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Cui X, Huang T, Jiang T, Wang H. Current status and prospects of targeted therapy for cholangiocarcinoma based on molecular characteristics. Cancer Lett 2025; 614:217540. [PMID: 39924074 DOI: 10.1016/j.canlet.2025.217540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/23/2025] [Accepted: 02/06/2025] [Indexed: 02/11/2025]
Abstract
Cholangiocarcinoma (CCA) is a serious public health issue due to its insidious onset and dismal prognosis. The past few years have witnessed and highlighted the development of understanding and management of CCA. The combination of gemcitabine and cisplatin (GP) chemotherapy regimen with immunotherapy using immune checkpoint inhibitors has been considered the new standard first-line treatment alternative for advanced CCA. Notably, the proportion of patients with advanced CCA with targetable genetic mutations is approximately 40 %, and these patients may be considered for molecularly targeted therapy in the second-line treatment. In this review, we highlight the advances and progress in targeted therapies for advanced CCA, with special attention to data from Asian populations, including Chinese. In addition, we present in detail the phosphatase tension homolog (PTEN), a novel biomarker for both of first-line chemotherapy and second-line targeted therapy in advanced CCA, and its ability to forecast prognosis in patients with CCA. The mechanisms of rapid resistance to targeted agents warrant further investigation and address in light of the development of new targeted therapies. Precision medicine is gradually playing an increasing role in achieving optimal therapeutic outcomes.
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Affiliation(s)
- Xiaowen Cui
- Department of Oncology, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Teng Huang
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, The Naval Medical University, Shanghai, China; Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
| | - Tianyi Jiang
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, The Naval Medical University, Shanghai, China.
| | - Hongyang Wang
- Department of Oncology, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China; International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, The Naval Medical University, Shanghai, China; Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
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Thongyoo P, Chindaprasirt J, Aphivatanasiri C, Intarawichian P, Kunprom W, Kongpetch S, Techasen A, Loilome W, Namwat N, Titapun A, Jusakul A. KRAS Mutations in Cholangiocarcinoma: Prevalence, Prognostic Value, and KRAS G12/G13 Detection in Cell-Free DNA. Cancer Genomics Proteomics 2025; 22:112-126. [PMID: 39730186 PMCID: PMC11696325 DOI: 10.21873/cgp.20492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 09/23/2024] [Accepted: 10/01/2024] [Indexed: 12/29/2024] Open
Abstract
BACKGROUND/AIM Cholangiocarcinoma (CCA) is an aggressive hepatobiliary malignancy characterized by genomic heterogeneity. KRAS mutations play a significant role in influencing patient prognosis and guiding therapeutic decision-making. This study aimed to determine the prevalence and prognostic significance of KRAS mutations in CCA, asses the detection of KRAS G12/G13 mutations in plasma cell-free DNA (cfDNA), and evaluate the prognostic value of KRAS G12/G13 mutant allele frequency (MAF) in cfDNA in relation to clinicopathological data and patient survival. MATERIALS AND METHODS A retrospective analysis of 937 CCA patients was performed using data from cBioPortal to examine KRAS mutation profiles and their association with survival. Plasma from 101 CCA patients was analyzed for KRAS G12/G13 mutations in the cfDNA using droplet digital PCR, and the results were compared with tissue-based sequencing from 78 matched samples. RESULTS KRAS driver mutations were found in 15.6% of patients, with common variants being G12D (37.0%), G12V (24.0%) and Q61H (8.2%). Patients harboring KRAS mutations exhibited decreased overall and recurrence-free survival. KRAS G12/G13 mutations were detected in 14.9% of cfDNA samples, showing moderate concordance with tissue sequencing, and achieving 80% sensitivity and 93% specificity. Elevated KRAS G12/G13 MAF in cfDNA, combined with high CA19-9 levels, correlated with poorer survival outcomes. CONCLUSION The presence of KRAS mutations was associated with poor survival in CCA, underscoring the importance of KRAS mutations as prognostic markers. The detection of KRAS mutations in cfDNA demonstrated potential as a promising non-invasive alternative for mutation detection and, when combined with CA19-9 levels, may improve prognostic efficacy in CCA.
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Affiliation(s)
- Pitchasak Thongyoo
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Jarin Chindaprasirt
- Medical Oncology Program, Department of Internal Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | | | | | - Waritta Kunprom
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sarinya Kongpetch
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Anchalee Techasen
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Watcharin Loilome
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Nisana Namwat
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Attapol Titapun
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Apinya Jusakul
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand;
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
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Yang Y, Wang J, Wan J, Cheng Q, Cheng Z, Zhou X, Wang O, Shi K, Wang L, Wang B, Zhu X, Chen J, Feng D, Liu Y, Jahan-Mihan Y, Haddock AN, Edenfield BH, Peng G, Hohenstein JD, McCabe CE, O'Brien DR, Wang C, Ilyas SI, Jiang L, Torbenson MS, Wang H, Nakhleh RE, Shi X, Wang Y, Bi Y, Gores GJ, Patel T, Ji B. PTEN deficiency induces an extrahepatic cholangitis-cholangiocarcinoma continuum via aurora kinase A in mice. J Hepatol 2024; 81:120-134. [PMID: 38428643 PMCID: PMC11259013 DOI: 10.1016/j.jhep.2024.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 02/09/2024] [Accepted: 02/18/2024] [Indexed: 03/03/2024]
Abstract
BACKGROUND & AIMS The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aimed to evaluate the role of PTEN in the pathogenesis of eCCA and identify novel therapeutic targets for this disease. METHODS The Pten gene was genetically deleted using the Cre-loxp system in biliary epithelial cells. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry, reverse-transcription PCR, cell culture, and RNA sequencing. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. We also tested the effectiveness of an Aurka inhibitor. RESULTS We observed that genetic deletion of the Pten gene in the extrahepatic biliary epithelium and peri-ductal glands initiated sclerosing cholangitis-like lesions in mice, resulting in enlarged and distorted extrahepatic bile ducts in mice as early as 1 month after birth. Histologically, these lesions exhibited increased epithelial proliferation, inflammatory cell infiltration, and fibrosis. With aging, the lesions progressed from low-grade dysplasia to invasive carcinoma. Trp53 inactivation further accelerated disease progression, potentially by downregulating senescence. Further mechanistic studies showed that both human and mouse eCCA showed high expression of AURKA. Notably, the genetic deletion of Aurka completely eliminated Pten deficiency-induced extrahepatic bile duct lesions. Furthermore, pharmacological inhibition of Aurka alleviated disease progression. CONCLUSIONS Pten deficiency in extrahepatic cholangiocytes and peribiliary glands led to a cholangitis-to-cholangiocarcinoma continuum that was dependent on Aurka. These findings offer new insights into preventive and therapeutic interventions for extrahepatic CCA. IMPACT AND IMPLICATIONS The aberrant PTEN-PI3K-AKT signaling pathway is commonly observed in human extrahepatic cholangiocarcinoma (eCCA), a disease with a poor prognosis. In our study, we developed a mouse model mimicking cholangitis to eCCA progression by conditionally deleting the Pten gene via Pdx1-Cre in epithelial cells and peribiliary glands of the extrahepatic biliary duct. The conditional Pten deletion in these cells led to cholangitis, which gradually advanced to dysplasia, ultimately resulting in eCCA. The loss of Pten heightened Akt signaling, cell proliferation, inflammation, fibrosis, DNA damage, epigenetic signaling, epithelial-mesenchymal transition, cell dysplasia, and cellular senescence. Genetic deletion or pharmacological inhibition of Aurka successfully halted disease progression. This model will be valuable for testing novel therapies and unraveling the mechanisms of eCCA tumorigenesis.
