Tumor Budding in Colorectal Cancer: Recent Progress in Colorectal Cancer Research (Horizons in Cancer Research, Volume 8)

Tumour "budding", which is focused on in this book, is generally defined as an isolated single cancer cell or a cluster composed of a very small number of undifferentiated cancer cells in the stroma of the actively invasive front. The correlation of tumour budding with clinical outcome in colorectal cancer was first reported in the 1980s by Japanese surgeons. Since then, the clinical usefulness of this finding in colorectal cancer has been recognised in many countries. Its usefulness has been clarified not only as a prognostic factor and a potential parameter for a grading system, but also as an indicator for therapeutic decision making. Recently, more objective evaluation of tumour budding has been advocated, and the underlying mechanisms of tumour budding formation have been investigated at the molecular level. In this book, tumour budding in colorectal cancer is discussed from various perspectives. This book provides useful information for all investigators trying to deepen their understanding of colorectal cancer and develop evidence-based therapeutic strategies. HORIZONS IN CANCER RESEARCH 4 TUMOR BUDDING IN COLORECTAL CANCER: RECENT PROGRESS IN COLORECTAL CANCER RESEARCH 5 NOTICE TO THE READER 6 CONTENTS 7 FOREWORD 9 PREFACE 11 PART 1: HISTORICAL ASPECTS OF TUMOR BUDDING 13 IN THE FIELD OF GASTROINTESTINAL PATHOLOGY 15 Introduction 15 TCD in Invasive Squamous Cell Carcinoma 17 Material and Methods 17 Results 19 TCD in Invasive Adenocarcinoma 20 Materials and Methods 20 Statistical Analysis 22 Results 22 Discussion 23 References 23 Acknowledgements 25 IN THE FIELD OF COLORECTAL SURGERY 27 Introduction 27 Histological Features at the Invasive Front in Western Countries 28 Histological Evaluation of the Invasive Front in Japan 28 The Mechanism of Tumor Budding 29 Clinical Significance of Tumor Budding in T1 (early invasive) Colorectal Cancer 30 Clinical Significance of Tumor Budding in Advanced Colorectal Cancer 32 A Trial of Preoperative Detection of Tumor Budding by Preoperative Biopsy 34 Conclusion 35 References 35 PART 2: BASIC RESEARCH 39 MOLECULAR MECHANISMS UNDERLYING COLORECTAL CARCINOGENESIS 41 Introduction 41 Genetic Alterations in Colon Cancer 42 Loss of Heterozygosity 42 K-ras 42 p53 43 APC 44 MSI 45 CTNNB1 (β-catenin) and AXIN2 (Conductin) 46 DPC4 46 Gene Amplification 47 Colorectal Tumorigenesis in Mouse Model 47 Abrogated Wnt/wingless Signaling in Colorectal Carcinogenesis 48 The Function of Target Genes in Tumorigenesis 49 Altered Gene Expression in Adenomas and Carcinomas of the Colon 50 Conclusion 52 References 53 BETA-CATENIN AND TUMOR BUDDING 61 Introduction 61 Physiological Functions of β-catenin 62 The E-cadherin/catenin Complex 62 The Wnt/wingless Pathway 63 Physiological Roles of β-catenin and Wnt-signaling: Embryonic Development and Adult Tissue Homeostasis 66 Oncogenic Potency of β-catenin 66 Expression of β-catenin in Colorectal Carcinomas 66 Effects of β-catenin in Carcinoma Cells 69 β-catenin and Tumor Cell Budding 70 Summary 74 References 75 PART 3: PATHOLOGICAL SESSION 83 MOLECULAR AND PATHOLOGICAL ASPECTS OF TUMOR BUDDING 85 Introduction 85 Budding – A Dynamic Process under Genetic Control 86 Budding and the WNT Signaling Pathway 88 APC Mutation, DNA Microsatellite Instability and Budding 89 E-cadherin, Fibronectin and Budding 90 Proliferation Markers and Budding 91 Conclusion 93 References 93 SIGNIFICANCE OF TUMOR BUDDING IN EARLY COLORECTAL CANCER BASED ON MICROMORPHOLOGIC AND STATISTICAL STUDIES 97 Introduction 97 Materials and Methods 98 Materials 98 Method of Preparing Specimens 98 Histologic Diagnosis 98 Definition of Lymphatic Permeation 99 Definition of Venous Invasion 99 Morphopathobiological Definition of Tumor Budding 99 Definition of the Depth of Submucosal Invasion 103 Statistical Analysis 103 Results 103 Chi-squared Test and Multivariate Logistic Regression Analysis Concerning Lymph Node Metastasis 103 Chi-squared Test and Multivariate Logistic Regression Analysis Applied to Budding 103 Lymphatic Permeation 105 Lymphatic Permeation and Budding 106 Transition of the Growing Bud as Seen in the Serial Thin Sections 106 Serial Thin