Systems Biology of Tumor Microenvironment: Quantitative Modeling and Simulations (Advances in Experimental Medicine and Biology Book 936)

"This edited volume discusses the complexity of tumor microenvironments during cancer development, progression and treatment. Each chapter presents a different mathematical model designed to investigate the interactions between tumor cells and the surrounding stroma and stromal cells. The topics covered in this book include the quantitative image analysis of a tumor microenvironment, the microenvironmental barriers in oxygen and drug delivery to tumors, the development of tumor microenvironmental niches and sanctuaries, intravenous transport of the circulating tumor cells, the role of the tumor microenvironment in chemotherapeutic interventions, the interactions between tumor cells, the extracellular matrix, the interstitial fluid, and the immune and stromal cells. Mathematical models discussed here embrace both continuous and agent-based approaches, as well as mathematical frameworks of solid mechanics, fluid dynamics and optimal control theory. The topics in each chapter will be of interest to a biological community wishing to apply the mathematical methods to interpret their experimental data, and to a biomathematical audience interested in exploring how mathematical models can be used to address complex questions in cancer biology. ". Font no determinada Foreword 6 References 8 Preface 10 Contents 14 Contributors 16 1 Image Analysis of the Tumor Microenvironment 19 1.1 Introduction 19 1.2 Imaging the Tumor Microenvironment 20 1.3 Brightfield Microscopy to Evaluate the Tumor Microenvironment 21 1.4 Fluorescent Microscopy to Evaluate the Tumor Microenvironment 22 1.5 Second Harmonic Generation to Evaluate the Tumor Microenvironment 25 1.6 Conclusion 25 References 26 2 Hypoxia in Gliomas: Opening Therapeutical Opportunities Using a Mathematical-Based Approach 29 2.1 The Glioma Microenvironment and its Macroscopic Fingerprints 29 2.1.1 The Hypoxic Tumor Microenvironment 30 2.1.2 Glioma Patterns of Invasion and Proliferation 30 2.1.3 Pseudopalisades and Coagulation in Gliomas 31 2.1.4 How Do Pseudopalisading Structures Arise in GBM? 32 2.1.5 Proliferation/Migration Dichotomy Validation from Biopsies 33 2.2 Mathematical Simulation of Pseudopalisade Formation Following Vaso-Occlusion Events 33 2.2.1 The Model 34 2.2.2 Results 34 2.2.3 Discussion and Therapeutical Implications for GBM Patients 36 2.3 Can Anti-thrombotics Delay the Malignant Transformation of Low-Grade Gliomas? 37 2.3.1 Mathematical Modeling of the Malignant Transformation of Low-Grade Gliomas 37 2.3.2 Results 38 2.3.3 Therapeutical Implications 40 2.4 Recreating the Glioblastoma Micro-environment In-Vitro: Cells in Microfluidic Devices 40 2.4.1 In Vivo Versus In-Vitro: The Microenvironment Problem 40 2.4.2 A Microfluidic Device for Mimicking the Hypoxic Glioblastoma Microenvironment 41 2.4.3 Synthetic Pseudopalisades are Generated in Microfluidic Devices 42 2.4.4 Mathematical Model 42 2.4.5 Comparison of Synthetic Versus Mathematical Pseudopalisades 43 2.5 Discussion and Conclusions 44 References 45 3 Computer Simulations of the Tumor Vasculature: Applications to Interstitial Fluid Flow, Drug Delivery, and Oxygen Supply 48 3.1 Introduction 48 3.1.1 Physiological Basics 49 3.1.2 Obstacles to Cancer Treatment 52 3.2 Theoretical Models 54 3.2.1 The Bulk of Tissue 54 3.2.2 Solutes in the Bulk of Tissue 56 3.2.3 Normal Blood Vessel Networks 56 3.2.4 Tumor Vascular Remodeling 60 3.2.5 Computation of Blood Flow and Hematocrit 