Development, Differentiation and Disease of the Para-Alimentary Tract (eBook)

Klaus Kaestner (Herausgeber)

eBook Download: PDF | EPUB

2010 | 1. Auflage
304 Seiten
Elsevier Science (Verlag)
978-0-12-385234-2 (ISBN)

Infos

Understanding how digestive organs develop, their physiology and structure is important for determining new therapies to combat diseases of the digestive organs. This volume reviews the latest research and developments in this field. - Discusses new discoveries, approaches, and ideas - Contributions from leading scholars and industry experts - Reference guide for researchers involved in molecular biology and related fields

Inhalt

Front Cover 1
Progress in Molecular Biology and Translational Science: Development, Differentiation and Disease of the Para-Alimentary Tract 4
Copyright 5
Contents 6
Contributors 10
Preface 12
Chapter 1: Transcriptional Control of Acinar Development and Homeostasis 14
I. Introduction 15
II. Formation of the Multipotent Progenitor Cell (MPC) Population 18
III. Transcriptional Induction of Acinar Cell-Fate and the Onset of Differentiation 23
IV. Acinar Cell Differentiation 30
V. Transcriptional Control of the Maintenance, Self-Renewal and Plasticity of Acinar Cells 41
Acknowledgement 45
References 45
Chapter 2: Molecular Biology of Pancreatic Ductal Adenocarcinoma Progression: Aberrant Activation of Developmental Pathways 54
I. Introduction 55
II. Anatomy of the Exocrine Pancreas 55
III. Development of the Exocrine Pancreas 57
IV. Genetic Alterations in PDAC 67
V. Activation of Developmental Pathways Driving Cancer Progression 73
VI. Concluding Remarks 79
References 79
Chapter 3: Transcriptional Control of Hepatocyte Differentiation 92
I. Overview of Liver Development 92
II. Transcription Factors Controlling Hepatic Competence of the Definitive Endoderm 94
III. Specification of Competent Endoderm Cells into Hepatoblasts and Expansion of the Liver Bud 96
IV. Differentiation of Hepatoblasts into Hepatocytes 98
V. Transcriptional Networks Define Maturation of Hepatocytes 101
VI. Conclusion 105
References 107
Chapter 4: Molecular Mechanisms of Biliary Development 116
I. Introduction 116
II. Morphogenesis of the Intrahepatic Bile Ducts 117
III. Signaling Mechanisms Controlling Cholangiocyte Differentiation and Biliary Tubulogenesis 121
IV. Transcriptional Regulation of Biliary Differentiation 126
V. Transcriptional Regulation of Biliary Tubulogenesis 128
VI. Regulation of Biliary Development by MicroRNAs 129
VII. Development of the Extrahepatic Biliary Tree 130
VIII. Conclusions 133
Acknowledgments 133
References 133
Chapter 5: Molecular Determinants of Liver Zonation 140
I. Introduction 141
II. The Concept of Liver Zonation 141
III. The Wnt/beta-Catenin ``Zonation-Keeper´´ Pathway 147
IV. The Control of a Zone-Specific Transcription by beta-Catenin 154
V. Future Prospects and Conclusion 158
Acknowledgments 158
References 158
Chapter 6: Fibrosis in the Liver: Acute Protection and Chronic Disease 164
I. Clinical Impact 165
II. Patterns of Fibrosis Progression 166
III. Fibrogenic Stimuli 167
IV. Extracellular Matrix 172
V. Cellular Sources of ECM 174
VI. Fibrosis-Related Receptors and Signaling Pathways 182
VII. Disease-Specific Mechanisms of Hepatic Fibrogenesis 186
VIII. Genetic Determinants of Hepatic Fibrosis 188
IX. Reversibility of Hepatic Fibrosis and Cirrhosis 191
References 194
Chapter 7: Hierarchies of Transcriptional Regulation During Liver Regeneration 214
I. Introduction: Models and Applications of Liver Regeneration 215
II. Preexisting Transcription Factors Dominate During the Early Response to Partial Hepatectomy 218
III. Nuclear Receptors and De Novo Synthesized Transcription Factors Control Cell Proliferation During Liver Regeneration 223
IV. Termination of Liver Regeneration and Liver Size Adjustment 230
V. Conclusions: Recent Progress and Significance of Molecular Mechanisms Controlling Liver Regeneration 233
References 234
Chapter 8: Biology of the Adult Hepatic Progenitor Cell: ‘‘Ghosts in the Machine’’ 242
I. Introduction: The Oval Cell 243
II. Canals of Hering: The Putative Oval Cell Niche 245
III. Oval Cell-Mediated Liver Regeneration 248
IV. Molecular Regulation of the Oval Cell Response 249
V. From Bench to Bedside: Isolation of Hepatic Progenitors and Their Use in Medicine 251
VI. Hepatic Stem Cells and Liver Cancer 255
VII. Conclusions 256
References 257
Chapter 9: Signaling Networks in Human Hepatocarcinogenesis-Novel Aspects and Therapeutic Options 264
I. Introduction 264
II. Molecular Mechanisms of HCC Development and Progression 266
III. Development of Tumor-Supporting Networks 274
IV. Development of Therapeutic Strategies for HCC 277
V. Conclusion 282
References 283
Index 292
Color Plate 300