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Affiliation(s)
- Yan Yang
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA; Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Jiale Wang
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Jianhua Wan
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Qianqian Cheng
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Zenong Cheng
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Xueli Zhou
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Oliver Wang
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Kelvin Shi
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Lingxiang Wang
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Bin Wang
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Xiaohui Zhu
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Jiaxiang Chen
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Dongfeng Feng
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Yang Liu
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | | | - Ashley N Haddock
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | | | - Guang Peng
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Chantal E McCabe
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Daniel R O'Brien
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Chen Wang
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Sumera I Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Liuyan Jiang
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, Florida, USA
| | - Michael S Torbenson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Huamin Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Raouf E Nakhleh
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, Florida, USA
| | - Xuemei Shi
- Greenwood Genetic Center, Greenwood, South Carolina, USA
| | - Ying Wang
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Yan Bi
- Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Tushar Patel
- Department of Transplantation, Mayo Clinic, Jacksonville, Florida, USA
| | - Baoan Ji
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA.
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Chen X, Ding Y, Yi Y, Chen Z, Fu J, Chang Y. Review of Animal Models of Colorectal Cancer in Different Carcinogenesis Pathways. Dig Dis Sci 2024; 69:1583-1592. [PMID: 38526618 DOI: 10.1007/s10620-024-08384-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 03/05/2024] [Indexed: 03/27/2024]
Abstract
Colorectal cancer (CRC) is a common malignant tumor of the gastrointestinal tract with increasing morbidity and mortality. Exploring the factors affecting colorectal carcinogenesis and controlling its occurrence at its root is as important as studying post-cancer treatment and management. Establishing ideal animal models of CRC is crucial, which can occur through various pathways, such as adenoma-carcinoma sequence, inflammation-induced carcinogenesis, serrated polyp pathway and de-novo pathway. This article aims to categorize the existing well-established CRC animal models based on different carcinogenesis pathways, and to describe their mechanisms, methods, advantages and limitations using domestic and international literature sources. This will provide suggestions for the selection of animal models in early-stage CRC research.
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Affiliation(s)
- Xue Chen
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China
| | - Yirong Ding
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China
| | - Yun Yi
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China
| | - Zhishan Chen
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China
| | - Jiaping Fu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China
| | - Ying Chang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China.
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Manzano-Núñez F, Prates Tiago Aguilar L, Sempoux C, Lemaigre FP. Biliary Tract Cancer: Molecular Biology of Precursor Lesions. Semin Liver Dis 2023; 43:472-484. [PMID: 37944999 DOI: 10.1055/a-2207-9834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2023]
Abstract
Biliary tract cancer is a devastating malignancy of the bile ducts and gallbladder with a dismal prognosis. The study of precancerous lesions has received considerable attention and led to a histopathological classification which, in some respects, remains an evolving field. Consequently, increasing efforts have been devoted to characterizing the molecular pathogenesis of the precursor lesions, with the aim of better understanding the mechanisms of tumor progression, and with the ultimate goal of meeting the challenges of early diagnosis and treatment. This review delves into the molecular mechanisms that initiate and promote the development of precursor lesions of intra- and extrahepatic cholangiocarcinoma and of gallbladder carcinoma. It addresses the genomic, epigenomic, and transcriptomic landscape of these precursors and provides an overview of animal and organoid models used to study them. In conclusion, this review summarizes the known molecular features of precancerous lesions in biliary tract cancer and highlights our fragmentary knowledge of the molecular pathogenesis of tumor initiation.
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Affiliation(s)
| | | | - Christine Sempoux
- Institute of Pathology, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland
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6
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Calvisi DF, Boulter L, Vaquero J, Saborowski A, Fabris L, Rodrigues PM, Coulouarn C, Castro RE, Segatto O, Raggi C, van der Laan LJW, Carpino G, Goeppert B, Roessler S, Kendall TJ, Evert M, Gonzalez-Sanchez E, Valle JW, Vogel A, Bridgewater J, Borad MJ, Gores GJ, Roberts LR, Marin JJG, Andersen JB, Alvaro D, Forner A, Banales JM, Cardinale V, Macias RIR, Vicent S, Chen X, Braconi C, Verstegen MMA, Fouassier L. Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance. Nat Rev Gastroenterol Hepatol 2023; 20:462-480. [PMID: 36755084 DOI: 10.1038/s41575-022-00739-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/20/2022] [Indexed: 02/10/2023]
Abstract
Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA.
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Affiliation(s)
- Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Scottish Centre, Institute of Genetics and Cancer, Edinburgh, UK
| | - Javier Vaquero
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Pedro M Rodrigues
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Cédric Coulouarn
- Inserm, Univ Rennes 1, OSS (Oncogenesis Stress Signalling), UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France
| | - Rui E Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Oreste Segatto
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Chiara Raggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC Transplantation Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Benjamin Goeppert
- Institute of Pathology and Neuropathology, Ludwigsburg, Germany
- Institute of Pathology, Kantonsspital Baselland, Liestal, Switzerland
| | - Stephanie Roessler
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Timothy J Kendall
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Ester Gonzalez-Sanchez
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - John Bridgewater
- Department of Medical Oncology, UCL Cancer Institute, London, UK
| | - Mitesh J Borad
- Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, AZ, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Jose J G Marin
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Alejandro Forner
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Liver Unit, Barcelona Clinic Liver Cancer (BCLC) Group, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Jesus M Banales
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Rocio I R Macias
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Silve Vicent
- University of Navarra, Centre for Applied Medical Research, Program in Solid Tumours, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, Instituto de Salud Carlos III), Madrid, Spain
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
| | - Chiara Braconi
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Monique M A Verstegen
- Department of Surgery, Erasmus MC Transplantation Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Laura Fouassier
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
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Testa U, Pelosi E, Castelli G. Cholangiocarcinoma: Molecular Abnormalities and Cells of Origin. Technol Cancer Res Treat 2023; 22:15330338221128689. [PMID: 36872875 PMCID: PMC9989414 DOI: 10.1177/15330338221128689] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 09/01/2022] [Accepted: 09/07/2022] [Indexed: 03/07/2023] Open
Abstract
Cholangiocarcinomas (CCAs) are a group of heterogeneous epithelial malignancies that can originate at the level of any location of the biliary tree. These tumors are relatively rare but associated with a high rate of mortality. CCAs are morphologically and molecularly heterogeneous and for their location can be distinguished as intracellular and extracellular, subdivided into perihilar and distal. Recent epidemiological, molecular, and cellular studies have supported that the consistent heterogeneity observed for CCAs may result from the convergence of various key elements mainly represented by risk factors, heterogeneity of the associated molecular abnormalities at genetic and epigenetic levels and by different potential cells of origin. These studies have consistently contributed to better defining the pathogenesis of CCAs and to identify in some instances new therapeutic targets. Although the therapeutic progress were still limited, these observations suggest that a better understanding of the molecular mechanisms underlying CCA in the future will help to develop more efficacious treatment strategies.