62 3.2.6 Time Dependent Intravascular Tracer Concentration 63 3.2.7 Interstitial Fluid Pressure 63 3.2.8 Transvascular Fluid Exchange 64 3.2.9 Interstitial Drug Transport 65 3.2.10 Oxygen Transport 65 3.3 Discussion of Model Predictions 67 3.3.1 Vascular Morphology and Compartmentalization 67 3.3.2 Fractal Properties of Tumor Vasculatures 70 3.3.3 Interrelation of Initial and Emergent Tumor Vasculature 71 3.3.4 Blood Flow and Blood Borne Drug Transport 72 3.3.5 Interstitial Fluid Flow 72 3.3.6 Interstitial Drug Transport 74 3.3.7 Oxygen Distribution 76 3.4 Limitations and Outlook 79 References 82 4 Cell-ECM Interactions in Tumor Invasion 90 4.1 Introduction 90 4.2 ECM in Cancer Invasion 91 4.3 Cell-ECM Interactions 93 4.3.1 Focal Adhesion 94 4.3.2 Intracellular Mechanical Structures 95 4.3.3 Cell Membrane Remodeling and Mechanotransduction Signaling Network 96 4.3.4 Cell Migration Modes 98 4.4 2D Cell Migration Models 100 4.5 3D Cell-ECM Model 101 4.6 Modeling Collective Behavior of Cell Migration 102 4.7 Summary 103 References 103 5 Circulating Tumor Cells: When a Solid Tumor Meets a Fluid Microenvironment 109 5.1 Introduction 109 5.2 The IBCell Mathematical Model of Circulating Tumor Cells 112 5.3 Circulating Tumor Cell Survival in the Blood Flow 114 5.4 Circulating Tumor Cell Collision Dynamics 115 5.5 Circulating Tumor Cell Adhesion and Rolling on the Endothelium 116 5.6 Circulating Tumor Cell Crawling Dynamics 116 5.7 Circulating Tumor Cell Anchorage to the Endothelium and Transmigration 118 5.8 The Dynamics of Circulating Tumor Cell Microemboli 118 5.9 Summary 119 References 119 6 Modeling Proteolytically Driven Tumor Lymphangiogenesis 123 6.1 Introduction 124 6.2 Mathematical Model Development 128 6.2.1 Estimation of Parameters 135 6.2.2 Scaling Coefficients c0,e0,m0,f0,ue0,uc0,pe0,pc0 135 6.2.2.1 Estimation of the Diffusion Coefficients D 135 6.2.2.2 Taxis Coefficients χ, ζ, ψ, ξ 136 6.2.2.3 Proliferation Rate Constants, μii 136 6.2.2.4 VEGF-C Parameters 137 6.2.2.5 uPA Parameters 138 6.2.2.6 Degradation of the ECM 140 6.2.2.7 Plasmin Parameters 141 6.3 Numerical Results for the PDE Model 141 6.4 Conclusions 146 References 147 7 Positive Feedback Loops Between Inflammatory, Bone and Cancer Cells During Metastatic Niche Construction 153 7.1 Introduction 153 7.2 Cellular Systems in Tumor Inflammation-Associated Bone Remodeling 155 7.2.1 Bone Basic Multi-cellular Unit (BMU) 156 7.3 Vicious Cycles Within the Bone Metastasis Microenvironment 156 7.3.1 Bone-Cancer Vicious Cycle 156 7.3.2 Cancer-Macrophage Vicious Cycle 158 7.3.3 Macrophage-Bone Vicious Cycle 158 7.4 Logical-Transient-Threshold Dynamics 159 7.4.1 Modules' Parameters Estimations 161 7.5 Conclusion 162 References 162 8 Microenvironmental Niches and Sanctuaries: A Route to Acquired Resistance 165 8.1 Introduction 166 8.2 Microenvironmental Niches and Sanctuaries 167 8.3 The Mathematical Model of the Tumor and Its Microenvironment 168 8.4 Non-resistant Tumor Dynamics Under Treatment 171 8.5 Tumor Dynamics with Acquired Resistance Under the Treatment 172 8.6 Development of a Drug Resistant Tumor 173 8.7 Tissue Niches and Sanctuaries and Their Relation to Resistance 175 8.8 Summary and Outlook 176 References 178 9 The Tumor Microenvironment as a Barrier to Cancer Nanotherapy 181 9.1 Dysregulation of the Tumor Microenvironment 182 9.2 Nanotherapy as a Means to Address the Tumor Microenvironment 182 9.3 Mathematical Modeling of Cancer Nanotherapy 185 9.3.1 Multi-dimensional Simulation of Nanotherapy in Vascularized Tumors 185 9.3.2 Coupling of Nanotherapy