Textauszug

Molecular Biology of Pancreatic Ductal Adenocarcinoma Progression

Aberrant Activation of Developmental Pathways

Andrew D. Rhim*,†; Ben Z. Stanger*,†    * Gastroenterology Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, USA
† Department of Cell and Developmental Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, USA

Abstract

Embryonic development marks a period of peak tissue growth and morphogenesis in the mammalian lifecycle. Many of the pathways that underlie cell proliferation and movement are relatively quiescent in adult animals but become reactivated during carcinogenesis. This phenomenon has been particularly well documented in pancreatic cancer, where detailed genetic studies and a robust mouse model have permitted investigators to test the role of various developmental signals in cancer progression. In this chapter, we review current knowledge regarding the signaling pathways that act during pancreatic development and the evidence that the reactivation of developmentally important signals is critical for the pathogenesis of this treatment-refractory malignancy.

Keywords

Pancreatic ductal adenocarcinoma

Development

Pancreatic intraepithelial neoplasia

Notch

Hedgehog

Signaling

TGF-β

Mouse model

Kras

Metastasis

I Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the 10th most prevalent cancer in the United States, with an estimated incidence of 42,000 people in 2009,1 and it is the fourth most common cause of cancer-related death. The prognosis of PDAC is poor, with only approximately 5% of patients surviving 5 years after diagnosis. The vast majority of PDAC patients die from complications of metastatic disease. Even patients who undergo pancreas resection for limited disease with no clinical evidence of metastasis have poor prognosis, as approximately 80% of these patients will also succumb to metastatic disease.2 Thus, while cancers of all origins share many of the same hallmarks,3 PDAC is unique in its ability to form large tumors and metastasize, ultimately killing the host and circumventing treatments that are efficacious in other malignancies. In order to intervene in this particularly lethal cancer, it will be essential to understand the unique features of pancreatic biology and the accumulation of molecular events that are seen exclusively in pancreatic cancer. We will begin with a brief review of the major themes of pancreas development and adult exocrine pancreas biology. Then, we will review the molecular underpinnings of PDAC, highlighting the reemergence of developmental pathways during cancer progression (Table I).

Table I

Reemergent Developmental Pathways in PDAC

Hedgehog

Suppression required for pancreas specification

Canonical: Desmoplasia

Noncanonical: Unclear

FGF

Pancreas specification, proliferation, differentiation, cell fate

Epithelial-to-mesenchymal transition (EMT), proliferation

Notch

Differentiation, cell fate

EMT, proliferation

TGF-β

Pancreas specification, proliferation, differentiation, cell fate

EMT, proliferation, desmoplasia

Retinoic acid

Pancreas specification, differentiation, cell fate

Unclear; putative marker of cancer stem cells

EGF

Proliferation, differentiation

Proliferation, desmoplasia

Wnt/β-catenin

Pancreas specification, cell fate

PanIN formation

II Anatomy of the Exocrine Pancreas

The pancreas is an endoderm-derived organ located in the upper abdomen of vertebrates, adjacent to the stomach, duodenum, and spleen. It maintains an independent blood supply from other abdominal organs. It also features a connection to the intestines via the main pancreatic duct, which serves to empty secretions from the pancreas into the intestinal lumen.

