdc42</p><p>6.3 Compensation of ROCK Inhibition by P2Y₂Activated Signaling Pathways</p><p>6.3.1 ROCK Inhibition in Glioma C6 Cells</p><p>6.3.2 Effect of P2Y₂ Receptor Stimulation on MLC Phosphorylation – the Role of MLCK</p><p>6.3.3 Effect of P2Y₂ Receptor Stimulation on Cofilin Phosphorylation – the Role of Rac1 Protein</p><p>6.3.4 Effect of Calcium Signal on Glioma C6 Cells Recovery from ROCK Inhibition - Essential Role of Integrins</p><p>6.4 Summary</p><p>References</p><p>7. SIGNALING DETERMINANTS OF GLIOMA CELL INVASION</p><p>Aneta Kwiatkowska and Marc Symons </p><p>Abstract</p><p>7.1 Invasiveness of Glioma Cells</p><p>7.2 Factors that Control Glioma Invasion. </p><p>7.2.1 Autocrine Factors.</p><p>7.2.2 Paracrine Factors.</p><p>7.3 Signaling Mechanisms that Control Glioma Invasion.</p><p>7.3.1 Integrins</p><p>7.3.2 Rho GTPases</p><p>7.3.3 PI3K and Phospholipid Signaling</p><p>7.3.4 Akt Kinase</p><p>7.4 Proteases</p><p>7.5 Conclusions and Future Directions</p><p>References</p><p>8. RECEPTOR TYROSINE KINASES: PRINCIPLES AND FUNCTIONS IN GLIOMA INVASION</p><p>Mitsutoshi Nakada, Daisuke Kita, Lei Teng, Ilya V. Pyko, Takuya Watanabe and Jun-ichiro Hamada</p><p>Abstract</p><p>8.1 Introduction</p><p>8.2 EGFR/EGF</p><p>8.3 PDGFR/PDGF </p><p>8.4 ERBB2</p><p>8.5 c-Met/HGF</p><p>8.6 Tie/Ang</p><p>8.7 Axl/Gas6</p><p>8.8 DDR1/Collagen</p><p>8.9 Eph/Ephrin</p><p>8.10 TrkA </p><p>8.11 Cross-Talk</p><p>8.12 Targeting Receptor Type Tyrosine Kinases</p><p>8.12.1 Targeting EGFR</p><p>8.12.2 Targeting PDGFR</p><p>8.12.3 Multiple Kinase Inhibitors</p><p>8.13 Prospective</p><p>References</p><p>9. TGF BETA SIGNALING AND ITS ROLE IN GLIOMA PATHOGENESIS</p><p>Bozena Kaminska and Magdalena Kijowska </p><p>Abstract</p><p>9.1 Introduction</p><p>9.2 A Brief Summary of Mechanisms of TGF-b Signaling in Normal and Malignant Cells</p><p>9.2.1 Components and Mechanisms of TGF-b Signaling</p><p>9.2.2 Negative Regulators of TGF-b Signaling 9.2.3 Transcriptional Responses Induced by TGF-b Signaling. </p><p>9.3 Deregulation of TGF-b Signaling in Gliomas. </p><p>9.4 Functions of TGF-b Signaling in Glioma Biology</p><p>9.4.1 TGF-b Signaling in Controlling Cell Proliferation</p><p>9.4.2 TGF-b Signaling in the Regulation of Invasion</p><p>9.4.3 TGF-β1 as Pro-Angiogenic Factor</p><p>9.4.4 A Role of TGF-b Signaling in Glioma Cancer Initiating Cells</p><p>9.4.5. TGF-b Signaling in Tumor-Mediated Immunosuppression</p><p>9.5 Molecular and Pharmacological Strategies to Interfere with TGF-b Signaling for Potential Therapeutic Intervention in Gliomas</p><p>References</p><p>10. STAT signaling in glioma cells</p><p>Karolina Swiatek-Machado and Bozena Kaminska </p><p>Abstract</p><p>10.1 Introduction </p><p>10.2 A Brief Summary of Mechanisms of STAT Activation in Normal and Malignant Signaling</p><p>10.2.1 Mechanisms of STAT Activation</p><p>10.2.2 Negative Regulators of STAT Signaling </p><p>10.2.3 Transcriptional Targets of STATs</p><p>10.3 Dysfunction of STAT Signaling in Gliomas</p><p>10.3.1 Constitutive Activation of STAT3 in Gliomas </p><p>10.3.2 STAT3 Activation in Gliomas Results from Dysfunction in Control Mechanisms</p><p>10.4 Functions of STAT3 in Gliomas</p><p>10.4.1 STAT3 as an Oncogene</p><p>10.4.2 STAT3 as a Tumor Suppressor </p><p>10.4.3 STAT3 in Glioma Cancer Initiating Cells</p><p>10.5 Molecular and Pharmacological Strategies to Interfere with STAT Signaling for Potential Therapeutic Intervention in Gliomas</p><p>References</p><p>11. CANNABINOID SIGNALING IN GLIOMA CELLS</p><p>Aleksandra Ellert-Miklaszewska, Iwona Ciechomska and Bozena Kaminska </p><p>Abstract</p><p>11.1 Introduction</p><p>11.2 Cannabinoids and their Receptors</p><p>11.3 Cannabinoid System in Gliomas</p><p>11.4 Action of Cannabinoids in Glioma Cells</p><p>11.4.1 Mechanism of Cannabinoids Pro-Apoptotic Action – Inhibition of Pro-Survival Pathways</p><p>11.4.2 The Role of ER Stress and Autophagy in Cannabinoid-Induced Cell Death</p><p>11.5 Therapeutic Potential of Targeting Cannabinoid Signaling in Gliomas</p><p>References</p>