Reichle From Molecular to Modular Tumor Therapy:

Tumors are Reconstructible Communicatively Evolving Systems
1. Auflage 2010
ISBN: 978-90-481-9531-2
Verlag: Springer Netherlands
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 568 Seiten

Reihe: Biomedical and Life Sciences (R0)

Autoren/Hrsg.

Reichle, Albrecht

Inhaltsverzeichnis

1;From Molecular to ModularTumor Therapy;3
1.1;Contents;5
1.2;Part I:Therapy-Derived Systems Biology:A Pragmatic Communication Theory;9
1.2.1;Chapter 1: Bridging Theory and Therapeutic Practice: From Generalized Disease Models to Particular Patients;10
1.2.1.1;1.1 Introduction;11
1.2.2;Chapter 2: Tumor Systems Need to be RenderedUsable for a New Action-Theoretical Abstraction:The Starting Point for Novel Therapeutic Options;15
1.2.2.1;2.1 Explorative Considerations (The ‘Now’);16
1.2.2.2;2.2 Methodological Approach;17
1.2.2.2.1;2.2.1 Theory of Communicative Interactions in Tumor Compartments;17
1.2.2.2.2;2.2.2 Structural Differentiation;17
1.2.2.2.3;2.2.3 Rationalization;18
1.2.2.2.4;2.2.4 Deformation;19
1.2.2.2.5;2.2.5 Resulting Observation Levels;19
1.2.2.2.6;2.2.6 Approach to an Action-Theoretical Systems Term: The Scientist as a Subject of the System;20
1.2.2.2.7;2.2.7 Tumor Systems Need to be Rendered Useable for a New Action-Theoretical Abstraction;20
1.2.2.2.8;2.2.8 Assignment of Systems-Theoretical and Action-Theoretical Inconsistencies;20
1.2.2.3;2.3 Conceptual Equipment;21
1.2.2.3.1;2.3.1 Sensitive Assessment Tools;23
1.2.2.3.2;2.3.2 Action-Oriented Research Approaches: Broadening of the Therapeutic Spectrum (Individualized Therapy);26
1.2.2.4;2.4 Discussion: Critical Reflection on Tumor Systems Biology (The ‘Then’);28
1.2.2.5;References;31
1.2.3;Chapter 3: Principles of Modular Tumor Therapy;35
1.2.3.1;3.1 Introduction;36
1.2.3.2;3.2 Methods: A Formal-Pragmatic Communication Theory;38
1.2.3.2.1;3.2.1 Definition of the Tumor’s Living World as a Holistic Communicative Unit;38
1.2.3.2.2;3.2.2 Situative Objectivation of the Tumor’s Living World;39
1.2.3.2.3;3.2.3 Formal-Pragmatic Theory About Denotation of a Communication Process;40
1.2.3.2.4;3.2.4 Perception of Validity;40
1.2.3.2.5;3.2.5 Novel Idealizations: Therapeutically Relevant Redemption of Validity;41
1.2.3.3;3.3 Implementation of the Formal-Pragmatic Communication Theory;42
1.2.3.3.1;3.3.1 Clinical Results Supporting a Formal-Pragmatic Communication Theory;42
1.2.3.3.2;3.3.2 Translation of Clinical Results in a Formal Communication Theory;43
1.2.3.3.3;3.3.3 Explication of a Formal-Pragmatic Communication Theory;44
1.2.3.4;3.4 Discussion;48
1.2.3.4.1;3.4.1 Glossary;50
1.2.3.4.1.1;3.4.1.1 Co-option;50
1.2.3.4.1.2;3.4.1.2 Evolvability;50
1.2.3.4.1.3;3.4.1.3 Modularity;50
1.2.3.4.1.4;3.4.1.4 Modular Communication (Therapies);51
1.2.3.4.1.5;3.4.1.5 Risk-Absorbing Background Knowledge;51
1.2.3.4.1.6;3.4.1.6 Tumor’s Living World;51
1.2.3.4.1.7;3.4.1.7 Reconstruction of Tumor-Associated Systems;51
1.2.3.4.1.8;3.4.1.8 Robustness;51
1.2.3.4.1.9;3.4.1.9 Separated or Separating ‘Social’ Tumor Systems;52
1.2.3.5;References;52