The pancreas comprises two compartments with distinct functions. The endocrine pancreas functions as a central regulator of glucose and metabolic homeostasis. Cells that compose the endocrine pancreas are organized within structures called the Islets of Langerhans (Fig. 1). Islets of Langerhans are nestled within the pancreatic parenchyma, often intimately associated with blood vessels. While islets are scattered throughout the pancreas, they are densely concentrated in the tail. Within these islets, α-, β-, δ-, γ-, and PP-cells secrete the hormones glucagon, insulin, somatostatin, ghrelin, and pancreatic polypeptide, respectively, in response to metabolic and chemical cues from the local blood supply. While carcinomas of the endocrine pancreas occur, these are relatively rare and are beyond the scope of this chapter.

Fig. 1 Histology of the pancreas. Hematoxylin and eosin staining of a normal pancreas, depicting an Islet of Langerhans (I), pancreatic duct (D), and blood vessel (V) surrounded by acini (A). 10×.

The exocrine pancreas, from which PDAC arises, aids in the digestion of carbohydrates, fats, and proteins. Composing more than 90% of the organ, the exocrine compartment contains acinar and centroacinar cells interconnected by an elaborate epithelial-lined ductal network (Fig. 1). Acinar cells form discrete units, appropriately called acini, which, in cross-section, represent a circular cluster of polarized cells organized around a small concentric lumen. The apical portions of acinar cells face the middle of these acinar units, adjacent to the centrally positioned centroacinar cells. In response to the ingestion of food or drink, the upper intestine releases secretin and cholecystokinin, leading acinar cells to secrete inactive forms of digestive enzymes called zymogens. Zymogens undergo activation in an acidic environment; hence, concomitant release of bicarbonate by ductal cells maintains an alkaline microenvironment and prevents activation of digestive enzymes prior to exiting the pancreas. The lumens of the acinar units drain into a complex, interconnected network of epithelium-lined ducts which then anastomose to the main pancreatic duct, which in turn traverses the length of the pancreas. In most vertebrates, the main pancreatic duct represents the major conduit of drainage of pancreatic juice. The pancreatic duct then connects with the common bile duct, and pancreatic juice enters the intestine through the ampulla of Vater, located in the second portion of the duodenum.

Intercalated within the pancreatic parenchyma are mesenchyme-derived stromal cells, composed mostly of endothelial cells and quiescent fibroblasts. In nondiseased states, the stroma represents less than 1% of the pancreas. These cells are thought to primarily support the normal functioning of the epithelium by maintaining the intercellular structure of the organ. However, accumulating evidence has implicated pancreatic fibroblasts—especially the stellate cell, a specialized fibroblast—in additional tasks important for the normal functioning of the pancreas, including storage of Vitamin A, immune system regulation and surveillance, and maintenance of endothelial cell turnover.4,5 A complex, bidirectional interplay of signals between the stromal and epithelial compartments coordinates homeostasis within the organ. As will be discussed later, upon injury or carcinogenesis, signaling pathways active during pancreas development are reactivated, leading to the activation, accumulation, and diversification of the stromal compartment.

III Development of the Exocrine Pancreas

Many cancers share common characteristics, as outlined previously3; however, each type of cancer is unique in its tissue of origin and developmental history. It is widely believed that the molecular events leading to carcinoma differ by tissue type and even by the specific cell of origin within a single organ. Consistent with these observations is the concept that key events leading to carcinogenesis involve the abnormal activation of developmental pathways specific to the ontogeny of the source or index cell.6 Indeed, recent work has supported the notion that this may be the case for PDAC. Thus, much insight into how PDAC forms has been attained by the assiduous study of normal exocrine pancreas development and mechanisms. Our understanding of early pancreas development comes from detailed studies using the mouse as a model system. By employing a variety of techniques, most importantly lineage labeling technology, investigators have been able to describe many of the morphogenic and genetic events involved in pancreas formation.

A Early Steps Preceding Pancreatic Budding

Regional specification of the pancreas anlagen occurs as early as gastrulation. In studies of chicken development, fibroblast growth factor 4 (FGF4) released by the mesectoderm enables a region of the mesoderm to become responsive to propancreatic signals secreted by the mesoderm-derived notochord. Later in gastrulation, retinoic...

Produkt-Details

• Erscheint lt. Verlag: 13.12.2010
• Sprache: englisch
• Themenwelt: Sachbuch/Ratgeber
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete
• Themenwelt: Naturwissenschaften ► Biologie ► Biochemie
• Themenwelt: Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie
• Themenwelt: Naturwissenschaften ► Physik / Astronomie ► Angewandte Physik
• Themenwelt: Technik
• ISBN-10: 0-12-385234-X / 012385234X
• ISBN-13: 978-0-12-385234-2 / 9780123852342