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Affiliation(s)
- Ugo Testa
- Department of Oncology, Istituto Supeirore di Sanità, Rome, Italy
| | - Elvira Pelosi
- Department of Oncology, Istituto Supeirore di Sanità, Rome, Italy
| | - Germana Castelli
- Department of Oncology, Istituto Supeirore di Sanità, Rome, Italy
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8
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Li M, Zhou X, Wang W, Ji B, Shao Y, Du Q, Yao J, Yang Y. Selecting an Appropriate Experimental Animal Model for Cholangiocarcinoma Research. J Clin Transl Hepatol 2022; 10:700-710. [PMID: 36062286 PMCID: PMC9396327 DOI: 10.14218/jcth.2021.00374] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 12/05/2021] [Accepted: 01/03/2022] [Indexed: 12/04/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive biliary tree malignancy with intrahepatic and extra-hepatic subtypes that differ in molecular pathogeneses, epidemiology, clinical manifestations, treatment, and prognosis. The overall prognosis and patient survival remains poor because of lack of early diagnosis and effective treatments. Preclinical in vivo studies have become increasingly paramount as they are helpful not only for the study of the fundamental molecular mechanisms of CCA but also for developing novel and effective therapeutic approaches of this fatal cancer. Recent advancements in cell and molecular biology have made it possible to mimic the pathogenicity of human CCA in chemical-mechanical, infection-induced inflammatory, implantation, and genetically engineered animal models. This review is intended to help investigators understand the particular strengths and weaknesses of the currently used in vivo animal models of human CCA and their related modeling techniques to aid in the selection of the one that is the best for their research needs.
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Affiliation(s)
- Man Li
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Xueli Zhou
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Wei Wang
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Baoan Ji
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Yu Shao
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Qianyu Du
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Jinghao Yao
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Yan Yang
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
- Correspondence to: Yan Yang, Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, China. ORCID: https://orcid.org/0000-0003-0887-2770. Tel: +86-552-3086178, Fax: +86-552-3074480, E-mail:
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9
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Fan G, Lou L, Song Z, Zhang X, Xiong XF. Targeting mutated GTPase KRAS in tumor therapies. Eur J Med Chem 2021; 226:113816. [PMID: 34520956 DOI: 10.1016/j.ejmech.2021.113816] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/24/2021] [Accepted: 08/29/2021] [Indexed: 12/13/2022]
Abstract
Kirsten rat sarcoma virus oncogene (KRAS) mutation accounts for approximately 85% of RAS-driven cancers, and participates in multiple signaling pathways and mediates cell proliferation, differentiation and metabolism. KRAS has been considered as an "undruggable" target due to the lack of effective direct inhibitors, although high frequency of KRAS mutations have been identified in multiple carcinomas in the past decades. Encouragingly, the KRASG12C inhibitor AMG510 (sotorasib), which has been approved for treating NSCLC and CRC recently, makes directly targeting KRAS the most promising strategy for cancer therapy. To better understand the current state of KRAS inhibitors, this review summarizes the biological functions of KRAS, the structure-activity relationship studies of the small-molecule inhibitors that directly target KRAS, and highlights the therapeutic agents with improved selectivity, bioavailability and physicochemical properties. Furthermore, the combined medication that can enhance efficacy and overcome drug resistance of KRAS covalent inhibitors is also reviewed.
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Affiliation(s)
- Guangjin Fan
- Guangdong Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Linlin Lou
- Guangdong Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Zhendong Song
- Guangdong Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
| | - Xiaolei Zhang
- Guangdong Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
| | - Xiao-Feng Xiong
- Guangdong Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
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10
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Jiang TY, Pan YF, Wan ZH, Lin YK, Zhu B, Yuan ZG, Ma YH, Shi YY, Zeng TM, Dong LW, Tan YX, Wang HY. PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma. Sci Transl Med 2021; 12:12/562/eaay0152. [PMID: 32967970 DOI: 10.1126/scitranslmed.aay0152] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 12/31/2019] [Accepted: 07/28/2020] [Indexed: 12/23/2022]
Abstract
Patient-derived xenografts (PDXs) and PDX-derived cells (PDCs) are useful in preclinical research. We performed a drug screening assay using PDCs and identified proteasome inhibitors as promising drugs for cholangiocarcinoma (CCA) treatment. Furthermore, we determined that phosphate and tensin homology deleted on chromosome ten (PTEN) deficiency promotes protein synthesis and proteasome subunit expression and proteolytic activity, creating a dependency on the proteasome for cancer cell growth and survival. Thus, targeting the proteasome machinery with the inhibitor bortezomib inhibited the proliferation and survival of CCA cells lacking functional PTEN. Therapeutic evaluation of PDXs, autochthonous mouse models, and patients confirmed this dependency on the proteasome. Mechanistically, we found that PTEN promoted the nuclear translocation of FOXO1, resulting in the increased expression of BACH1 and MAFF BACH1 and MAFF are transcriptional regulators that recognize the antioxidant response element, which is present in genes encoding proteasome subunits. PTEN induced the accumulation and nuclear translocation of these proteins, which directly repressed the transcription of genes encoding proteasome subunits. We revealed that the PTEN-proteasome axis is a potential target for therapy in PTEN-deficient CCA and other PTEN-deficient cancers.