1.3;Part II:Tumors Share Common Processes DuringTumor Evolution: Communicative Aspectsof a Situation’s Interpretation for CreatingSystems-Directed Therapies;54
1.3.1;Chapter 4: Cancer and Coagulation; Focusing on Tissue Factor and Heparanase55
1.3.1.1;4.1 Introduction;56
1.3.1.2;4.2 Tissue Factor (TF);57
1.3.1.2.1;4.2.1 TF Structure and Expression;57
1.3.1.2.2;4.2.2 TF and the Coagulation System;57
1.3.1.2.3;4.2.3 Increased TF Expression in Tumors;59
1.3.1.2.4;4.2.4 TF and Angiogenesis;59
1.3.1.2.5;4.2.5 TF Signaling;60
1.3.1.2.6;4.2.6 Blood-Borne TF;60
1.3.1.3;4.3 Thrombin;61
1.3.1.4;4.4 Tissue Factor Pathway Inhibitor (TFPI);62
1.3.1.4.1;4.4.1 TFPI Structure and Expression;62
1.3.1.4.2;4.4.2 TFPI in Blood and Cells;63
1.3.1.5;4.5 Heparanase;63
1.3.1.5.1;4.5.1 Heparanase Structure;63
1.3.1.5.2;4.5.2 Pro-angiogenic Properties;64
1.3.1.5.3;4.5.3 Pro-metastatic Properties;65
1.3.1.5.4;4.5.4 Non-enzymatic Functions;66
1.3.1.5.5;4.5.5 Hematopoetic Cells and Heparanase;66
1.3.1.5.6;4.5.6 Inhibition of Heparanase by Heparins;66
1.3.1.5.7;4.5.7 Heparanase and TF;67
1.3.1.5.8;4.5.8 Heparanase and TFPI;68
1.3.1.5.9;4.5.9 A Model for Interaction Between Heparanase, TF, and TFPI;69
1.3.1.6;References;70
1.3.2;Chapter 5: The Role of Mesenchymal Cells in Cancer: Contribution to Tumor Stroma and Tumorigenic Capacity;79
1.3.2.1;5.1 Introduction;79
1.3.2.2;5.2 Current Status of Pre-clinical Attempts and Clinical Trials Using Isolated MSCs;82
1.3.2.3;5.3 Homing and Engraftment of MSCs Following Transplantation;84
1.3.2.4;5.4 MSCs as a Double-Edged Sword: Do They Support Tumor Cell Growth or Are They Safe for Use in Tumor Ablation?;85
1.3.2.4.1;5.4.1 MSCs in Tumor Promotion;86
1.3.2.4.2;5.4.2 MSCs in Tumor Inhibition;87
1.3.2.5;5.5 MSCs as Tumor-Initiating Cells: Does MSC Transplantation Pose a Threat in Terms of Cancer Formation?;88
1.3.2.5.1;5.5.1 In Vitro Senescence of MSCs;89
1.3.2.5.2;5.5.2 Aneuploidy and Chromosomal Aberrations in Cultured MSCs;90
1.3.2.5.3;5.5.3 MSC Tumorigenicity;91
1.3.2.6;5.6 Possible Mechanisms Underlying MSC Tumorigenicity: Chromosomal Instability – Culprit or Savior?;92
1.3.2.7;5.7 Summary;94
1.3.2.8;References;95
1.3.3;Chapter 6: Shaping Tumor Associated Macrophages: The Role of NF-kB;101
1.3.3.1;6.1 Introduction;101
1.3.3.2;6.2 Macrophage Polarisation;102
1.3.3.3;6.3 Tumor Associated Macrophages: An Alternative Macrophage Phenotype;103
1.3.3.4;6.4 The NF-kB Signaling Pathway;104
1.3.3.5;6.5 NF-k.B and Macrophage Polarization;107
1.3.3.6;6.6 Crosstalk Between Hypoxia Inducible Factor and NF-k.B;110
1.3.3.7;6.7 Concluding Remarks;111
1.3.3.8;References;111
1.3.4;Chapter 7: The Metabolic Achilles Heel: Tumor Cell Metabolism as Therapeutic Target;115
1.3.4.1;7.1 Tumor Glucose Metabolism: The Warburg Phenotype;115
1.3.4.2;7.2 Amino Acid Metabolism in Cancer: Increased Glutaminolysis and Expression of IDO and Arginase in the Tumor Environment;117
1.3.4.3;7.3 Alterations in Tumor Lipid Metabolism: COX Expression and Ganglioside Production;118
1.3.4.4;7.4 Adenosine Accumulation in the Tumor Environment;119
