From Malignant Transformation to Metastasis: Ion Transport in Tumor Biology (Reviews of Physiology, Biochemistry and Pharmacology, 182)

This second book of the three-volume collection "Ion Transport in Tumor Biology" helps readers gain comprehensive knowledge of the pathophysiology of cancer. The authors highlight that ion transport proteins, channels and transporters - collectively referred to as the transportome - are significantly involved in the development and progression of cancer. Nearly 90% of malignant tumor diseases originate from epithelial cells, the function of which, for the most part, is based on the transportome. This volume focuses on molecular principles by showing that dysregulated expression and/or function of ion transporters have been correlated with malignancy in the vast majority of tumor diseases. Within the story of the various chapters, the authors line out various malfunctions of the transportome and where they can be found at different stages of the metastatic cascade. The authors describe how the interactions between the tumor cells' transportome and the environment reinforce mesenchymal behaviour of cancer cells and contribute to their uncontrolled proliferation, migration, invasion, intra- and extravasation up to the formation of metastases. As part of a three-volume collection, this book will fascinate members of the active research community, as well as clinicians from the cancer field. Preface 6 References 8 Acknowledgements 13 Contents 14 How Reciprocal Interactions Between the Tumor Microenvironment and Ion Transport Proteins Drive Cancer Progression 15 1 Introduction 16 2 The Tumor Microenvironment 18 2.1 The Cellular Component 18 2.1.1 Other Cell Types in the TME 20 2.2 The Acellular Component 20 2.2.1 Hypoxia and Oxidative Stress 21 2.2.2 Acidosis 22 2.2.3 Lactate 23 2.2.4 Other Physicochemical Factors Shaping the TME 25 2.3 Heterogeneity of the Primary Tumor and Metastatic Sites 27 3 Regulation of Transport Proteins by the TME 29 3.1 Na+/H+ Exchangers 29 3.2 Na+/HCO3- Cotransporters 34 3.3 Monocarboxylate Transporters 35 3.4 Vacuolar H+-ATPases 36 3.5 Other Transport Proteins Regulated by the TME 38 3.5.1 Drug Efflux Transporters Are Regulated by Hypoxia and Lactate 38 3.5.2 Nutrient Transporters Maintain Redox Homeostasis and Are Regulated by Hypoxia 38 3.5.3 Proton-Coupled Folate Transporters Are Thermodynamically Driven by Extracellular Acidosis 39 4 Conclusions and Perspectives 39 References 40 Ion Channels, Transporters, and Sensors Interact with the Acidic Tumor Microenvironment to Modify Cancer Progression 53 1 Introduction 54 2 H+ 55 2.1 H+ Transporters in the Plasma Membrane 56 2.2 Organellar H+ Sequestration 58 2.3 Cellular Sensors and Consequences of H+ 61 2.4 Effects of H+ on Stromal Cells 63 3 HCO3- 64 3.1 HCO3- Transporters in the Plasma Membrane 66 3.2 Cellular Sensors and Consequences of HCO3- 67 3.3 Effects of HCO3- on Stromal Cells 69 4 Lactate and Other Signaling Metabolites 69 4.1 Transport of Lactate Across the Plasma Membrane 71 4.2 Cellular Sensors and Consequences of Lactate 72 4.3 Other Signaling Metabolites 73 5 Other Deregulated Ions in the Tumor Microenvironment 73 5.1 Interactions Between Ca2+ and Acid-Base Homeostasis 73 5.2 Interactions Between Na+, K+, and Acid-Base Homeostasis 75 5.3 Interactions Between Cl- and Acid-Base Homeostasis 77 6 Conclusions 78 References 80 Role of pH Regulatory Proteins and Dysregulation of pH in Prostate Cancer 99 1 Introduction 100 1.1 Prostate Cancer, General 100 1.2 Tumor Microenvironments, General 101 1.3 Acid-Extruding Ion Transporters 104 1.4 Acid-Extruding Transporters in Prostate Cancer 104 1.5 Na+/H+ Exchangers 105 1.6 Na+HCO3- Cotransporter NBCn1 (SLC4A7) 107 1.7 Anion Exchangers 108 1.8 Lactate-H+ Cotransporters (MCT1 and MCT4) 109 1.9 Vacuolar-Type H+-ATPase 110 1.10 Carbonic Anhydrases 112 2 Summary and Future Directions 114 References 116 Calcium-Permeable Channels in Tumor Vascularization: Peculiar Sensors of Microenvironmental Chemical and Physical Cues 125 1 Tumor Vascularization 127 2 Ca2+-Signals and Ca2+-Permeable Channels in Activated ECs 128 3 Role of Ca2+ Permeable Channels in Hypoxia-Induced Angiogenesis 133 4 Role of Ca2+-Permeable Channels in Stiffness-Induced Angiogenesis 137 5 Conclusions 142 References 143 Circulating Tumor Cells: Does Ion Transport Contribute to Intravascular Survival, Adhesion, Extravasation, and Metastatic Orga... 152 1 Introduction 153 2 Surviving the Intravascular Milieu 154 2.1 Coping with Mechanical Stress 154 2.2 Resistance to Anoikis 155 2.3 Defeating Attacks by the Immune System 157 3 Adhesion to the Vessel Wall 159 4 Extravasation 160 4.1 With the Assistance of Blood Cells 161 4.1.1 Platelets 161 4.1.2 Neutrophils 162 4.1.3 Monocytes/Macrophages 163 5 Organotropism 163 5.1 Locally Released Chemokines Lure CTCs 164 5.1.1 CXCL12/CXCR4 166 5.1.2 CCL20/CCR6 167 5.1.3 CCL19 and 21/CCR7 168 5.2 Given Factors at the Premetastatic Niche 168 5.2.1 Falling Asleep and Awakening 169 5.2.2 Local Nutrient Supply 169 5.2.3 Defeating the Local Defense System 169 5.3 Lack of E-Cadherin, Reduced NHE1 Activity, and the Presence of CAIX Each Contribute to Lung Tropism 170 6 Conclusion and Outlook 171 References 173