Sections of the Budding Region 107 Case Report of Lymph Node Metastasis 108 Budding as Seen in an Interesting Creature: “Polyandrocarpa Misakiensis” 108 Discussion 109 References 113 AGGRESSIVE AND NON-AGGRESSIVE TUMOR BUDDING IN COLORECTAL CANCERS 117 Introduction 117 Patients and Methods 118 Immunohistochemical Study 119 Method of Determining Budding (Microtubular Cancer Clusters or Undifferentiated Cancer Cells) 119 Statistical Analysis 120 Results 120 Discussion 124 References 126 Acknowledgements 128 COHORT MIGRATION AND IQGAP1 129 Introduction 129 Cohort Migration 130 Cohort Migration and Tumor Budding 130 In vitro Cohort Migration Model 131 Mechanisms Involved in the Localized Release from the Cell-cell Adhesion during Cohort Migration 132 The E-cadherin/catenin System 132 IQGAP1 133 IQGAP1 in Cohort Migration 134 Involvement of IQGAP1 in Cross-talk between Signals Induced by Motogenic Factors and Cell-extracellular Matrix (ECM) Interactions 137 Expression of IQGAP1 in Human Colorectal Carcinomas 139 IQGAP1 Expression and Carcinomas 139 Tumor Cell Migration and MMP 140 Front Cell-specific Expression of MT1-MMP and Gel A during Cohort Migration 140 MMP-Dependent Reorganization of ECM and Exposure of Putative Cryptic Promigratory Sites within ECM Proteins, including Laminin-5 γ2 Chain 141 Perspectives 143 References 143 PART 4: CLINICAL RESEARCH 149 NEW PROGNOSTIC MARKERS IN SUBMUCOSALLY INVASIVE COLORECTAL CARCINOMAS: CLINICAL IMPLICATION OF TUMOR BUDDING 151 Introduction 151 Malignant Potential of Submucosally Invasive Carcinomas 152 Tumor Budding at the Invasive Margin 154 Evaluation of Tumor Budding 155 Decision Analysis 156 References 160 TUMOR BUDDING IN ADVANCED RECTAL CARCINOMA 163 Introduction 163 Value of Tumor Budding as a Prognosticator 167 Clinical Implication of Tumor Budding in Biopsy Specimens 172 Assessment of the Extent of Extramural Spread 173 Assessment of the Possibility of Intramural Distal Spread (IM) 176 References 178 MOLECULAR PATHOLOGIC APPLICATION AS A PREDICTOR OF LYMPH NODE METASTASIS IN SUBMUCOSAL COLORECTAL CARCINOMA: IMPLICATION OF IMMUNOHISTOCHEMICAL ALTERATIONS AT THE DEEPEST INVASIVE MARGIN 183 Introduction 183 Criteria for EMR Radical Cure of Colorectal Sm Carcinoma Based on Conventional Histopathologic Findings in HE Sections 184 Molecular Organization in Colorectal Carcinoma Infiltration and Metastasis 185 Prediction of Lymph Node Metastasis by Means of Molecular Pathologic Markers 186 Prediction of Lymph Node Metastasis by Combining Several Molecular Pathologic Markers 188 Guidelines for Treatment of Colorectal Sm Carcinoma of the Colon Using Molecular Pathologic Markers 190 Conclusion 190 References 191 INDEX 193 HORIZONS IN CANCER RESEARCH......Page 4 TUMOR BUDDING IN COLORECTAL CANCER: RECENT PROGRESS IN COLORECTAL CANCER RESEARCH......Page 5 NOTICE TO THE READER......Page 6 CONTENTS......Page 7 FOREWORD......Page 9 PREFACE......Page 11 PART 1: HISTORICAL ASPECTS OF TUMOR BUDDING......Page 13 Introduction......Page 15 Material and Methods......Page 17 Results......Page 19 Materials and Methods......Page 20 Results......Page 22 References......Page 23 Acknowledgements......Page 25 Introduction......Page 27 Histological Evaluation of the Invasive Front in Japan......Page 28 The Mechanism of Tumor Budding......Page 29 Clinical Significance of Tumor Budding in T1 (early invasive) Colorectal Cancer......Page 30 Clinical Significance of Tumor Budding in Advanced Colorectal Cancer......Page 32 A Trial of Preoperative Detection of Tumor Budding by Preoperative Biopsy......Page 34 References......Page 35 PART 2: BASIC RESEARCH......Page 39 Introduction......Page 41 K-ras......Page 42 p53......Page 43 APC......Page 44 MSI......Page 45 DPC4......Page 46 Colorectal Tumorigenesis in Mouse Model......Page 47 Abrogated Wnt/wingless Signaling in Colorectal Carcinogenesis......Page 48 The Function of Target Genes in Tumorigenesis......Page 49 Altered Gene Expression in Adenomas and Carcinomas of the Colon......Page 50 Conclusion......Page 52 References......Page 53 Introduction......Page 61 The E-cadherin/catenin Complex......Page 62 The Wnt/wingless Pathway......Page 63 Expression of β-catenin in Colorectal Carcinomas......Page 66 Effects of β-catenin in Carcinoma