Novel cancer-related biomarkers (eBook)

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Viktor Magdolen, Technical UniversityMunich; Christian Sommerhoff and Hans Fritz, Ludwig Maximilian University, Munich; Manfred Schmitt, Technical UniversityMunich, Germany.

Preface 5
List of contributing authors 7
Table of Contents 11
Introduction to Volume 2: Kallikrein-related Peptidases. Novel Cancer-related Biomarkers 17
Bibliography 18
1 Pathophysiology of Kallikrein-related Peptidases in Lung Cancer 19
1.1 Introduction 19
1.2 Expression pattern of KLKs in the normal lung 19
1.3 KLKs in lung cancer 22
1.4 Regulation of KLKs in the lung 24
1.4.1 Control of gene transcription 24
1.4.2 Post-translational control of KLK function 26
1.5 Potential KLK targets in the lung 27
1.5.1 Substrates involved in host defense 27
1.5.2 Cytokines and growth factors 29
1.5.3 Pericellular and membrane-associated substrates 32
1.6 Conclusion 34
Acknowledgements 35
Bibliography 35
2 Clinical Relevance of Kallikrein-related Peptidases in Gastric and Colorectal Cancer 43
2.1 Introduction 43
2.2 Features of gastric and colorectal cancers 43
2.3 Established biomarkers in gastric and colorectal cancer 44
2.4 KLKs: novel biomarkers in gastric and colorectal cancer 46
2.4.1 Review of the clinical relevance of KLK expression in gastric cancer 47
2.4.2 Review of the clinical relevance of KLK expression in colorectal cancer 51
2.5 Proteolytic activity of KLKs in gastric/colorectal cancers 54
2.6 Effect of KLK expression on cell regulation and metabolic pathways 55
2.7 Conclusion 56
Bibliography 56
3 Pathophysiology of Kallikrein-related Peptidases in Head and Neck Cancer 61
3.1 Introduction 61
3.2 A murine orthotopic xenograft model using urinary-type plasminogen activator receptor (uPAR) overexpressing OSCC cells mimics aggressive human OSCC 63
3.3 Expression of KLKs in OSCC 65
3.4 Potential functional role of KLK5 in regulating cell-cell junctional integrity in OSCC 66
3.5 Conclusions and future directions 70
Acknowledgement 71
Bibliography 71
4 PSA (Prostate-Specific Antigen) and other Kallikrein-related Peptidases in Prostate Cancer 77
4.1 Introduction 77
4.2 The role of KLKs in prostate cancer diagnosis, prognosis and monitoring 77
4.2.1 PSA 77
4.2.2 KLK2 81
4.2.3 Other KLKs 81
4.2.4 Splicing and polymorphic variants 82
4.3 Potential functional roles of KLKs in prostate cancer 82
4.3.1 Sustaining proliferative signaling and evading growth suppressors 83
4.3.2 Resisting cell death 85
4.3.3 Inducing angiogenesis 85
4.3.4 Activating invasion and metastasis 87
4.3.5 Concerns about biological studies 88
4.4 Conclusions and outlook 88
Bibliography 89
5 Cellular Model Systems to Study the Tumor Biological Role of Kallikrein-related Peptidases in Ovarian and Prostate Cancer 99
5.1 Introduction 99
5.2 Development of cellular model systems in cancer research 99
5.3 Traditional 3D cellular models commonly used in both ovarian and prostate cancers 100
5.3.1 Soft agar colony assay 100
5.3.2 3D-Matrigel™ 101
5.4 Novel 3D cellular models in ovarian cancer biology 102
5.4.1 Ovarian cancer 102
5.4.2 3D-suspension model to mimic ascites suspension 102
5.4.3 In vitro models for ovarian cancer invasion into the peritoneal membrane 106
5.4.4 The role of 3D-collagen I matrix in ovarian cancer cell behavior 108