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Affiliation(s)
- Tian-Yi Jiang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.,National Center for Liver Cancer, Shanghai 201805, China
| | - Yu-Fei Pan
- National Center for Liver Cancer, Shanghai 201805, China.,Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai 200438, China
| | - Zheng-Hua Wan
- National Center for Liver Cancer, Shanghai 201805, China
| | - Yun-Kai Lin
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.,National Center for Liver Cancer, Shanghai 201805, China
| | - Bin Zhu
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Zhen-Gang Yuan
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Yun-Han Ma
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.,National Center for Liver Cancer, Shanghai 201805, China
| | - Yuan-Yuan Shi
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China
| | - Tian-Mei Zeng
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Li-Wei Dong
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China. .,Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai 200438, China
| | - Ye-Xiong Tan
- National Center for Liver Cancer, Shanghai 201805, China. .,Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai 200438, China
| | - Hong-Yang Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China. .,National Center for Liver Cancer, Shanghai 201805, China.,Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai 200438, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.,Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Second Military Medical University & Ministry of Education, Shanghai 200438, China
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11
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Recent Advances in Implantation-Based Genetic Modeling of Biliary Carcinogenesis in Mice. Cancers (Basel) 2021; 13:cancers13102292. [PMID: 34064809 PMCID: PMC8151177 DOI: 10.3390/cancers13102292] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/07/2021] [Accepted: 05/10/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Biliary tract cancer (BTC) is often refractory to conventional therapeutics and is difficult to diagnose in the early stages. In addition, the pathogenesis of BTC is not fully understood, despite recent advances in cancer genome analysis. To address these issues, the development of fine disease models is critical for BTC. Although still limited in number, there are various platforms for genetic models of BTC owing to newly emerging technology. Among these, implantation-based models have recently drawn attention for their convenience, flexibility, and scalability. To highlight the relevance of this approach, we comprehensively summarize the advantages and disadvantages of BTC models developed using diverse approaches. Currently available research data on intra- and extrahepatic cholangiocarcinoma and gallbladder carcinoma are presented in this review. This information will likely help in selecting the optimal models for various applications and develop novel innovative models based on these technologies. Abstract Epithelial cells in the biliary system can develop refractory types of cancers, which are often associated with inflammation caused by viruses, parasites, stones, and chemicals. Genomic studies have revealed recurrent genetic changes and deregulated signaling pathways in biliary tract cancer (BTC). The causal roles have been at least partly clarified using various genetically engineered mice. Technical advances in Cre-LoxP technology, together with hydrodynamic tail injection, CRISPR/Cas9 technology, in vivo electroporation, and organoid culture have enabled more precise modeling of BTC. Organoid-based genetic modeling, combined with implantation in mice, has recently drawn attention as a means to accelerate the development of BTC models. Although each model may not perfectly mimic the disease, they can complement one another, or two different approaches can be integrated to establish a novel model. In addition, a comparison of the outcomes among these models with the same genotype provides mechanistic insights into the interplay between genetic alterations and the microenvironment in the pathogenesis of BTCs. Here, we review the current status of genetic models of BTCs in mice to provide information that facilitates the wise selection of models and to inform the future development of ideal disease models.
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12
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Precision modeling of gall bladder cancer patients in mice based on orthotopic implantation of organoid-derived tumor buds. Oncogenesis 2021; 10:33. [PMID: 33866327 PMCID: PMC8053198 DOI: 10.1038/s41389-021-00322-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 03/20/2021] [Accepted: 03/30/2021] [Indexed: 12/18/2022] Open
Abstract
Genetically engineered mice (GEM) are the gold standard for cancer modeling. However, strict recapitulation of stepwise carcinogenesis from a single tumor-initiating epithelial cell among genetically intact cells in adults is not feasible with the currently available techniques using GEM. In previous studies, we partially overcame this challenge by physically isolating organs from adult animals, followed by genetic engineering in organoids and subcutaneous inoculation in nude mice. Despite the establishment of suitable ex vivo carcinogenesis models for diverse tissues, tumor development remained ectopic and occurred under immunodeficient conditions. Further refinement was, therefore, necessary to establish ideal models. Given the poor prognosis and few models owing to the lack of gall bladder (GB)-specific Cre strain, we assumed that the development of authentic models would considerably benefit GB cancer research. Here, we established a novel model using GB organoids with mutant Kras and Trp53 loss generated in vitro by lentiviral Cre transduction and CRISPR/Cas9 gene editing, respectively. Organoid-derived subcutaneous tumor fragments were sutured to the outer surface of the GB in syngeneic mice, which developed orthotopic tumors that resembled human GB cancer in histological and transcriptional features. This model revealed the infiltration of similar subsets of immune cells in both subcutaneous and orthotopic tumors, confirming the appropriate immune environment during carcinogenesis. In addition, we accurately validated the in vivo efficacy of gemcitabine, a common therapeutic agent for GB cancer, in large cohorts. Taken together, this model may serve as a promising avatar of patients with GB cancer in drug discovery and precision medicine.
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13
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Moeini A, Haber PK, Sia D. Cell of origin in biliary tract cancers and clinical implications. JHEP Rep 2021; 3:100226. [PMID: 33665585 PMCID: PMC7902553 DOI: 10.1016/j.jhepr.2021.100226] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/14/2020] [Accepted: 12/16/2020] [Indexed: 12/12/2022] Open
Abstract
Biliary tract cancers (BTCs) are aggressive epithelial malignancies that can arise at any point of the biliary tree. Albeit rare, their incidence and mortality rates have been rising steadily over the past 40 years, highlighting the need to improve current diagnostic and therapeutic strategies. BTCs show high inter- and intra-tumour heterogeneity both at the morphological and molecular level. Such complex heterogeneity poses a substantial obstacle to effective interventions. It is widely accepted that the observed heterogeneity may be the result of a complex interplay of different elements, including risk factors, distinct molecular alterations and multiple potential cells of origin. The use of genetic lineage tracing systems in experimental models has identified cholangiocytes, hepatocytes and/or progenitor-like cells as the cells of origin of BTCs. Genomic evidence in support of the distinct cell of origin hypotheses is growing. In this review, we focus on recent advances in the histopathological subtyping of BTCs, discuss current genomic evidence and outline lineage tracing studies that have contributed to the current knowledge surrounding the cell of origin of these tumours.
