Hepatobiliary Cancers: Translational Advances and Molecular Medicine

1st Edition, Volume 156 - August 10, 2022
Editors: Alphonse E. Sirica, Paul B. Fisher
Language: English
Hardback ISBN:
9 7 8 - 0 - 3 2 3 - 9 8 3 9 2 - 1
eBook ISBN:
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Hepatobiliary cancer refers to primary malignant tumors originating in cells of the liver, bile ducts, and gallbladder. Globally, primary liver cancer, which includes… Read more

Hepatobiliary Cancers: Translational Advances and Molecular Medicine

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Hepatobiliary cancer refers to primary malignant tumors originating in cells of the liver, bile ducts, and gallbladder. Globally, primary liver cancer, which includes hepatocellular carcinoma (~75 % of all cases) and intrahepatic biliary cancer or cholangiocarcinoma (~10-15 % 0f all cases) is the 6th most commonly diagnosed cancer and 3rd leading cause of cancer deaths worldwide. The vast majority of these highly malignant cancers are diagnosed at an advanced stage where treatment options are limited and patient survival outcomes are poor. The biological and therapeutic challenges posed by hepatobililiary cancers such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are daunting, emphasizing a critical need to review and assess current and evolving basic, translational, and clinical research focused on addressing the critical obstacles that continue to limit progress towards achieving significant improvements in HCC and CCA clinical management and patient survival outcomes. Towards this goal, this special edition of Advances in Cancer Research is focused on providing a comprehensive, timely and authoritative reviews covering such topics of significant scientific and clinical relevance, including hepatobiliary cancer risk mechanisms and risk-predictive molecular biomarkers; causes and functional intricacies of inter- and intratumor heterogeneity; novel insights into the role of tumor microenvironment and key signaling pathways in promoting hepatobiliary cancer progression, therapeutic resistance and immunosuppression; emerging biomarkers of HCC and CCA prognosis; advances in molecular genomics for personalizing tumor classification and targeted therapies; innovative preclinical cell culture modeling for hepatobiliary cancer drug discovery; and current and emerging trends in hepatobiliary cancer molecular therapeutic targeting and immunotherapies.