1.3.4.5;7.5 Molecular Background of Metabolic Alterations in the Tumor Environment;120
1.3.4.5.1;7.5.1 Oncogenic Transformation and Hypoxia Lead to Metabolic Alterations;120
1.3.4.6;7.6 Impact of Tumor Metabolism on Immune Cell Function;121
1.3.4.7;7.7 Tumor-Derived Lipids Suppress Immune Cell Activity;123
1.3.4.8;7.8 Immunosuppression by Adenosine;123
1.3.4.9;7.9 Tumor Metabolism as Therapeutic Target;124
1.3.4.10;7.10 Inhibition of Tumor Glycolysis;124
1.3.4.11;7.11 Targeting the Glucose Uptake;125
1.3.4.12;7.12 Acceleration of the Mitochondrial Activity;125
1.3.4.13;7.13 Modulation of Tumor Lipid Metabolism;125
1.3.4.14;7.14 Rescuing Anti-tumor Immune Response;126
1.3.4.15;7.15 Summary and Concluding Remarks;127
1.3.4.16;References;127
1.3.5;Chapter 8: Could Be Systems-Directed Therapy Approaches Promising in Glioblastoma Patients?;137
1.3.5.1;8.1 The Target: Glioblastoma;138
1.3.5.2;8.2 Therapy Resistance in Glioblastoma;138
1.3.5.3;8.3 Insufficient Activity of Targeted Agents in Monotherapy;138
1.3.5.4;8.4 Glioblastomas’ Intrinsic Resistance;139
1.3.5.5;8.5 Resistance Induced by Treatment;139
1.3.5.6;8.6 Consequences of Therapy Resistance;139
1.3.5.7;8.7 Systems Biology in Glioblastoma;140
1.3.5.8;8.8 Pathophysiology of Glioblastoma as Therapeutic Target;140
1.3.5.9;8.9 Glioblastoma Cells with Stem Cell Function;141
1.3.5.10;8.10 The Glioblastoma Stem Cell Niche;143
1.3.5.11;8.11 Key Regulators of the Tumor Niche;144
1.3.5.12;8.12 Tumor Metabolism;144
1.3.5.13;8.13 Tumor-Associated Inflammation in GBM;145
1.3.5.14;8.14 Proliferation Behavior;145
1.3.5.15;8.15 Invasion;146
1.3.5.16;8.16 Angiogenesis;146
1.3.5.17;8.17 Local Immunosuppression;147
1.3.5.18;8.18 Pathophysiology-Based Therapy in Glioblastoma;147
1.3.5.18.1;8.18.1 Diagnostics Promoting Systems Comprehension;147
1.3.5.19;8.19 Targeting the Invasive Feature;149
1.3.5.20;8.20 Targeting Angiogenesis;149
1.3.5.21;8.21 Targeting Immunosuppressive Features;150
1.3.5.22;8.22 Multi-Targeted Treatment;151
1.3.5.23;8.23 Approaches for Personalizing GBM Therapy;152
1.3.5.24;8.24 Outlook;152
1.3.5.25;References;153
1.4;Part III:Systems-Relevant Molecularand Cellular Targets: Implementationof Modular ‘Knowledge’;162
1.4.1;Chapter 9: Functional Impacts of Signal Integration:Regulation of Inflammation-Related Transcription Factors by Heterotrimeric G Proteins;163
1.4.1.1;9.1 Introduction;166
1.4.1.2;9.2 G protein-Mediated NFkB Regulation in Inflammation and Cancer;167
1.4.1.3;9.3 The Modulation of STAT Activity by Heterotrimeric G Proteins;172
1.4.1.4;9.4 Interaction Between NF-kB and STAT3 in Inflammatory Responses;176
1.4.1.5;9.5 Other Transcription Factors Regulated by Heterotrimeric G Proteins;176
1.4.1.6;9.6 Functional Impacts of Signal Integration;181
1.4.1.7;9.7 Future Perspectives;182
1.4.1.8;References;182
1.4.2;Chapter 10: Molecular Cross-Talk Between Nuclear Receptors and Nuclear Factor-kB;192
1.4.2.1;10.1 Introduction;195
1.4.2.2;10.2 Nuclear Factor-kB (NF-kB): A Central Player;196
1.4.2.3;10.3 Nuclear Receptors: The Road to Relief;199
1.4.2.3.1;10.3.1 NF-kB and the Glucocorticoid Receptor, GR;203