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Key Words
- ARID1A, AT-rich interactive domain-containing protein 1A
- BAP1, BRCA1-associated protein 1
- BRAF, v-Raf murine sarcoma viral oncogene homolog B
- BTC, biliary tract cancer
- Biliary tract cancers
- CCA, cholangiocarcinoma
- CDKN2A/B, cyclin-dependent kinase inhibitor 2A/B
- CK, cytokeratin
- CLC, cholangiolocarcinoma
- Cell of origin
- Cholangiocarcinoma
- CoH, Canal of Hering
- DCR, disease control rate
- ER, estrogen receptor
- ERBB2/3, Erb-B2 Receptor Tyrosine Kinase 2/3
- FGFR, fibroblast growth factor receptor
- FGFR2, Fibroblast Growth Factor Receptor 2
- GBC, gallbladder cancer
- GEMM, genetically engineered mouse models
- Genomics
- HCC, hepatocellular carcinoma
- HPCs, hepatic progenitor cells
- IDH, isocitrate dehydrogenase
- KRAS, Kirsten Rat Sarcoma Viral Oncogene Homolog
- Lineage tracing
- MET, Hepatocyte Growth Factor Receptor
- MST1, Macrophage Stimulating 1
- NA, not applicable
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NGS, next-generation sequencing
- NR, not reported
- NTRK, Neurotrophic Receptor Tyrosine Kinase 1
- ORR, objective response rate
- OS, overall survival
- PBG, peribiliary gland
- PFS, progression- free survival
- PIK3CA, Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha
- PLC, primary liver cancer
- PRKACA/B, Protein Kinase CAMP-Activated Catalytic Subunit Alpha/Beta
- PROM1, Prominin 1
- PSC, primary sclerosing cholangitis
- Personalized therapy
- RNF43, Ring Finger Protein 43
- SMAD4, SMAD Family Member 4
- TBG, thyroid binding globulin
- TP53, Tumor Protein P53
- WHO, World Health Organization
- dCCA, distal cholangiocarcinoma
- eCCA, extrahepatic cholangiocarcinoma
- iCCA, intrahepatic cholangiocarcinoma
- mo, months
- pCCA, perihilar cholangiocarcinoma
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Affiliation(s)
- Agrin Moeini
- Cancer Inflammation and Immunity Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Manchester, UK
| | - Philipp K Haber
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Daniela Sia
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
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14
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Sirica AE, Strazzabosco M, Cadamuro M. Intrahepatic cholangiocarcinoma: Morpho-molecular pathology, tumor reactive microenvironment, and malignant progression. Adv Cancer Res 2020; 149:321-387. [PMID: 33579427 PMCID: PMC8800451 DOI: 10.1016/bs.acr.2020.10.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a relatively rare, but highly lethal and biologically complex primary biliary epithelial cancer arising within liver. After hepatocellular carcinoma, iCCA is the second most common primary liver cancer, accounting for approximately 10-20% of all primary hepatic malignancies. Over the last 10-20 years, iCCA has become the focus of increasing concern largely due to its rising incidence and high mortality rates in various parts of the world, including the United States. The challenges posed by iCCA are daunting and despite recent progress in the standard of care and management options for iCCA, the prognosis for this cancer continues to be dismal. In an effort to provide a framework for advancing our understanding of iCCA malignant aggressiveness and therapy resistance, this review will highlight key etiological, biological, molecular, and microenvironmental factors hindering more effective management of this hepatobiliary cancer. Particular focus will be on critically reviewing the cell origins and morpho-molecular heterogeneity of iCCAs, providing mechanistic insights into high risk fibroinflammatory cholangiopathies associated with iCCA development, and notably discussing the deleterious role played by the tumor reactive desmoplastic stroma in regulating iCCA malignant progression, lymphangiogenesis, and tumor immunobiology.
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Affiliation(s)
- Alphonse E Sirica
- Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA, United States.
| | - Mario Strazzabosco
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States
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15
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Abstract
PURPOSE OF REVIEW Biliary tract cancers which include intrahepatic and extrahepatic cholangiocarcinomas and gallbladder cancer, are characterized by poor outcome. Therefore, identifying the molecular mechanisms of the disease has become a priority. However, such identification has to cope with extreme heterogeneity of the disease, which results from the variable anatomical location, the numerous cell types of origin and the high number of known genetic alterations. RECENT FINDINGS Animal models can develop invasive and metastatic tumours that recapitulate as faithfully as possible the molecular features of the human tumours. To generate animal models of cholangiocarcinoma, investigators resorted to the administration of carcinogens, induction of cholestasis, grafting of tumour cells and induction of genetic modifications. SUMMARY Here, we summarize the currently available genetically engineered animal models, and focus on mice and zebrafish. The experimental strategies that were selected to induce cholangiocarcinoma in a time-controlled and cell-type-specific manner are critically examined. We discuss their strengths and limitations while considering their relevance to human pathophysiology.
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16
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Erice O, Vallejo A, Ponz-Sarvise M, Saborowski M, Vogel A, Calvisi DF, Saborowski A, Vicent S. Genetic Mouse Models as In Vivo Tools for Cholangiocarcinoma Research. Cancers (Basel) 2019; 11:cancers11121868. [PMID: 31769429 PMCID: PMC6966555 DOI: 10.3390/cancers11121868] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 11/22/2019] [Indexed: 02/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular mechanisms of human CCA will increase our current knowledge of the disease and expedite the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is effectively supported by genetic mouse models, which serve as sophisticated tools to systematically investigate CCA pathobiology and treatment response. These in vivo models feature many of the genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis (encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease) and provide an ideal experimental setting to study the interplay between tumor cells and the surrounding stroma. This review is intended to serve as a compendium of CCA mouse models, including traditional transgenic models but also genetically flexible approaches based on either the direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a resource for CCA researchers to aid in the selection of the most appropriate in vivo model system.
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Affiliation(s)
- Oihane Erice
- Center for Applied Medical Research, Program in Solid Tumors, University of Navarra, 31008 Pamplona, Spain; (O.E.); (A.V.)
| | - Adrian Vallejo
- Center for Applied Medical Research, Program in Solid Tumors, University of Navarra, 31008 Pamplona, Spain; (O.E.); (A.V.)
| | - Mariano Ponz-Sarvise
- Department of Medical Oncology, Clinica Universidad de Navarra, 31008 Pamplona, Spain;
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
| | - Michael Saborowski
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (M.S.); (A.V.)
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (M.S.); (A.V.)
| | - Diego F. Calvisi
- Institute for Pathology, Regensburg University, 93053 Regensburg, Germany;
| | - Anna Saborowski
- Department of Medical Oncology, Clinica Universidad de Navarra, 31008 Pamplona, Spain;
- Correspondence: (A.S.); (S.V.); Tel.: +49-511-532-9590 (A.S.); +34-948194700 (ext. 812029) (S.V.)
| | - Silvestre Vicent
- Center for Applied Medical Research, Program in Solid Tumors, University of Navarra, 31008 Pamplona, Spain; (O.E.); (A.V.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
- Correspondence: (A.S.); (S.V.); Tel.: +49-511-532-9590 (A.S.); +34-948194700 (ext. 812029) (S.V.)