Cover image
Title page
Table of Contents
Copyright
Contributors
Preface
Chapter One: Liver cancer risk-predictive molecular biomarkers specific to clinico-epidemiological contexts
Abstract
1: Introduction
2: Clinico-epidemiological contexts relevant to liver cancer risk
3: Molecular indicators of high-risk liver
4: Host and systemic factors associated with liver cancer risk
5: Clinical implementation of molecular liver cancer risk assessment
6: Conclusion
Acknowledgments
Conflict of interest
References
Chapter Two: Inflammatory pathways and cholangiocarcinoma risk mechanisms and prevention
Abstract
1: Introduction
2: Diseases prodromal to cholangiocarcinoma development
3: Mechanisms of neoplastic transformation
4: Role of inflammatory cells in modulating CCA malignant features
5: Conclusions
Grant support
Conflict of interest statement
References
Chapter Three: Causes and functional intricacies of inter- and intratumor heterogeneity of primary liver cancers
Abstract
1: Introduction
2: Liver cancer heterogeneity
3: Spatial architecture and tumor heterogeneity
4: Concluding remarks and future perspectives
Acknowledgments
Author contributions
Declaration of interests
References
Chapter Four: Implications of genetic heterogeneity in hepatocellular cancer
Abstract
1: Introduction
2: Approaches to studying heterogeneity in HCC
3: Molecular heterogeneity in HCC
4: Clinical implications of genetic heterogeneity in HCC
5: Therapeutic implications of genetic heterogeneity in HCC
6: Current perspectives and future directions
Acknowledgements
Grant support
Conflict of interest statement
References
Chapter Five: Understanding the genetic basis for cholangiocarcinoma
Abstract
1: Introduction
2: Germline mutations in risk factors associated with cholangiocarcinoma
3: Overview of germline mutations and variants associated with cholangiocarcinoma
4: Key candidate gene studies of CCA risk variants
5: Pathogenic germline alteration (PGA) sequencing studies
6: Conclusion
Conflict of interest statement
Grant support
References
Chapter Six: Novel insights into molecular and immune subtypes of biliary tract cancers
Abstract
1: Introduction
2: The mutational landscape of biliary tract cancers
3: Multi-omics classifications of intrahepatic cholangicoarcinoma
4: Molecular classifications of other biliary tract cancers
5: Therapeutic implications
6: Conclusions and future perspectives
Acknowledgments
Grant support
Conflict of interest statement
References
Chapter Seven: Cancer-associated fibroblasts in intrahepatic cholangiocarcinoma progression and therapeutic resistance
Abstract
1: Introduction
2: Tumor microenvironment in iCCA
3: Cancer-associated fibroblasts in iCCA
4: Role of cancer-associated fibroblasts in iCCA
5: Therapeutic relevance of cancer associated fibroblasts in iCCA
6: Current and future perspectives
Acknowledgment
Grant support
Conflict of interest
References
Chapter Eight: Mechanisms and clinical significance of TGF-β in hepatocellular cancer progression
Abstract
1: Introduction
2: Overview of the TGF-β pathway
3: TGF-β signaling in liver homeostasis
4: Mouse models for TGF-β-Smad signaling in HCC development and progression
5: TGF-β pathway activity in HCC patients
Grant support
Conflict of interest statement
References
Chapter Nine: Matricellular proteins in intrahepatic cholangiocarcinoma
Abstract
1: Introduction
2: Overview of classes, structures, and complexities of matricellular proteins aberrantly expressed in iCCA
3: Matricellular proteins as modulators of iCCA microenvironment and malignant progression
4: Clinical relevance of matricellular proteins in iCCA
5: Perspectives and conclusions
Grant support
Conflict of interest statement
References
Chapter Ten: YAP1 activation and Hippo pathway signaling in the pathogenesis and treatment of intrahepatic cholangiocarcinoma
Abstract
1: Introduction
2: Overview of Hippo-YAP1 signaling pathway
3: Biologic function and pathologic impact of Hippo-YAP1 pathway in ICCA
4: Clinical relevance and therapeutic potential of modulation of Hippo-YAP1 pathway in ICCA
5: Concluding remarks
Acknowledgments
Conflict of interest statement
References
Chapter Eleven: Patient-derived functional organoids as a personalized approach for drug screening against hepatobiliary cancers
Abstract
1: Introduction
2: Hepatobiliary cancer treatment: Challenges
3: Tumor organoids for personalized drug screening
4: Conclusion and future perspectives
Grant support
Conflict of interest statement
References
Chapter Twelve: Molecular therapeutic targets for cholangiocarcinoma: Present challenges and future possibilities
Abstract
1: Introduction
2: Genomic alterations as therapeutic targets in CCA
3: Non-genomic alterations as therapeutic targets in CCA
4: Present challenges and future possibilities for therapeutic targets in CCA
5: Predictive Biomarkers & Treatment Resistance
6: Current & future perspectives
Acknowledgment
Conflict of interest statement
References
Chapter Thirteen: Immunotherapies for hepatocellular carcinoma and intrahepatic cholangiocarcinoma: Current and developing strategies
Abstract
1: The immune biology of the liver
2: The immunosuppressive environment of hepatocellular carcinoma
3: Immunotherapy of HCC
4: Immunotherapy of intrahepatic cholangiocarcinoma
5: Concluding remarks
Grant support
Conflict of interest
References
Chapter Fourteen: Immunotherapy for hepatobiliary cancers: Emerging targets and translational advances
Abstract
1: Introduction
2: Emerging targets for liver cancer immunotherapy
3: The role of GPC3 in HCC
4: The role of mesothelin in iCCA
5: Conclusion and future perspectives
Acknowledgments
Conflict of interest statement
Grant support
References