1.4.2.3.1.1;10.3.1.1 Transactivation of Promoters of Inflammation-Repressing Proteins;203
1.4.2.3.1.2;10.3.1.2 Destabilization of Pro-inflammatory Gene mRNA;205
1.4.2.3.1.3;10.3.1.3 Transrepression of NF-kB-Dependent Gene Expression;206
1.4.2.3.1.3.1;Direct GR:NF-kB Association;206
1.4.2.3.1.3.2;Modulation of Activational NF-kB Signalling Cascades;207
1.4.2.3.1.3.3;GR Targeting the Enhanceosome;209
1.4.2.3.2;10.3.2 NF-k.B and the Peroxisome Proliferator-Activated Receptors, PPAR;211
1.4.2.3.3;10.3.3 NF-k.B and Liver X Receptor, LXR;214
1.4.2.3.4;10.3.4 NF-k.B and the Estrogen Receptor, ER;214
1.4.2.3.5;10.3.5 NF-k.B and the Androgen Receptor, AR;217
1.4.2.3.6;10.3.6 NF-k.B and the Progesterone Receptor, PR;218
1.4.2.3.7;10.3.7 NF-k.B and the RARs, RXRs, RORs;219
1.4.2.3.8;10.3.8 NF-k.B and the Thyroid Hormone Receptor, TR;220
1.4.2.3.9;10.3.9 NF-k.B and the Vitamin D Receptor, VDR;220
1.4.2.3.10;10.3.10 NF-k.B and Other Nuclear Receptors;221
1.4.2.4;10.4 Conclusions;224
1.4.2.5;References;224
1.4.3;Chapter 11: The Biomodulatory Capacities of Low-Dose Metronomic Chemotherapy: Complex Modulation of the Tumor Microenvironment;244
1.4.3.1;11.1 Introduction;245
1.4.3.2;11.2 Conventional Chemotherapy: Beyond Cytotoxic Effects;245
1.4.3.3;11.3 Low-Dose Metronomic Chemotherapy;247
1.4.3.3.1;11.3.1 Principles;247
1.4.3.3.2;11.3.2 Clinical Applications;249
1.4.3.4;11.4 Low-Dose Metronomic Chemotherapy: Beyond Antiangiogenic Effects;250
1.4.3.4.1;11.4.1 Hypoxia-Inducible Factor 1a Inhibition;251
1.4.3.4.2;11.4.2 TSP-1 Induction;252
1.4.3.4.3;11.4.3 Immunomodulation;252
1.4.3.4.4;11.4.4 Lack of Pro-Thrombotic Activity;253
1.4.3.5;11.5 Low-Dose Metronomic Chemotherapy: The Pharmacogenetic Perspective;253
1.4.3.5.1;11.5.1 How to Integrate Pharmacogenetic Investigations into Metronomic Phase II/III Clinical Trials?;254
1.4.3.5.2;11.5.2 What Is the Most Effective Pharmacogenetic Strategy to be Used?;254
1.4.3.5.3;11.5.3 How to Decide About Candidate Genes to be Investigated?;254
1.4.3.6;11.6 Outlook;255
1.4.3.7;References;256
1.5;Part IV:Tumors are Evolvable Modularand Rationalized Systems: FromMolecular to Modular Tumor Therapy;264
1.5.1;Chapter 12: Systems Biology: A Therapeutic Target for Tumor Therapy;265
1.5.1.1;12.1 Introduction;266
1.5.1.2;12.2 Patients and Methods;267
1.5.1.2.1;12.2.1 Selection of Metastatic Diseases;267
1.5.1.2.2;12.2.2 Patients’ Characteristics;269
1.5.1.2.3;12.2.3 Basic Treatment Considerations;269
1.5.1.2.4;12.2.4 Anti-Inflammatory Therapies;269
1.5.1.2.5;12.2.5 Angiostatic Therapies;270
1.5.1.3;12.3 Systems Biology: A Therapeutic Target for Tumor Therapy;270
1.5.1.3.1;12.3.1 Treatment Schedules;270
1.5.1.3.2;12.3.2 Combined Targeting of Wound Healing Processes;271
1.5.1.4;12.4 Pre-Treatment Evaluation Is Indicated in the Respective Publications;271
1.5.1.4.1;12.4.1 Evaluation of Efficacy;271
1.5.1.5;12.5 Modulation of Tumor-Associated Disease Traits;271
1.5.1.5.1;12.5.1 ECOG Status: ECOG Performance Status Was Routinely Monitored;271
1.5.1.5.2;12.5.2 Metastatic Sites;272
1.5.1.5.3;12.5.3 Statistics and Data Analysis;272