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17
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Ochiai M, Yoshihara Y, Maru Y, Matsuura T, Izumiya M, Imai T, Hippo Y. Kras-driven heterotopic tumor development from hepatobiliary organoids. Carcinogenesis 2019; 40:1142-1152. [PMID: 30753336 DOI: 10.1093/carcin/bgz024] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 01/15/2019] [Accepted: 02/01/2019] [Indexed: 12/12/2022] Open
Abstract
Cancers arising from the biliary tract are refractory to conventional therapies, requiring the development of novel therapeutics. However, only a limited number of genetically engineered mouse models have been created, partly because of time-consuming work required. Besides, liver-specific gene manipulation mostly resulted in concurrent development of hepatocellular carcinoma, another type of liver cancer, and gallbladder-restricted gene targeting is still not feasible. Consequently, establishment of cancer type-specific disease modeling remains a technical challenge. To address this issue, we took an alternative cell-based approach to quickly induce tumorigenesis ex vivo. Specifically, murine primary organoids from liver and gallbladder were transduced with lentiviral vectors to reconstitute genetic alterations common in biliary tract cancers, followed by inoculation in immunodeficient mice. Although any single genetic alteration did not induce tumors, mutant Kras and repression of major tumor suppressors cooperated for tumor development within 2 months. Induced lesions varied among normal, dysplastic and papillary lesions to adenocarcinoma, recapitulating multistep tumorigenesis even in a heterotopic situation. We further demonstrated that two putative oncogenes in intrahepatic cholangiocellular carcinoma, mutant Pik3ca and FGFR2-AHCYL1 fusion, were rather modest drivers for liver-derived organoids, probably requiring additional mutations or hepatic niche to robustly induce full-blown tumors. Thus, we showed that cancer cells could be readily generated from primary cells in the biliary tract, at least in cases where genetic factors play dominant roles. Collectively, this study will likely contribute to gaining mechanistic insights into biliary carcinogenesis and providing valuable resources for drug discovery.
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Affiliation(s)
- Masako Ochiai
- Central Animal Division, National Cancer Center Research Institute, Tokyo, Japan
| | - Yasunori Yoshihara
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Yoshiaki Maru
- Division of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Tetsuya Matsuura
- Central Animal Division, National Cancer Center Research Institute, Tokyo, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yokohama City University, Kanagawa, Japan
| | - Masashi Izumiya
- Central Animal Division, National Cancer Center Research Institute, Tokyo, Japan
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- Division of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Toshio Imai
- Central Animal Division, National Cancer Center Research Institute, Tokyo, Japan
| | - Yoshitaka Hippo
- Central Animal Division, National Cancer Center Research Institute, Tokyo, Japan
- Division of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba, Japan
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18
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Vicent S, Lieshout R, Saborowski A, Verstegen MMA, Raggi C, Recalcati S, Invernizzi P, van der Laan LJW, Alvaro D, Calvisi DF, Cardinale V. Experimental models to unravel the molecular pathogenesis, cell of origin and stem cell properties of cholangiocarcinoma. Liver Int 2019; 39 Suppl 1:79-97. [PMID: 30851232 DOI: 10.1111/liv.14094] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 02/10/2019] [Accepted: 02/25/2019] [Indexed: 12/11/2022]
Abstract
Human cholangiocarcinoma (CCA) is an aggressive tumour entity arising from the biliary tree, whose molecular pathogenesis remains largely undeciphered. Over the last decade, the advent of high-throughput and cell-based techniques has significantly increased our knowledge on the molecular mechanisms underlying this disease while, at the same time, unravelling CCA complexity. In particular, it becomes clear that CCA displays pronounced inter- and intratumoural heterogeneity, which is presumably the consequence of the interplay between distinct tissues and cells of origin, the underlying diseases, and the associated molecular alterations. To better characterize these events and to design novel and more effective therapeutic strategies, a number of CCA experimental and preclinical models have been developed and are currently generated. This review summarizes the current knowledge and understanding of these models, critically underlining their translational usefulness and limitations. Furthermore, this review aims to provide a comprehensive overview on cells of origin, cancers stem cells and their dynamic interplay within CCA tissue.
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Affiliation(s)
- Silvestre Vicent
- Program in Solid Tumors, Center for Applied Applied Medical Research, University of Navarra, Pamplona, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Ruby Lieshout
- Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Monique M A Verstegen
- Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Chiara Raggi
- Humanitas Clinical and Research Center, Rozzano, Italy.,Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Stefania Recalcati
- Department of Biomedical Sciences for Health, University of Milan, Milano, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center of Autoimmune Liver Diseases, Department of Medicine and Surgery, San Gerardo Hospita, l, University of Milano, Bicocca, Italy
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
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19
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Wei G, Yuan Y, He X, Jin L, Jin D. Enhanced plasma miR-142-5p promotes the progression of intrahepatic cholangiocarcinoma via targeting PTEN. Exp Ther Med 2019; 17:4190-4196. [PMID: 31007750 DOI: 10.3892/etm.2019.7438] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 08/10/2018] [Indexed: 01/04/2023] Open
Abstract
The aim of the present study was to evaluate the expression and specific role of microRNA (miR)-142-5p in the progression of intrahepatic cholangiocarcinoma (ICC). Reverse transcription-quantitative polymerase chain reaction was performed to evaluate miR-142-5p expression in patients with ICC and healthy control subjects. The results revealed that plasma miR-142-5p was significantly increased in patients with ICC compared with the control group. Furthermore, miR-142-5p was also increased in ICC tissues compared with adjacent non-neoplastic tissues. Compared with patients with Ta-T1 stage ICC, miR-142-5p was significantly elevated in patients with ICC ≥T2 stage. Patients with ICC at G3 stage had much higher plasma miR-142-5p levels compared with those at G1/2 stage. Receiver operating characteristic analysis indicated that miR-142-5p could be used as a biomarker to differentiate patients with ICC from healthy controls. Kaplan-Meier analysis demonstrated that plasma miR-142-5p was negatively correlated with survival in patients with ICC. A dual luciferase reporter assay indicated that miR-142-5p significantly suppressed the relative luciferase activity of pmirGLO-PTEN-3' untranslated region compared with the control group. In summary, the results of the present study provide novel data indicating that plasma miR-142-5p is significantly upregulated in patients with ICC. miR-142-5p may therefore have potential as a biomarker for screening patients with ICC from healthy controls.
