Molecular Aspects of Hepatocellular Carcinoma


by

Liang Qiao

DOI: 10.2174/97816080507271120101
eISBN: 978-1-60805-072-7, 2012
ISBN: 978-1-60805-378-0

  
  


Indexed in: Scopus, Chemical Abstracts

Therapeutic options for late-stage liver cancer are very limited and the prognosis is often poor. A better understanding of the molec...[view complete introduction]
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Table of Contents

Foreword , Pp. i

Morris Sherman

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Preface , Pp. ii-iii (2)

Liang Qiao, Yumin Li, Xiang Yan and Jacob George

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List of Contributors , Pp. iv-vi (3)

Liang Qiao, Yumin Li, Xiang Yan and Jacob George

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Acknowledgements , Pp. vii

Liang Qiao, Yumin Li, Xiang Yan and Jacob George

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The Relationship between Liver Fibrosis and Hepatocellular Carcinoma , Pp. 3-7 (5)

Hai Li and Ji-D. Jia

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A Possible Link between Non-Alcoholic Steatohepatitis and Hepatocellular Cancer , Pp. 8-20 (13)

Elisabetta Bugianesi and Federico Salamone

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Viral Associated Hepatocellular Carcinoma , Pp. 21-31 (11)

Alfred S.-L. Cheng and Henry L.-Y. Chan

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Non-Viral Cause of Liver Cirrhosis: Do they Lead to Hepatocellular Carcinoma? , Pp. 32-38 (7)

Yuan-W. Chen and Jian-G. Fan

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Signaling Pathways Involved in Molecular Carcinogenesis of Hepatocellular Carcinoma , Pp. 39-55 (17)

Tatsuo Kanda, Fumio Imazeki, Fumihiko Kanai, Motohisa Tada, Osamu Yokosuka and Masao Omata

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MicroRNAs in Human Hepatocellular Carcinoma , Pp. 56-66 (11)

Wilson K.C. Leung and Nathalie Wong

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Characteristics of Liver Stem/Progenitor Cells and their Relation to Cancer: Response to Inflammatory and Cell Death Signals , Pp. 67-79 (13)

Cornelia S. Viebahn, Bernard Callus and George C.T. Yeoh

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Aging and Hepatocellular Carcinoma: Possible Molecular Mechanisms , Pp. 80-85 (6)

Aiping Tian, Liang Qiao and Xiang Yan

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Molecular Mechanisms of Liver Cancer Metastasis , Pp. 86-105 (20)

Maria L. Balmer and Jean-F. Dufour

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Biomarkers for Diagnosis and Surveillance in Hepatocellular Carcinoma , Pp. 106-115 (10)

Thomas Wex, Kerstin Schutte, Jan Bornschein and Peter Malfertheiner

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Animal Models of Hepatocellular Carcinoma , Pp. 116-128 (13)

Sarah L. Walker, Jacob George and Lionel W. Hebbard

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Chemoprevention of Hepatocellular Carcinoma , Pp. 129-137 (9)

Massimo Colombo

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An Overview on Molecular Therapy for Hepatocellular Carcinoma , Pp. 138-148 (11)

Quanda Liu, Yongning Zhou, Zenan Hu and Liang Qiao

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Role of Angiogenesis in HCC Development and Therapy , Pp. 149-161 (13)

Lionel W. Hebbard

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Non-Surgical Management of Hepatocellular Carcinoma: Possible Mechanisms , Pp. 162-166 (5)

Yumin Li, Wenting He, Tao Liu and Yingtai Chen

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Treatment of Hepatocellular Carcinoma with Traditional Chinese Medicine: Possible Molecular Mechanisms , Pp. 167-173 (7)

Cai-Y. Zhao, Xiaoyu Liu, Chuan Shen, Yadong Wang and Liang Qiao

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Randomised Controlled Trials in the Primary Treatment of Hepatocellular Carcinoma , Pp. 174-195 (22)

Monica Robotin

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Subject Index , Pp. 196-199 (4)