1.5.1.6;12.6 Results;272
1.5.1.7;12.7 Tailored Modeling of Tumor-Associated Disease Traits;274
1.5.1.7.1;12.7.1 ECOG Performance Status;274
1.5.1.7.2;12.7.2 Paraneoplastic Syndromes;275
1.5.1.7.3;12.7.3 Serum CRP Level in Follow-Up;275
1.5.1.7.4;12.7.4 Impact of Anti-inflammatory Therapy;275
1.5.1.7.5;12.7.5 Intensification of Anti-inflammatory Therapy;276
1.5.1.7.6;12.7.6 Combined Transcriptional Modulation;276
1.5.1.7.7;12.7.7 Angiostatic Therapy;276
1.5.1.7.8;12.7.8 Metastatic Sites and Response;277
1.5.1.7.9;12.7.9 Metastatic Sites at Progression;277
1.5.1.8;12.8 Safety Profile;277
1.5.1.9;12.9 Discussion;278
1.5.1.10;References;283
1.5.2;Chapter 13: The Comparative Uncovering of Tumor Systems Biology by Modularly Targeting Tumor-Associated Inflammation;286
1.5.2.1;13.1 Introduction;287
1.5.2.2;13.2 Methods;290
1.5.2.3;13.2.1 Tumor-Specific and Stage-Specific Therapeutic Accessibility of Inflammation-Related Processes;292
1.5.2.4;13.2.2 Statistics and Data Analysis;293
1.5.2.5;13.3 Results;293
1.5.2.6;13.3.1 CRP Response as Predictor for Clinical Tumor Response;294
1.5.2.7;13.4 Discussion;297
1.5.2.8;13.4.1 Systems Rationalization and Inter-systemic Exchange Processes;298
1.5.2.9;13.4.2 The Systems Biology of a Tumor: An Independent Feature at a Distinct Stage?;300
1.5.2.10;References;302
1.5.3;Chapter 14: Searching for the ‘Metabolism’ of Evolution;303
1.5.3.1;14.1 Letter;303
1.5.3.2;References;307
1.6;Part V:Biomodulatory Therapy Approachesin Metastatic Cancer;308
1.6.1;Chapter 15: The Impact of Inflammation Control and Active Cancer Palliation on Metabolic Pathways Determining Tumor Progressio and Patient Survival*;309
1.6.1.1;15.1 Introduction;310
1.6.1.1.1;15.1.1 Tumor–Host Interaction;310
1.6.1.1.2;15.1.2 Cancer Cachexia;311
1.6.1.1.2.1;15.1.2.1 Prostaglandin Biosynthesis;311
1.6.1.1.3;15.1.3 Prostanoid Related Effects in Tumor Bearers;314
1.6.1.1.3.1;15.1.3.1 Inflammation and Tumor Growth;314
1.6.1.1.3.2;15.1.3.2 Prostanoids and Metabolic Alterations;314
1.6.1.1.3.3;15.1.3.3 Tumor Angiogenesis;316
1.6.1.1.4;15.1.4 Inflammatory Mediators in Colon Cancer;317
1.6.1.1.5;15.1.5 Prostanoids and Immunological Tumor Alterations;322
1.6.1.1.6;15.1.6 Anti-Inflammatory Therapy;324
1.6.1.2;References;326
1.6.2;Chapter 16: Pioglitazone and Rofecoxib Combined with Angiostatically Scheduled Capecitabine in Far-Advanced Hepatobiliary Carcinoma;337
1.6.2.1;16.1 Introduction;338
1.6.2.2;16.2 Patients and Methods;338
1.6.2.2.1;16.2.1 Patients’ Characteristics;338
1.6.2.2.2;16.2.2 Treatment;338
1.6.2.2.3;16.2.3 Evaluation of Efficacy and Safety;339
1.6.2.2.4;16.2.4 Pre-treatment Evaluation and Follow-Up;339
1.6.2.2.5;16.2.5 Statistics and Data Analysis;340
1.6.2.3;16.3 Results;340
1.6.2.3.1;16.3.1 Patients;340
1.6.2.3.2;16.3.2 Antitumor Activity;340
1.6.2.3.3;16.3.3 Progression-Free Survival (PFS);342
1.6.2.3.4;16.3.4 Pre-treatment with Pioglitazone and Rofecoxib;344
1.6.2.3.5;16.3.5 Response Characteristics;344
1.6.2.3.6;16.3.6 Survival;344
1.6.2.3.7;16.3.7 Tolerability and Safety;344
1.6.2.4;16.4 Discussion;346
1.6.2.5;References;347
