Cell Biology of the Ovary : Stem Cells, Development, Cancer, and Clinical Aspects

This unique compilation focuses on a very curious organ, the ovary. There are still many unknown facts about the origins of ovarian tissue and ovarian cancer, and each chapter describes in detail the latest insights into the ovary from basic to clinical aspects. Expert authors reveal the most recent findings on ovariogenesis and ovarian carcinogenesis by shedding light on stem cell biology for the ovarian surface epithelial cells or primordial germ cells. Readers will greatly increase their understanding of the relevance of the cells that constitute the ovary, which is of vast significance in comprehending the occurrence mechanism of ovarian tissue and ovarian cancer. In this way the book covers a wide range of fields concerned with the ovary. This work benefits not only gynecologists and obstetricians, but also basic researchers in the field of stem cell biology and all clinicians who are involved in the management of fertility preservation or ovarian cancer. Preface 5 Contents 6 1: Reconstitution of Germ Cell Development In Vitro 8 1.1 Introduction 9 1.2 In Vitro Reconstitution of Mouse Germ Cell Development 10 1.2.1 Signaling Pathways for the Specification of Mouse Primordial Germ Cells 10 1.2.2 Induction of PGC-Like Cells (PGCLCs) from Mouse Pluripotent Stem Cells 11 1.2.3 Completion of Mouse Oogenesis In Vitro 13 1.2.4 Induction of Spermatogonia-Like Cells from PGCLCs 14 1.2.5 Propagation of PGCLCs In Vitro 15 1.3 Induction of Human Germ Cell Fate In Vitro 15 1.3.1 In Vitro Systems to Induce Human PGCLCs from hPSCs 15 1.3.2 Competence for the Induction of Human PGCLCs 17 1.4 Future Perspectives for Reconstituting Human Germ Cell Development In Vitro 19 References 20 2: The Role of Hedgehog-BMP4 Signaling in the Patterning of Coelomic Mesoderm and the Onset of Gonadogenesis 27 2.1 Introduction 28 2.1.1 Contrasting Cellular Behaviors in the Dorsal and Ventral Parts of Medial LPM at the Onset of Gonadogenesis 28 2.1.2 Hedgehog (Hh) Signaling Establishes Dorsoventral Pattern in M-LPM and Initiates Gonadogenesis 29 2.1.3 Dynamic Transition of BMP4 Expression and Roles at the Downstream of Hh Signaling in LPM 33 2.1.4 Candidate Molecules Regulating Cellular Behaviors Involved in the Onset of Gonadogenesis Downstream of Hh-BMP4 Signaling 35 References 37 3: Regulation of Metabolic Pathways in Steroidogenic Cells by Ad4BP/SF-1 40 3.1 Introduction 41 3.1.1 Metabolic Pathways Activated in Steroidogenic Cells 41 3.1.2 Implication of Ad4BP/SF-1 into Glycolytic Gene Regulation 42 3.1.3 Implication of Ad4BP/SF-1 into NADPH Synthetic Gene Regulation 45 3.1.4 Orchestration of Metabolic Pathways by a Single Transcription Factor 46 References 47 4: Role of Lgr5-Expressing Stem Cells in Epithelial Renewal and Cancer in the Reproductive Tract 49 4.1 Introduction 49 4.2 Methods Employed to Identify and Characterise Reproductive Epithelial Stem Cells 51 4.3 Lgr5+ Stem Cell Precursors Give Rise to Adult OSE and Cortical Granulosa Lineages 54 4.4 Regulation of Lgr5+ Stem Cell-Driven OSE Regeneration: Intrinsic Versus Niche Signals 55 4.5 Cancer of the Reproductive Tract: Lgr5+ OSE Stem Cells as Ovarian Cancer Origins 56 4.6 Future Directions and Conclusion 58 References 59 5: Tumor-Initiating Cells in Ovarian Cancer 64 5.1 Introduction 65 5.2 Stem Cells in the Normal Ovary and in Ovarian Cancer 65 5.3 Redefining Reversible Quiescence as a Functional Property of CSCs Reappropriated Their Recognition as Tumor-Initiating Cells (TICs) 68 5.4 CSC/TIC Identification Through the Maze of Intra-Tumor Heterogeneity and Their Differential Regulation Under Conditions of Stress 69 5.5 Future Perspectives 71 References 72 6: Emerging Role of CD44 Variant 6 in Driving the Metastatic Journey of Ovarian Cancer Stem Cells 75 6.1 Introduction 76 6.2 Genomic and Protein Structure of CD44 78 6.3 CD44 and Cancer Stemness 80 6.4 CD44 Variant 6 and Cancer Metastasis 81 6.4.1 CD44 Variant 6 and Peritoneal Disseminated Metastasis 81 6.4.2 CD44 Variant 6 and Distant Parenchymal Metastasis 83 6.4.3 CD44 Variant 6 and the Epithelial–Mesenchymal Transition 83 6.4.4 CD44 Variant 6 and the Metastatic Niche 84 6.5 CD44 Variant 6 and