Liang Qiao, Yumin Li, Xiang Yan and Jacob George

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Foreword

The incidence of hepatocellular carcinoma (HCC) is rising in many Western countries, but has always been high in Eastern countries. Much of the knowledge that we have about HCC was developed in Asia, particularly in Japan. However, the majority of all HCCs that develop each year arises in China. Over many years of Western medicine, studies from China have not been major contributors. In part, no doubt this was due to restrictions before China opened up to the West, in part to language difficulties, and in part because of a lack of a Western scientific tradition. Of course, this is all changing, and more and more articles in the medical literature are from China. It is appropriate therefore that many of the contributors to the volume on hepatocellular carcinoma are from China, and that Chinese authors are contributing to the solutions to what is a major Chinese problem. In so doing, they also inform those of us in the West who deal with this disease. Just as in the past we have learned from our Japanese colleagues, so we will in future learn from our Chinese colleagues. This book is an excellent start in that direction.

The editors are to be congratulated on persuading such a distinguished panel of authors to contribute to this volume. Many of the authors are well known not only in China, but also elsewhere in Asia and in the West. It has been my personal pleasure to meet a number of these authors.

This book differs from other volumes on HCC that have been published in the recent past in the choice of topics, which reflect a much more experimental emphasis, and a strong emphasis on scientific discovery and analysis. As a Westerner I find the choice of topics no less refreshing than the choice of authors. This book has much to teach us, and I expect that it will be widely read.

Morris Sherman
Associate Professor of Medicine
Chairman, Canadian Viral Hepatitis Network and Canadian Liver Foundation
University of Toronto and Toronto General Research Institute
Toronto
Canada


Preface

Hepatocellular carcinoma (HCC) accounts for over 90% of primary liver cancer and is more prevalent in Africa, South East Asia and China. Epidemiological data indicate that the incidence of HCC in Western countries has been on the rise over the past two decades and it has been predicted that this trend will continue for the foreseeable future. On a global scale, HCC is the fifth most common malignancy and the third most common cause of cancer-related death. Curative therapy for HCC is possible in less than 20% of patients, with the vast majority receiving only non-curative or palliative treatments. Conventional chemotherapy and radiotherapy are of little value in extending patient survival. Clearly, more effective therapeutic approaches, informed by an understanding of tumor biology and progression, is required for the management of this devastating malignancy.

The development of novel therapeutic approaches to treat HCC is entirely dependent on a better understanding of what causes these tumors and how they behave. The risk factors for HCC development have been well, if not completely, characterized. The most common etiological factors are chronic viral hepatitis (HBV, HCV) and chronic alcohol abuse. Other less common risk factors such as prolonged exposure to toxic chemicals, certain drugs and biological toxins (Aflatoxin B1), parasitic infections (Schistosomiasis Japonica), iron overload (hemachromotosis), and non-alcoholic steatohepatitis (NASH) have also been identified. Looking to the future, NASH-associated HCC is likely to represent an increasing burden of primary liver cancer in both developed and developing nations. However, the mechanisms of how these risk factors lead to tumor development are not fully understood.

This book edited by Dr. Qiao et al., provides a broad overview of the molecular aspects of HCC, ranging from how HCC develop and metastasize, to the possible approaches for preventing and treating these tumors. The broad range of topics include how viral infections cause HCC (Cheng and Chan, Chapter 3), how non-viral factors contribute to tumor development (Chen and Fan, Chapter 4), and what role is played by liver fibrosis, a common consequence of chronic liver diseases (Li and Jia, Chapter 1). NAFLD and NASH now represent the most common liver disease and it is appropriate that Drs. Bugianesi and Salamone discuss the possible link between NASH and HCC in Chapter 2. Finally, with regard to pathogenesis, Dr. Tian et al., discuss the molecular mechanisms of HCC development in older individuals (Chapter 8).