1.6.3;Chapter 17: C-Reactive Protein As a Secretome-Derived Biomarker for Predicting Response to Biomodulatory Therapy in Metastatic Renal Clear Cell Carcinoma;349
1.6.3.1;17.1 Introduction;350
1.6.3.2;17.2 Patients and Methods;351
1.6.3.3;17.3 Eligibility;351
1.6.3.4;17.4 Pre-treatment Evaluation;352
1.6.3.5;17.5 Treatment;352
1.6.3.6;17.6 Efficacy Assessment;352
1.6.3.7;17.7 Dosage Modification;353
1.6.3.8;17.8 Statistical Considerations;353
1.6.3.9;17.9 Results;353
1.6.3.9.1;17.9.1 Patients’ Characteristics;353
1.6.3.10;17.10 Treatment;355
1.6.3.11;17.11 Treatment Efficacy;355
1.6.3.12;17.12 CRP Response;358
1.6.3.13;17.13 Tolerability and Safety;358
1.6.3.14;17.14 Discussion;360
1.6.3.15;References;361
1.6.4;Chapter 18: Modular Therapy Approach in Metastatic Castration-Resistent Prostate Cancer;363
1.6.4.1;18.1 Introduction;364
1.6.4.2;18.2 Patients and Methods;365
1.6.4.3;18.3 Results;367
1.6.4.4;18.4 Biochemical and Objective Responses;369
1.6.4.5;18.5 PFS and Overall Survival;370
1.6.4.6;18.6 Toxicity;370
1.6.4.7;18.7 Discussion;371
1.6.4.8;References;372
1.6.5;Chapter 19: Systems-Directed Therapy in Metastatic Castration-Resistent Prostate Cancer (CRCP);374
1.6.5.1;References;377
1.7;Part VI:Criteria for Checking SystemsBehavior and Creating Predictions:Systems-Associated Biomarkersand Molecular Imaging;378
1.7.1;Chapter 20: Early Detection of Systems Response: Molecular and Functional Imaging of Angiogenesis;379
1.7.1.1;20.1 Introduction;380
1.7.1.2;20.2 Vascular Volume Fraction, Tumor Perfusion, Vessel Permeability and Vessel Maturation;382
1.7.1.2.1;20.2.1 PET and SPECT;382
1.7.1.2.2;20.2.2 Computed Tomography;382
1.7.1.2.3;20.2.3 Magnetic Resonance Imaging;383
1.7.1.2.4;20.2.4 Vessel Size Imaging;385
1.7.1.2.5;20.2.5 Ultrasound Imaging;386
1.7.1.3;20.3 Molecular Imaging;387
1.7.1.3.1;20.3.1 (Bimodal) Molecular MRI Probes;388
1.7.1.3.2;20.3.2 Ultrasound (US);389
1.7.1.3.3;20.3.3 PET and SPECT;391
1.7.1.3.4;20.3.4 Optical Imaging (OI);393
1.7.1.4;20.4 Outlook;394
1.7.1.5;References;395
1.7.2;Chapter 21: Secretome Proteomics, a Novel Tool for Biomarkers Discovery and for Guiding Biomodulatory Therapy Approaches;398
1.7.2.1;21.1 Introduction;399
1.7.2.1.1;21.1.1 The Proteome;399
1.7.2.1.2;21.1.2 Clinical Proteomics;399
1.7.2.1.3;21.1.3 Metastasis and Tumor Microenvironment;400
1.7.2.2;21.2 Biomarker;401
1.7.2.2.1;21.2.1 Definition;401
1.7.2.2.2;21.2.2 Biomarker in Cancer;401
1.7.2.2.3;21.2.3 Stages of Biomarker Development;402
1.7.2.2.4;21.2.4 Proteomic Technology in Biomarker Discovery;402
1.7.2.3;21.3 Secretome as Reservoir for Biomarker Discovery;403
1.7.2.3.1;21.3.1 Definition;403
1.7.2.3.2;21.3.2 The Cancer Secretome;403
1.7.2.3.3;21.3.3 Development of Rational Therapy Design by Secretome Analysis;404
1.7.2.3.4;21.3.4 Clinical Application;406
1.7.2.4;21.4 Methods;407
1.7.2.4.1;21.4.1 2D-gel Electrophoresis;407
1.7.2.4.2;21.4.2 Mass Spectrometry;409
1.7.2.5;21.5 Bioinformatics;411
1.7.2.6;21.6 Identification of Biomarker Candidates by Secretome Analysis;416
1.7.2.7;21.7 Conclusion;419
1.7.2.8;References;422