Clinical Outcome 85 References 86 7: Clinical Management of Primary Ovarian Insufficiency 91 7.1 Introduction 92 7.2 Etiology 92 7.3 Animal Models 93 7.4 Chemotherapy-Induced Mechanism 95 7.5 Diagnosis 96 7.6 Clinical Management of POI 96 References 98 8: Rescue for Primary Ovarian Insufficiency 102 8.1 Introduction 102 8.2 Assessment of Ovarian Aging 103 8.3 Effect of Ovarian Angiogenesis on Oocyte Aging 105 8.4 Regulation of Ovarian Angiogenesis 106 8.5 Rescue of Oocyte Quality by the Activation of Ovarian Angiogenesis 107 References 109 9: Current Status of Ovarian Tissue Vitrification as a Fertility Preservation for the Young Cancer Patients 114 9.1 Introduction 115 9.2 Development of an Ovarian Tissue Vitrification Protocol 115 9.3 Vitrification Versus Slow Freezing 118 9.4 Clinical Application of Ovarian Tissue Cryopreservation Using Vitrification 120 References 121 10: Molecular Pathogenesis of Ovarian Cancer: An Inextricable Maze 123 10.1 Introduction 124 10.2 Ovarian Surface Epithelium as the Putative Origin of Serous Ovarian Cancer 125 10.3 Fallopian Tube as a Putative Origin of Serous Ovarian Cancer 126 10.4 Ovarian Cancer Associated with Ovarian Endometriotic Cyst 127 10.5 Stressful Microenvironment in Endometriotic Cysts and Carcinogenesis 128 10.6 Ovarian Clear Cell Carcinoma as a Stress-Resistant Cancer with Specific Glucose Metabolism 130 10.7 Ovarian Carcinogenesis: What We Will Know in the Future 131 References 132 11: Clinical Management of Epithelial Ovarian Cancer 135 11.1 Introduction 136 11.1.1 Diagnosis 136 11.1.1.1 Tumor Markers 136 11.1.1.2 Diagnostic Imaging 137 11.1.2 Surgical Therapy 138 11.1.2.1 Staging Laparotomy 138 11.1.2.2 Primary Debulking Surgery 138 11.1.2.3 Fertility Preservation Techniques 139 11.1.2.4 Surgery in Elderly Patients 140 11.1.2.5 Risk-Reducing Salpingo-Oophorectomy 140 11.1.3 Chemotherapy 140 11.1.3.1 Neoadjuvant Chemotherapy 140 11.1.3.2 Adjuvant Chemotherapy 141 11.1.3.3 Molecular-Targeted Drugs in Chemotherapy 142 11.1.3.4 Chemotherapy in Elderly Patients 142 11.1.4 Treatment of Recurrent Ovarian Cancer 142 11.1.5 Management After Treatment 143 11.1.5.1 Follow-Up After Treatment 143 11.1.5.2 Hormone Replacement Therapy 144 References 145 12: Molecular Targeted Therapy for Epithelial Ovarian Cancer 152 12.1 Introduction 153 12.2 Specific Targets Associated with Tumor Molecular Pathologic Characteristics 153 12.2.1 Molecular Pathologic Characteristics of EOC 153 12.2.2 Specific Molecular Targets for BRCA1/BRCA2 Tumors: PARP Inhibitors 154 12.3 Common Molecular Targets Related to the Tumor Microenvironment 156 12.3.1 Molecular Targets for the Tumor Microenvironment 156 12.3.1.1 Angiogenesis: Vascular Endothelial Growth Factor 156 12.3.1.2 The Immune System: Immune Checkpoint Inhibitors 158 References 161 Front Matter ....Pages i-viii Reconstitution of Germ Cell Development In Vitro (Shihori Yokobayashi, Mitinori Saitou)....Pages 1-19 The Role of Hedgehog-BMP4 Signaling in the Patterning of Coelomic Mesoderm and the Onset of Gonadogenesis (Takashi Yoshino)....Pages 21-33 Regulation of Metabolic Pathways in Steroidogenic Cells by Ad4BP/SF-1 (Ken-ichirou Morohashi, Miki Inoue, Bing Li, Takashi Baba)....Pages 35-43 Role of Lgr5-Expressing Stem Cells in Epithelial Renewal and Cancer in the Reproductive Tract (Annie Ng, Nick Barker)....Pages 45-59 Tumor-Initiating Cells in Ovarian Cancer (Sharmila A. Bapat)....Pages 61-71 Emerging Role of CD44 Variant 6 in Driving the Metastatic Journey of Ovarian Cancer Stem Cells (Takeshi Motohara, Hidetaka Katabuchi)....Pages 73-88 Clinical Management of Primary Ovarian Insufficiency (Yoshinori Okamura)....Pages 89-99 Rescue for Primary Ovarian Insufficiency (Kyu Sup Lee)....Pages 101-112 Current Status of Ovarian Tissue Vitrification as a Fertility Preservation for the Young Cancer Patients (Nao Suzuki)....Pages 113-121 Molecular Pathogenesis of Ovarian Cancer: An Inextricable Maze (Masaki Mandai)....Pages 123-134 Clinical Management of Epithelial Ovarian Cancer (Yusuke Kobayashi, Hiroyuki Nomura, Fumio Kataoka, Eiichiro Tominaga, Kouji Banno, Daisuke Aoki)....Pages 135-151 Molecular Targeted Therapy for Epithelial Ovarian Cancer (Hironori Tashiro, Hidetaka Katabuchi)....Pages 153-166