Animal model of HCC are critical in HCC research and the data generated are invaluable in understanding the molecular mechanisms of human HCC development and progression, and in testing newer therapies. This broad area is summarized by Dr. Walker and colleagues (Chapter 11).

Although some of the precise molecular mechanisms for HCC development vary according to etiological risk factor, several common themes emerge. In particular, pathways involving cancer stem cells/progenitor cells, microRNA abnormalities, and deregulated cell proliferation and angiogenesis have attracted much attention. In this context, the chapters by Dr. Kanda et al. (Chapter 5) and Drs. Luisa and Dufour (Chapter 9) deal with the common molecular mechanisms leading to the development and spread of HCC. Over recent years, HCC has been regarded as a stem cell disease in that malignant clones may derive from stem cells that usually exist in a dormant state. This notion opens a novel avenue for understanding HCC development and holds great promise for developing stem cell-based therapies. Viebahn et al. (Chapter 7) discuss the latest developments on the mechanisms by which liver cancer stem cells (or progenitor cells) evolve into malignant cells and how these stem cells are regulated. Recent data on the role of microRNA in the development of HCC is presented by Drs. Leung and Wong (Chapter 6).

How we can leverage our basic understanding of the molecular mechanisms of cancer formation in the prevention and treatment of HCC is important. In this aspect, Dr. Hebbard addresses the issue of how tumor angiogenesis contributes to cancer formation, and how targeting angiogenesis can be achieved and used as a therapeutic approach for treatment (Chapter 14). An overview of currently characterized molecular pathways that could lead to the development of diagnostic approaches and HCC prevention strategies is discussed by Dr. Wex et al. (Chapter 10) and Dr. Colombo (Chapter 12). Dr. Liu et al. provide an overview on how the best-described molecular pathways, especially cell proliferation and angiogenesis, can be used as targets in the management of liver cancer (Chapter 13). A broad overview of current clinical trials of newer therapies in HCC informed by the previous chapters is provided by Dr. Robotin (Chapter 17). Data on the non-surgical treatment of HCC is provided in Chapter 15 (Dr Li et al.).

Traditional Chinese Medicine (TCM) is frequently used by patients with all forms of cancer including those of the liver. Many laboratory studies have generated valuable data on how TCM may work in the context of HCC, and several herbal extracts are currently undergoing clinical trials in China. The chapter by Dr. Zhao et al. (Chapter 16) provides a brief overview on possible molecular mechanisms by which herbal extracts may exert anticancer effects, at least in experimental models.

This book represents a combined effort from basic scientists who are working on liver cancer biology and molecular biology, as well as clinicians who are either senior hepatologists or hepatic surgeons. The contributions from the authors of various countries would enrich the readers with their respective experience and knowledge on liver cancer. In particular, as HCC is much more common and is frequently encountered in the daily medical practice in China, the contributions made by the scientists and clinicians from China would help the readers to catch a glimpse of the current status in liver cancer research and clinical practice in China.

Overall, this book provides a wealth of information covering the mechanisms of HCC development and metastasis, diagnosis, prevention, and treatment of primary liver cancer. The volume should be particularly useful to basic investigators, oncologists and hepatologists who wish to appraise themselves of the latest advances in the field of liver cancer research.

The authors welcome comments from the readers on the contents of this book.

Liang Qiao (Editor-in-Chief)
Storr Liver Unit
Westmead Millennium Institute
University of Sydney
Australia

Yumin Li (Co-Editor)
Department of Surgery
The Second Hospital of Lanzhou University
Lanzhou
China

Xiang Yan (Co-Editor)
Department of Geriatric Medicine
The First Hospital of Lanzhou University
Lanzhou
China

Jacob George (Co-Editor)

Storr Liver Unit
Westmead Millennium Institute
Australia

List of Contributors

Editor(s):
Liang Qiao

The University of Sydney
Australia




Co-Editor(s):
Yumin Li

The Lanzhou University
China


Xiang Yan

The Lanzhou University
China


Jacob George

The University of Sydney
Australia




Contributor(s):
Maria L. Balmer
Fellow, Department of Gastoenterology
Inselspital, University of Bern
Bern
Switzerland


Jan Bornschein
Dr. med., Fellow, Department of Gastroenterology
Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg,
Str. 44, D-39120
Leipziger
Germany


Elisabetta Bugianesi MD
Associate Professor, Department of Internal Medicine
Division of Gastro-Hepatology, San Giovanni Battista Hospital, University of Torino
Torino
Italy.