Modeling with Vascular Flow 187 9.3.3 Modeling of Nanotherapy in Combination with In Vivo Imaging 188 9.3.4 Modeling of Nanoparticle Transport Based on In Vitro Data 191 9.3.5 Modeling of Vasculature-Bound Nanoparticles 192 9.3.6 Evaluation of Nanotherapy Using Pharmacokinetic Modeling 198 9.3.7 Modeling of Nanotherapy Induced Hyperthermia 201 9.4 Conclusion 201 References 202 10 Microenvironment-Mediated Modeling of Tumor Response to Vascular-Targeting Drugs 207 10.1 Introduction 208 10.2 Mathematical Model of Tumor Progression and Treatment 209 10.2.1 Spatial Model of Tumor-Vascular Interactions 209 10.2.2 Treatment Protocols 212 10.2.2.1 Vascular-Targeting Drug 1: Angiogenesis Inhibitors 212 10.2.2.2 Vascular-Targeting Drug 2: Vascular Disrupting Agents 213 10.2.2.3 Cytotoxic Chemotherapy 213 10.3 Benchmarking Model Performance Against Preclinical and Clinical Data 214 10.3.1 Angiogenesis Inhibitor in Isolation 214 10.3.2 Vascular Disrupting Agents 216 10.4 Antitumor Activity of Combination Therapies 218 10.4.1 Angiogenesis Inhibitors with Vascular Disrupting Agents 218 10.4.2 Optimal Dosing Schedule for Angiogenesis Inhibitor and Chemotherapy 220 10.5 Conclusions 221 References 223 11 Optimizing Chemotherapeutic Anti-cancer Treatment and the Tumor Microenvironment: An Analysis of Mathematical Models 225 11.1 Introduction: Anti-cancer Treatment as an Optimal Control Problem 226 11.2 Optimal Administration of Cancer Chemotherapy for Homogeneous and Heterogeneous Tumor Populations 227 11.3 Optimal Control of Anti-angiogenic Mono- and Combination Therapies 230 11.4 Optimal Control with Tumor Immune System Interactions 232 11.5 Metronomic Chemotherapy: A Mathematical Model for Its Effects on the Tumor Microenvironment 235 11.6 Conclusion 237 References 238 12 Progress Towards Computational 3-D Multicellular Systems Biology 240 12.1 Introduction 241 12.2 Progress Towards 3-D Multicellular Systems Biology 242 12.2.1 Simulating Tumor Growth in a Heterogeneous Microenvironment 242 12.2.2 Simulating the Chemical Microenvironment with Many Substrates 245 12.2.3 Simulating the Physical Microenvironment 248 12.2.4 Simulating the Evolving Microvasculature and Interstitial Flow 252 12.2.5 Calibration to and Validation Against Clinical and Experimental Data 253 12.2.6 Data Standards and Reproducibility 255 12.3 Next Steps and Closing Thoughts 256 References 258 Index 262 Front Matter....Pages i-xvii Image Analysis of the Tumor Microenvironment....Pages 1-10 Hypoxia in Gliomas: Opening Therapeutical Opportunities Using a Mathematical-Based Approach....Pages 11-29 Computer Simulations of the Tumor Vasculature: Applications to Interstitial Fluid Flow, Drug Delivery, and Oxygen Supply....Pages 31-72 Cell-ECM Interactions in Tumor Invasion....Pages 73-91 Circulating Tumor Cells: When a Solid Tumor Meets a Fluid Microenvironment....Pages 93-106 Modeling Proteolytically Driven Tumor Lymphangiogenesis....Pages 107-136 Positive Feedback Loops Between Inflammatory, Bone and Cancer Cells During Metastatic Niche Construction....Pages 137-148 Microenvironmental Niches and Sanctuaries: A Route to Acquired Resistance....Pages 149-164 The Tumor Microenvironment as a Barrier to Cancer Nanotherapy....Pages 165-190 Microenvironment-Mediated Modeling of Tumor Response to Vascular-Targeting Drugs....Pages 191-208 Optimizing Chemotherapeutic Anti-cancer Treatment and the Tumor Microenvironment: An Analysis of Mathematical Models....Pages 209-223 Progress Towards Computational 3-D Multicellular Systems Biology....Pages 225-246 Back Matter....Pages 247-249