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Affiliation(s)
- Guifen Wei
- Department of Hepatobiliary and Pancreatic Surgery, The First People's Hospital of Tongxiang, Tongxiang, Zhejiang 314500, P.R. China
| | - Yiting Yuan
- Department of Hepatobiliary and Pancreatic Surgery, The First People's Hospital of Tongxiang, Tongxiang, Zhejiang 314500, P.R. China
| | - Xinzhong He
- Department of Hepatobiliary and Pancreatic Surgery, The First People's Hospital of Tongxiang, Tongxiang, Zhejiang 314500, P.R. China
| | - Liming Jin
- Department of Hepatobiliary and Pancreatic Surgery, The First People's Hospital of Tongxiang, Tongxiang, Zhejiang 314500, P.R. China
| | - Di Jin
- Department of Hepatobiliary and Pancreatic Surgery, The First People's Hospital of Tongxiang, Tongxiang, Zhejiang 314500, P.R. China
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20
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Kaavya J, Mahalaxmi I, Devi SM, Santhy KS, Balachandar V. Targeting phosphoinositide-3-kinase pathway in biliary tract cancers: A remedial route? J Cell Physiol 2018; 234:8259-8273. [PMID: 30370571 DOI: 10.1002/jcp.27673] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 10/04/2018] [Indexed: 01/17/2023]
Abstract
Biliary tract cancers (BTC) are aggressive tumours with a low survival rate. At the advent of the genomic era, various genetic mutations in cell signalling pathways have been incriminated in carcinogenesis. Genomic analysis studies have connected main components of the phosphoinositide-3-kinase (PI3K) signalling pathway to BTC. PI3K pathway playing a central role in cell signalling and being deregulated in various tumours has been studied as a target for chemotherapy. Novel compounds have also been identified in preclinical trials that specifically target the PI3K pathway in BTCs, but these studies have not accelerated to clinical use. These novel compounds can be examined in upcoming studies to validate them as potential therapeutic agents, as further research is required to combat the growing need for adjuvant chemotherapy to successfully battle this tumour type. Furthermore, these molecules could also be used along with gemcitabine, cisplatin and 5-fluorouracil to improve sensitivity of the tumour tissue to chemotherapy. This review focuses on the basics of PI3K signalling, genetic alterations of this pathway in BTCs and current advancement in targeting this pathway in BTCs. It emphasizes the need for gene-based drug screening in BTC. It may reveal various novel targets and drugs for amelioration of survival in patients with BTC and serve as a stepping stone for further research.
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Affiliation(s)
- Jayaramayya Kaavya
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Avinashilingam University for Women, Coimbatore, India
| | - Iyer Mahalaxmi
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Avinashilingam University for Women, Coimbatore, India
| | | | - K S Santhy
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Avinashilingam University for Women, Coimbatore, India
| | - Vellingiri Balachandar
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India
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21
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Lin YK, Fang Z, Jiang TY, Wan ZH, Pan YF, Ma YH, Shi YY, Tan YX, Dong LW, Zhang YJ, Wang HY. Combination of Kras activation and PTEN deletion contributes to murine hepatopancreatic ductal malignancy. Cancer Lett 2018; 421:161-169. [PMID: 29452147 DOI: 10.1016/j.canlet.2018.02.017] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Revised: 01/23/2018] [Accepted: 02/06/2018] [Indexed: 12/30/2022]
Abstract
Kras mutations are among the most common genetic abnormalities in human neoplasms, including cholangiocarcinomas, pancreatic cancer and colon cancer. PTEN has previously been associated with cholangiocarcinoma development in murine models. Here, we have established novel mouse models of neoplasms by liver-specific and biliary-pancreatic Kras activation and PTEN deletion. By liver-specific disruption of PTEN and activation of Kras in mice caused rapid development of intrahepatic biliary epithelial proliferative lesions (Intrahepatic cholangiocarcinoma, ICC), which progress through dysplasia to invasive carcinoma. In contrast, Kras activation in combination with heterozygous PTEN deletion induced mixed carcinomas of liver (both ICC and hepatocellular carcinoma, HCC), whereas Kras activation alone did not induce biliary tract neoplasm. Use of Sox9-Cre-LoxP-based approach to coordinately delete PTEN and activate Kras in the adult mouse resulted in not only development of low-grade biliary lesions (ICC and extrahepatic bile duct carcinoma, ECC) but also pancreatic carcinomas. Our data provide a functional link between PTEN gene status, hepatobiliary cell fate, and HCC, biliary carcinoma, pancreatic cancer pathogenesis, and present novel genetically engineered mouse models of PTEN loss-driven malignancy.
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Affiliation(s)
- Yun-Kai Lin
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, PR China
| | - Zheng Fang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, PR China; The Second Department of Biliary Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, PR China
| | - Tian-Yi Jiang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, PR China; National Center for Liver Cancer, Shanghai, PR China
| | - Zheng-Hua Wan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, PR China
| | - Yu-Fei Pan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, PR China
| | - Yun-Han Ma
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, PR China
| | - Yuan-Yuan Shi
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, PR China
| | - Ye-Xiong Tan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, PR China; National Center for Liver Cancer, Shanghai, PR China
| | - Li-Wei Dong
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, PR China; National Center for Liver Cancer, Shanghai, PR China.
| | - Yong-Jie Zhang
- The Second Department of Biliary Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, PR China.
| | - Hong-Yang Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, PR China; National Center for Liver Cancer, Shanghai, PR China.
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22
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Dong M, Liu X, Evert K, Utpatel K, Peters M, Zhang S, Xu Z, Che L, Cigliano A, Ribback S, Dombrowski F, Cossu A, Gordan J, Calvisi DF, Evert M, Liu Y, Chen X. Efficacy of MEK inhibition in a K-Ras-driven cholangiocarcinoma preclinical model. Cell Death Dis 2018; 9:31. [PMID: 29348467 PMCID: PMC5833851 DOI: 10.1038/s41419-017-0183-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 11/20/2017] [Accepted: 11/21/2017] [Indexed: 12/11/2022]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a deadly malignancy with limited treatment options. Gain-of-function mutations in K-Ras is a very frequent alteration, occurring in ~15 to 25% of human iCCA patients. Here, we established a new iCCA model by expressing activated forms of Notch1 (NICD) and K-Ras (K-RasV12D) in the mouse liver (K-Ras/NICD mice). Furthermore, we investigated the therapeutic potential of MEK inhibitors in vitro and in vivo using human CCA cell lines and K-Ras/NICD mice, respectively. Treatment with U0126, PD901, and Selumetinib MEK inhibitors triggered growth restraint in all CCA cell lines tested, with the most pronounced growth suppressive effects being observed in K-Ras mutant cells. Growth inhibition was due to reduction in proliferation and massive apoptosis. Furthermore, treatment of K-Ras/NICD tumor-bearing mice with PD901 resulted in stable disease. At the molecular level, PD901 efficiently inhibited ERK activation in K-Ras/NICD tumor cells, mainly leading to increased apoptosis. Altogether, our study demonstrates that K-Ras/NICD mice represent a novel and useful preclinical model to study K-Ras-driven iCCA development and the effectiveness of MEK inhibitors in counteracting this process. Our data support the usefulness of MEK inhibitors for the treatment of human iCCA.