Bernard A. Callus
Senior Research Fellow, School of Biomedical
Biomolecular and Chemical Sciences, The University of Western Australia,
Australia.


Professor Henry L.-Y. Chan MD
Institute of Digestive Disease and Department of Medicine and Therapeutics
The Chinese University of Hong Kong
Hong Kong


Yingtai Chen
Resident Physician, MD, The Second Clinical School of Lanzhou University
Key Laboratory of Digestive System Tumors
Lanzhou
Gansu, 730030
China


Yuanwen Chen
Physician, MD and PhD, Department of Gastroenterology
Xinhua Hospital, Shanghai Jiaotong University School of Medicine
Shanghai, 200092
China


Alfred S.-L. Cheng Ph.D
Research Assistant Professor,Institute of Digestive Disease and Department of Medicine and Therapeutics
The Chinese University of Hong Kong
Hong Kong


Massimo Colombo
Professor,The First Division of Gastroentrology
Fondazione IRCCS Maggiore Hospital, Mangiagalli & Regina Elena
Centro A. M. e A. Migliavacca Università degli Studi di Milano, Milan
Italy


Jean-F. Dufour
Head of Hepatology, University Clinic of Visceral Surgery and Medicine
Inselspital, Bern, Hepatology, Department of Clinical Research, University of Bern
Bern
Switzerland


Jiangao Fan
Professor and Director, Department of Gastroenterology
Xinhua Hospital, Shanghai Jiaotong University School of Medicine
Shanghai, 200092
China


Jacob George
Professor and Director, Storr Liver Unit
Westmead Millennium Institute and The University of Sydney at Westmead Hospital
PO Box 412, Darcy Road, Westmead, NSW 2145
Australia


Wenting He
Research Associate, Ph.D (Cell Biology)
Department of General Surgery Ⅱ of The First Hospital of Lanzhou University
Key Laboratory of Digestive System Tumors, Gansu, Lanzhou 730030
China


Lionel W. Hebbard
Senior Research Fellow, Storr Liver Unit, Westmead Hospital
Western Clinical School and Westmead Millennium Institute
Faculty of Medicine, the University of Sydney, Westmead, NSW 2145
Sydney
Australia


Zenan Hu
Ph.D, student and Physician, Division of Gastroenterology
Department of Medicine, The First Hospital of Lanzhou University
Lanzhou
China.


Fumio Imazeki MD
Associate Professor, Department of Medicine and Clinical Oncology
Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670,
Japan


Jidong Jia
Professor and Director, Liver Research Center
Beijing Friendship Hospital, Capital Medical University
Beijing , 100050
China


Fumihiko Kanai MD
Associate Professor, Department of Medicine and Clinical Oncology
Graduate School of Medicine, Chiba University
1-8-1 Inohana, Chuo-ku
Chiba , 260-8670
Japan


Tatsuo Kanda MD
Associate Professor, Department of Medicine and Clinical Oncology
Graduate School of Medicine, Chiba University
1-8-1 Inohana, Chuo-ku
Chiba , 260-8670
Japan


Wilson K.C. Leung
PhD student, Department of Anatomical and Cellular Pathology at the Li Ka-Shing Institute of Health Sciences
The Chinese University of Hong Kong
Shatin NT
Hong Kong
China


Hai Li
Physician, Liver Research Center
Beijing Friendship Hospital
Capital Medical University
Beijing , 100050
China