5.4.5 A 3D-organotypic model to mimic ovarian cancer metastasis 108
5.4.6 Bioengineered 3D culture systems for ovarian cancer 109
5.5 Cellular models in prostate cancer 111
5.5.1 Prostate cancer 111
5.5.2 3D-suspension models for prostate cancer growth and metastasis 113
5.5.3 In vitro models for prostate cancer angiogenesis 114
5.5.4 Bioengineered 3D culture systems for prostate cancer growth and metastasis 114
5.6 Challenges and future direction 118
Acknowledgment 118
Bibliography 119
6 Clinical Relevance of Kallikrein-related Peptidases in Breast Cancer 127
6.1 Introduction 127
6.2 Expression of KLKs in normal breast tissue 129
6.3 Clinical relevance of KLKs in breast cancer 129
6.4 Hormonal regulation of KLKs in breast cancer 143
6.5 Tumor suppressor role of KLKs in breast cancer 145
6.6 DNA-methylation of KLKs as the basis of KLK downregulation in breast cancer 146
6.7 Conclusions 148
Bibliography 148
7 Clinical Relevance of Kallikrein-related Peptidases in Ovarian Cancer 161
7.1 Introduction 161
7.2 Ovarian cancer pathology, diagnosis, and therapy 161
7.3 KLKs in ovarian cancer 163
7.3.1 Circulating KLKs as screening/diagnostic and/or prognostic ovarian cancer biomarkers 164
7.3.2 Serum ovarian cancer biomarkers CA125 and KLKs 171
7.3.3 Tumor tissue-associated KLKs as prognostic ovarian cancer biomarkers 172
7.4 Tumor tissue-associated and blood-borne KLKs as predictive ovarian cancer biomarkers 173
7.5 Conclusion 174
Abbreviations 175
Bibliography 176
8 microRNAs: A New Control Mechanism for Kallikrein-related Peptidases in Kidney and Other Cancers 183
8.1 Introduction 183
8.1.1 KLK expression in normal kidney tissue 183
8.1.2 KLKdysregulation in kidney cancer 184
8.2 microRNAs (miRNA) 185
8.2.1 Biogenesis 185
8.2.2 miRNAs and cancer 186
8.2.3 miRNA dysregulation in renal cell carcinoma 186
8.2.4 The miRNA-KLK interaction 187
8.3 miRNA control of KLK expression in renal cell carcinoma 190
8.4 miRNA control of KLK expression in other cancers 191
8.5 Conclusions and outlook 192
Bibliography 193
9 Genomic Instability of the KLK-locus in Cancer 199
9.1 Introduction 199
9.2 Defining genomic instability 199
9.2.1 Defining CIN and its underlying mechanisms 200
9.2.2 Methods for detecting CIN 201
9.3 Chromosome 19 and the KLK locus in cancer 202
9.3.1 Chromosome 19 202
9.3.2 The KLK locus and cancer 203
9.3.3 KLK sequence mutations and single nucleotide polymorphisms in cancer 204
9.3.4 KLK translocations 205
9.3.5 Copy-number changes of the KLK locus 207
9.4 Closing remarks 209
Bibliography 210
10 Kallikrein-related Peptidases as Biomarkers in Personalized Cancer Medicine 217
10.1 Introduction 217
10.2 The role of KLKs as cancer biomarkers for predicting and monitoring response to chemotherapy or endocrine therapy 220
10.2.1 Prostate cancer 222
10.2.2 Breast cancer 223
10.2.3 Ovarian cancer 223
10.3 Modulation of expression levels of KLK genes upon chemotherapy administration in vitro 225
10.3.1 Prostate cancer cells 226
10.3.2 Gastric cancer cells 226
10.3.3 Breast cancer cells 227
10.3.4 The role of microRNAs (miRNAs) that target KLK expression and the methylation status of KLK genes in the in vitro response of cancer cells to chemotherapy 228
10.4 Conclusions and future directions 229
Bibliography 230
Index 235