Cells......Page 69 β-catenin and Tumor Cell Budding......Page 70 Summary......Page 74 References......Page 75 PART 3: PATHOLOGICAL SESSION......Page 83 Introduction......Page 85 Budding – A Dynamic Process under Genetic Control......Page 86 Budding and the WNT Signaling Pathway......Page 88 APC Mutation, DNA Microsatellite Instability and Budding......Page 89 E-cadherin, Fibronectin and Budding......Page 90 Proliferation Markers and Budding......Page 91 References......Page 93 Introduction......Page 97 Histologic Diagnosis......Page 98 Morphopathobiological Definition of Tumor Budding......Page 99 Chi-squared Test and Multivariate Logistic Regression Analysis Applied to Budding......Page 103 Lymphatic Permeation......Page 105 Transition of the Growing Bud as Seen in the Serial Thin Sections......Page 106 Serial Thin Sections of the Budding Region......Page 107 Budding as Seen in an Interesting Creature: “Polyandrocarpa Misakiensis”......Page 108 Discussion......Page 109 References......Page 113 Introduction......Page 117 Patients and Methods......Page 118 Method of Determining Budding (Microtubular Cancer Clusters or Undifferentiated Cancer Cells)......Page 119 Results......Page 120 Discussion......Page 124 References......Page 126 Acknowledgements......Page 128 Introduction......Page 129 Cohort Migration and Tumor Budding......Page 130 In vitro Cohort Migration Model......Page 131 The E-cadherin/catenin System......Page 132 IQGAP1......Page 133 IQGAP1 in Cohort Migration......Page 134 Involvement of IQGAP1 in Cross-talk between Signals Induced by Motogenic Factors and Cell-extracellular Matrix (ECM) Interactions......Page 137 IQGAP1 Expression and Carcinomas......Page 139 Front Cell-specific Expression of MT1-MMP and Gel A during Cohort Migration......Page 140 MMP-Dependent Reorganization of ECM and Exposure of Putative Cryptic Promigratory Sites within ECM Proteins, including Laminin-5 γ2 Chain......Page 141 References......Page 143 PART 4: CLINICAL RESEARCH......Page 149 Introduction......Page 151 Malignant Potential of Submucosally Invasive Carcinomas......Page 152 Tumor Budding at the Invasive Margin......Page 154 Evaluation of Tumor Budding......Page 155 Decision Analysis......Page 156 References......Page 160 Introduction......Page 163 Value of Tumor Budding as a Prognosticator......Page 167 Clinical Implication of Tumor Budding in Biopsy Specimens......Page 172 Assessment of the Extent of Extramural Spread......Page 173 Assessment of the Possibility of Intramural Distal Spread (IM)......Page 176 References......Page 178 Introduction......Page 183 Criteria for EMR Radical Cure of Colorectal Sm Carcinoma Based on Conventional Histopathologic Findings in HE Sections......Page 184 Molecular Organization in Colorectal Carcinoma Infiltration and Metastasis......Page 185 Prediction of Lymph Node Metastasis by Means of Molecular Pathologic Markers......Page 186 Prediction of Lymph Node Metastasis by Combining Several Molecular Pathologic Markers......Page 188 Conclusion......Page 190 References......Page 191 INDEX......Page 193 Historical aspects of tumor budding in the field of gastrointestinal pathology / Kazuhito Ichikawa and Takahiro Fujimori In the field of colorectal surgery / Kazuo Hase Basic research: molecular mechanisms underlying colorectal carcinogenesis / Youichi Furukawa Molecular mechanism of tumor budding with reference to microenvironment / Bernard Sordat [Beta]-catenin and tumor budding / Thomas Brabletz Pathological session: molecular and pathological aspects of tumor budding / Jeremy Jass Significance of tumor budding in early colorectal cancer based on micromorphologic and statistical studies / Kazuo Shirouzu Aggressive and non-aggressive tumor budding in colorectal cancers / Katarzyna Guzin'ska-Ustymowicz Cohort migration and IQGAP1 / Kazuki Nabeshima Clinical research: new prognostic markers in submucosally invasive colorectal carcinomas, clinical implication of tumor budding / Tadahiko Masaki Tumor budding in advanced rectal carcinoma / Hideki Ueno and Hidetaka Mochizuki Molecular pathologic application as a predictor of lymph node metastasis in submucosal colorectal carcinoma : implication of immunohistochemical alterations at the deepest invasive margin / Shinji Tanaka.