Yumin Li
Hospital President, Professor of Hepatobilary Surgery
Department of General Surgery and the Key Laboratory of Digestive System Tumors
The Second Hospital and the Second Clinical School of Lanzhou University
Lanzhou , 730030
China


Quanda Liu
Associate Professor, Institute of Hepatobiliary Gastrointestinal Diseases
PLA Second Artillery General Hospital
Beijing, 100088
China


Tao Liu
Research Associate, PhD (Molecular Medicine)
The Key Laboratory of Digestive System Tumors and Lanzhou University Second Hospital
Lanzhou , 730030
China


Xiaoyu Liu
Resident physician, Post-graduate student
Department of Infectious Diseases
the Third Hospital of Hebei Medical University
Shijiazhuang , 050051
China.


Peter Malfertheiner
Professor. Dr. Med, Director, Department of Gastroenterology
Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg
Str. 44, D-39120
Leipziger
Germany


Masao Omata MD
Professor, Department of Gastroenterology
University of Tokyo, and Yama-nashi Prefecture
Japan


Liang Qiao
Senior Lecture and Senior research Fellow, Storr Liver Unit
Westmead Hospital, Western Clinical School and Westmead Millennium Institute
the Faculty of Medicine, the University of Sydney, Westmead
Sydney
NSW , 2145
Australia


Monica Robotin
Senior Lecturer, School of Public Health
the University of Sydney, and Medical Director of the Cancer Council NSW,
Australia


Federico Salamone MD
Research Fellow, Department of Internal Medicine
Division of Gastro-Hepatology, San Giovanni Battista Hospital
University of Torino
Torino
Italy


Kerstin Schütte
Dr. med., Consultant, Department of Gastroenterology
Hepatology and Infectious Diseases
Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120
Leipziger
Germany


Chuan Shen
Resident physician, Department of Infectious Diseases
the Third Hospital of Hebei Medical University
Shijiazhuang , 050051
China


Motohisa Tada MD
Assistant Professor, Department of Medicine and Clinical Oncology
Graduate School of Medicine, Chiba University
1-8-1 Inohana, Chuo-ku
Chiba
260-8670
Japan


Aiping Tian PhD student and Physician
Division of Geriatrics, Department of Medicine
The First Hospital of Lanzhou University
China


Cornelia S. Viebahn
Research Fellow, Department of Clinical Sciences of Companion Animals
Faculty of Veterinary Medicine, Utrecht University
The Netherlands.


Sarah L. Walker
Gastroenterologist, Storr Liver Unit
Westmead Hospital, Western Clinical School and Westmead Millennium Institute
the Faculty of Medicine, the University of Sydney
Westmead
NSW , 2145
Australia


Yadong Wang
Resident physician, Department of Infectious Diseases
the Third Hospital of Hebei Medical University
Shijiazhuang, 050051
China


Thomas Wex
PD Dr. rer. nat., Laboratory Head, Department of Gastroenterology
Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg
Leipziger Str. 44, D-39120
Germany


Nathalie Wong
Professor,Department of Anatomical and Cellular Pathology at the Li Ka-Shing Institute of Health Sciences
The Chinese University of Hong Kong, Shatin
Hong Kong
NT
China


Xiang Yan
Hospital President, Professor of Medicine
Division of Geriatrics, Department of Medicine
The First Hospital and First Clinical School of Lanzhou University
Lanzhou , 730000
China


George C.T. Yeoh
Professor,School of Biomedical
Biomolecular and Chemical Sciences, The University of Western Australia
Australia.


Osamu Yokosuka MD
Professor and Chairman, Department of Medicine and Clinical Oncology
Graduate School of Medicine, Chiba University
1-8-1 Inohana, Chuo-ku
Chiba , 260-8670
Japan


Cai-Y. Zhao
Professor and Director, Department of Infectious Diseases
the Third Hospital of Hebei Medical University
Shijiazhuang , 050051
China


Yongning Zhou
Professor and Director, Division of Gastroenterology
Department of Medicine, the First Hospital of Lanzhou University
Lanzhou , 730000
China




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