1.8;Part VII:Pharmacological Considerationson Systems Biological Therapy Approaches;458
1.8.1;Chapter 22: Cyclooxygenase 2 (COX2) and Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Are Stage-Dependent Prognostic Markers of Malignant Melanoma;425
1.8.1.1;22.1 Introduction;427
1.8.1.2;22.2 Materials and Methods;428
1.8.1.3;22.3 Results;435
1.8.1.4;22.4 Discussion;450
1.8.1.5;References;455
1.8.2;Chapter 23: Uncovering Tumor Systems Biology by Biomodulatory Therapy Strategies;459
1.8.2.1;23.1 Introduction;459
1.8.2.2;23.2 Problems with Therapy Strategies in Metastatic Tumors in a Historical Context;460
1.8.2.3;23.3 Explorative Considerations;462
1.8.2.4;23.4 Uncovering Systems-Biological Processes in Tumor Tissues by Biomodulatory Therapy Strategies;462
1.8.2.5;23.5 Program of a Scientific Theory;465
1.8.2.6;23.6 Constitution of a New Kind of Consideration About Objects of Interest;467
1.8.2.7;23.7 Discussion;469
1.8.2.8;References;470
1.8.3;Chapter 24: Breathing New Life into Old Drugs: Indication Discovery by Systems Directed Therapy;472
1.8.3.1;24.1 Introduction;473
1.8.3.2;24.2 IMiDs;475
1.8.3.2.1;24.2.1 History of Thalidomide;475
1.8.3.2.2;24.2.2 IMiDs in Cancer;475
1.8.3.2.3;24.2.3 IMiDs in Clinical Trials;476
1.8.3.3;24.3 COX 2 Inhibitors;477
1.8.3.3.1;24.3.1 Cyclooxygenase – Isoforms and Function;477
1.8.3.3.2;24.3.2 COX 2 in Cancer;477
1.8.3.4;24.4 mTOR Antagonists;480
1.8.3.4.1;24.4.1 The mTOR Receptor;480
1.8.3.4.2;24.4.2 mTOR Antagonists;480
1.8.3.4.3;24.4.3 Blocking mTOR Function in Cancer;480
1.8.3.4.4;24.4.4 mTOR Antagonists in Clinical Trials;481
1.8.3.5;24.5 PPARg Agonists;484
1.8.3.5.1;24.5.1 The PPARg Receptor;484
1.8.3.5.2;24.5.2 PPARg in Cancer;484
1.8.3.6;References;486
1.9;Part VIII:Tumors’ Systems Biology: Implicationsfor Personalized Therapy;493
1.9.1;Chapter 25: A Methodological Approach to Personalized Therapies in Metastatic Cancer;494
1.9.1.1;25.1 Personalized Medicine: Post-metaphysic Thinking;495
1.9.1.1.1;25.1.1 Therapy-Relevant Phenotype;496
1.9.1.1.2;25.1.2 The Reductionist Therapy Approach;496
1.9.1.1.3;25.1.3 The Holistic Therapy Approach;497
1.9.1.2;25.2 The Idea of Homogeneous Patient Subsets;497
1.9.1.2.1;25.2.1 Evidence-Based Therapy: Uncovering Prognostic Parameters;497
1.9.1.2.2;25.2.2 Individual Tumor Disease;498
1.9.1.2.3;25.2.3 Novel Therapy-Relevant Methodological Approaches;499
1.9.1.3;25.3 Differential Model-Creating Determinants;499
1.9.1.3.1;25.3.1 Hierarchical Therapy-Relevant Structures;499
1.9.1.3.2;25.3.2 May Hierarchical Structures Be Abated for Therapeutic Purposes?;501
1.9.1.3.3;25.3.3 Model-Creating Determinants;501
1.9.1.4;25.4 Modularity and Rationalization of Tumor-Associated Functions: Therapeutic Targets for the Therapy of Metastatic Tumors;503
1.9.1.5;25.5 Creating a Cancer-Drug Portfolio: Interest in the Technical Disposability over Verifiable Tumor-Associated Processes;504
1.9.1.5.1;25.5.1 The Classic Approach: Cytotoxic Therapy;504
1.9.1.5.2;25.5.2 Targeted Therapy;505
1.9.1.5.3;25.5.3 A Tumor’s Holistic Communicative Structure as a Therapeutic Target;505
1.9.1.5.4;25.5.4 Expansion of Therapeutic Options;508