Alphonse E. Sirica

Alphonse E. Sirica, PhD, MS received his PhD degree in Biomedical Science from the University of Connecticut and his MS degree in Biology from Fordham University. After completing his Postdoctoral training in experimental oncology (liver carcinogenesis) with Dr. Henry C. Pitot at the McArdle Laboratory for Cancer Research at the University of Wisconsin-Madison, he remained as faculty at the University of Wisconsin School of Medicine from 1979 to 1984. In June 1984, he joined the VCU Department of Pathology faculty to develop a program in Experimental Pathology and in 1990 was promoted to the rank of full professor with tenure. From 1993 to 1999, he served as Chair of the Division of Experimental Pathology in the Department of Pathology. In 1999, he founded the Department's Division of Cellular and Molecular Pathogenesis and continued to serve as Division Chair for another 15 years, stepping down from this position in July 2014 to devote full time to his NIH funded research program. In 2019, he was appointed to a Distinguished Career Professorship at Virginia Commonwealth University and in 2020 appointed Professor Emeritus of Pathology at VCU. Dr. Sirica is an internationally recognized biomedical researcher and scholar in the areas of liver carcinogenesis, cholangiocyte biology and pathobiology, and cholangiocarcinoma, with extensive experience and expertise in cell and molecular cholangiocarcinogenesis and preclinical experimental therapeutics of cholangiocarcinoma. As principal investigator, Dr. Sirica had been funded by the National Cancer Institute of the National Institutes of Health for 37 years. In June 2019, he was recognized by Expertscape as an Expertscape World Expert in Cholangiocarcinoma. He has previously edited four books on topics including the pathobiology of neoplasia, cellular and molecular pathogenesis, hepatocarcinogenesis, and bile duct pathobiology and pathophysiology, and has published in journals such as Proceedings of the National Academy of Science USA, Cancer Research, Hepatology, Gastroenterology, Nature Reviews Gastroenterology & Hepatology, Hepatology Research, Nature Reviews Disease Primers, Hepatology Communications, and the American Journal of Pathology. He has organized several national conferences on hepatobiliary cancers, most recently a Keystone Symposium titled “Hepatobiliary Cancers: Pathobiology and Translational Advances”, which was held as a Keystone e-symposium in March 22-24, 2021, as well as a FASEB Catalyst Conference titled “Cholangiocarcinoma: Molecular Drivers, Microenvironment, and Precision Medicine” held as a virtual event on April 7, 2021. Currently, he is serving as primary organizer of an approved 2023 FASEB Science Research Conference, “The Cholangiocarcinoma Conference: Molecular Drivers, Microenvironment, and Precision Medicine”.

Affiliations and expertise

Cellular & Molecular Pathogenesis Professor Emeritus of Pathology and Distinguished Career Professor Department: Pathology, Virginia Commonwealth University

Paul B. Fisher

Paul B. Fisher, MPh, PhD, FNAI, Professor and Chairman, Department of Human and Molecular Genetics, Director, VCU Institute of Molecular Medicine Thelma Newmeyer Corman Chair in Cancer Research in the VCU Massey Cancer Center, VCU, School of Medicine, Richmond, VA, and Emeritus Professor, Columbia University, College of Physicians & Surgeons, New York, NY. Dr. Fisher is among the top 10% of NIH funded investigators over the past 35-years, published approximately 625 papers and reviews, and has 55 issued patents. He pioneered novel gene/discovery approaches (subtraction hybridization), developed innovative therapeutic approaches (Cancer Terminator Viruses), presented numerous named and distinguished lectures, founded several start-up companies, was Virginia Outstanding Scientist of 2014 and elected to the National Academy of Inventors in 2018. Dr. Fisher is a prominent nationally and internationally recognized cancer research scientist focusing on understanding the molecular and biochemical basis of cancer development and progression to metastasis and using this garnered information to develop innovative approaches for diagnosing and treating cancer. He discovered and patented novel genes and gene promoters relevant to cancer growth control, differentiation and apoptosis. His discoveries include the first cloning of p21 (CDK inhibitor), human polynucleotide phosphorylase, mda-9/syntenin (a pro-metastatic gene), mda-5 and mda-7/IL-24, which has shown promising clinical activity in Phase I/II clinical trials in patients with advanced cancers. Dr. Fisher alsohas a documented track record as a successful seasoned entrepreneur. He was Founder and Director of GenQuest Incorporated, a functional genomics company, which merged with Corixa Corporation in 1998, traded on NASDAQ and was acquired by GlaxoSmithKline in 2006. He discovered the cancer-specific PEG-Prom, which is the core technology of Cancer Targeting Systems (CTS, Inc.), a Virginia/Maryland-based company (at Johns Hopkins Medical Center) focusing on imaging and therapy (“theranostics”) of metastatic cancer (2014) by Drs. Fisher and Martin G. Pomper. He co-founded InVaMet Therapeutics (IVMT) and InterLeukin Combinatorial Therapies (ILCT) with Dr. Webster K. Cavenee (UCSD) (2017/2018).

Affiliations and expertise

Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Virginia, USA

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Hepatobiliary Cancers: Translational Advances and Molecular Medicine

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Institutional subscription on ScienceDirect

Alphonse E. Sirica

Paul B. Fisher