1.9.1.6;25.6 Monitoring Therapy;508
1.9.1.6.1;25.6.1 Integration of the Classic Reductionist Approach;509
1.9.1.6.2;25.6.2 Are Therapeutic Approaches Developing into a Systems-Associated Marker-Guided Therapy?;509
1.9.1.6.3;25.6.3 Tumor Type-Specific and Systems Stage-Specific Therapy;510
1.9.1.6.4;25.6.4 Guiding Systems-Directed Therapies;511
1.9.1.7;25.7 Implementation of New Therapy Models;512
1.9.1.7.1;25.7.1 Can Patient Selection for Therapy Be Improved or, Vice Versa, Can Therapy Selection Be Improved for Patients?;512
1.9.1.7.2;25.7.2 Using and Incorporating Systems-Relevant Information in Clinical Trial Designs for Metastatic Tumors;513
1.9.1.8;25.8 Therapeutic Aims;514
1.9.1.9;25.9 Challenging Space;515
1.9.1.9.1;25.9.1 Communication Theory, Basic Science, and Therapy of Metastases;515
1.9.1.9.2;25.9.2 Reverse Engineering, Reconstruction of Systems Features (Intensio Obliqua) Versus Forward Engineering (Intensio Recta);515
1.9.1.9.3;25.9.3 Biomodulatory Therapy: Gene-Based and Non-DNA-Based Heritage;516
1.9.1.10;References;517
1.10;Part IX:Summary;521
1.10.1;Chapter 26: To Be an Object in a Biological System;522
1.10.1.1;26.1 The Problematization of Established Interpretations of Evolving Tumor Systems;522
1.10.1.2;26.2 Re-interpretation of Reductionist Considerations on Tumor Evolution;524
1.10.1.3;26.3 The Collapsed Reductionist Interpretations of Observations on Tumor Evolution Have Now to Be Reconstructed with Novel ;525
1.10.1.4;26.4 Implementation of Internally-Derived or Externally-Derived Modular Knowledge;525
1.10.1.5;26.5 Objects Anticipate the Attitudes of Subjects;526
1.10.1.6;26.6 The Accomplishment of the Interactive Roles of Cells Within a Tumor Tissue may Never Only Imply their Reproduction;526
1.10.1.7;26.7 Homeostasis-Preserving ‘Social’ Subject;527
1.10.1.8;26.8 The Situative Identity of Systems Objects Proves the Sustained Subjectivity of Communication;527
1.10.1.9;26.9 Discussion: The Privileged Access of Systems Actors;528
1.10.1.10;References;528
1.10.2;Chapter 27: From Molecular to Modular, from Theme-Dependent to Evolution-Adjusted Tumor Therapy;530
1.10.2.1;27.1 Introduction;530
1.10.2.2;27.2 Tumors Are Communicative Networks;531
1.10.2.3;27.3 From Molecular to Modular Tumor Biology;532
1.10.2.4;27.4 Model-Creating Capacity of Biomodulatory Therapies;532
1.10.2.5;27.5 Therapy-Derived Systems Biology: A Formal-Pragmatic Communication Theory;533
1.10.2.6;27.6 Novel Systems Determinants Constitute a ‘Big World’ Inside Small World Networks;534
1.10.2.7;27.7 Tumors May Be Viewed and Uncovered as Communicatively Structured Holistic Systems;535
1.10.2.8;27.8 Evolutionary Systems Development;536
1.10.2.9;27.9 Adaptive Trial Designs;538
1.10.2.10;27.10 Biomodulatory Therapies Accentuate and Focus Practical Issues;539
1.10.2.11;27.11 Holism and Reductionism Represent Separate, Scientifically Accessible Scopes of View;539
1.10.2.12;27.12 The Ambition for Personalized Tumor Therapy: Configuring Situational, Stage- and Tumor-Specific Systems Features;540
1.10.2.13;27.13 Outlook;541
1.11;Index;542