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Affiliation(s)
- Mingjie Dong
- Department of Gastroenterology, 307 Hospital of Academy of Military Medical Science, Beijing, China
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, CA, USA
| | - Xianqiong Liu
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, CA, USA
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, China
| | - Katja Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Kirsten Utpatel
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Michele Peters
- Institute of Pathology, University of Greifswald, Greifswald, Germany
| | - Shanshan Zhang
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, CA, USA
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhong Xu
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, CA, USA
| | - Li Che
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, CA, USA
| | - Antonio Cigliano
- Institute of Pathology, University of Greifswald, Greifswald, Germany
| | - Silvia Ribback
- Institute of Pathology, University of Greifswald, Greifswald, Germany
| | - Frank Dombrowski
- Institute of Pathology, University of Greifswald, Greifswald, Germany
| | - Antonio Cossu
- Unit of Pathology, Azienda Ospedaliero Universitaria Sassari, Sassari, Italy
| | - John Gordan
- Department of Medicine, University of California, San Francisco, CA, USA
| | - Diego F Calvisi
- Institute of Pathology, University of Greifswald, Greifswald, Germany
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany.
| | - Yan Liu
- Department of Gastroenterology, 307 Hospital of Academy of Military Medical Science, Beijing, China.
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
- Liver Center, University of California, San Francisco, CA, USA.
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, China.
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23
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Wang S, Liu JC, Ju Y, Pellecchia G, Voisin V, Wang DY, Leha L R, Ben-David Y, Bader GD, Zacksenhaus E. microRNA-143/145 loss induces Ras signaling to promote aggressive Pten-deficient basal-like breast cancer. JCI Insight 2017; 2:93313. [PMID: 28768903 DOI: 10.1172/jci.insight.93313] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 06/23/2017] [Indexed: 11/17/2022] Open
Abstract
The tumor suppressor PTEN is frequently inactivated in breast and other cancers; yet, germ-line mutations in this gene induce nonmalignant hamartomas, indicating dependency on additional cooperating events. Here we show that most tumors derived from conditional deletion of mouse pten in mammary epithelium are highly differentiated and lack transplantable tumor-initiating cells (TICs) capable of seeding new tumors following orthotopic injection of FACS-sorted or tumorsphere cells. A rare group of poorly differentiated tumors did harbor transplantable TICs. These transplantable tumors exhibited distinct molecular classification, signaling pathways, chromosomal aberrations, and mutational landscape, as well as reduced expression of microRNA-143/145 (miR-143/145). Stable knockdown of miR-143/145 conferred tumorigenic potential upon poorly transplantable pten-deficient tumor cells through a mechanism involving induction of RAS signaling, leading to increased sensitivity to MEK inhibition. In humans, miR-145 deficiency significantly correlated with elevated RAS-pathway activity in basal-like breast cancer, and patients with combined PTEN/miR-145 loss or PTEN-loss/high RAS-pathway activity exhibited poor clinical outcome. These results underscore a selective pressure for combined PTEN loss together with RAS-pathway activation, either through miR-145 loss or other mechanisms, in basal-like breast cancer, and a need to identify and prioritize these tumors for aggressive therapy.
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Affiliation(s)
- Sharon Wang
- Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada.,Laboratory Medicine & Pathobiology, and
| | - Jeff C Liu
- Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada
| | - YoungJun Ju
- Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada
| | | | - Veronique Voisin
- The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada
| | - Dong-Yu Wang
- Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada
| | - Rajwinder Leha L
- Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada
| | - Yaacov Ben-David
- The Key laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, and State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
| | - Gary D Bader
- The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.,Department of Molecular Genetics, and
| | - Eldad Zacksenhaus
- Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada.,Laboratory Medicine & Pathobiology, and.,Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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24
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Kayhanian H, Smyth EC, Braconi C. Emerging molecular targets and therapy for cholangiocarcinoma. World J Gastrointest Oncol 2017; 9:268-280. [PMID: 28808500 PMCID: PMC5534395 DOI: 10.4251/wjgo.v9.i7.268] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 01/05/2017] [Accepted: 03/24/2017] [Indexed: 02/05/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a rare cancer arising from the biliary tree with a poor prognosis and limited therapeutic options. Recent large scale molecular characterisation studies have identified recurrent genetic alterations in CCA which may be amenable to therapeutic targeting. In this review we explore the genomic landscape of CCA and examine results from trials of molecularly targeted agents and immunotherapy in this disease. Challenges in CCA diagnosis, treatment and trial design are discussed and we reflect on future directions which may lead to improved outcomes for CCA patients.
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25
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Ji H, Lu Y, Shi Y. Seeds in the liver. Acta Histochem 2017; 119:349-356. [PMID: 28389020 DOI: 10.1016/j.acthis.2017.03.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 02/28/2017] [Accepted: 03/21/2017] [Indexed: 02/05/2023]
Abstract
The liver is a crucial organ for homeostasis and has a tremendous self-renewal and regenerative capacity. It has long been believed that the self-renewal and repair of the liver within a given physiological condition or its repopulation in chronic liver diseases, when hepatocyte proliferation is impaired, will primarily be conducted by the proliferating duct cells, termed "oval cells" or hepatic progenitor cells (HPCs). In addition, numerous studies have revealed that HPCs are the initial tumor cells of liver cancer under certain micro-environments. However, benefit from the extensive application of lineage tracing strategies using the Cre/LoxP system, researchers have redefined the fate of these bipotential cells, raising obvious controversies regarding the capacity of liver cells to control their own biology and differentiation. Here, we review the relevant articles, focusing on cell-lineage tracing to better understanding seed cells and their distinct fate in the liver.
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26
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A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion. Sci Rep 2016; 6:23899. [PMID: 27032374 PMCID: PMC4817147 DOI: 10.1038/srep23899] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 03/16/2016] [Indexed: 12/15/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with poor prognosis and its incidence is increasing worldwide. Recently, several types of cells have been considered as the origin of ICC, namely cholangiocytes, liver progenitor cells, and hepatocytes. Here, we have established a novel mouse model of ICC by liver-specific Kras activation and Pten deletion. An activating mutation of Kras in combination with deletion of Pten was introduced in embryonic hepatic bipotential progenitor cells (so-called hepatoblasts) and mature hepatocytes using the Cre-loxP system. As a result, liver-specific Kras activation and homozygous Pten deletion cooperated to induce ICCs exclusively. In contrast, Kras activation in combination with heterozygous Pten deletion induced both ICCs and HCCs, whereas Kras activation alone resulted in HCCs but not ICCs. Furthermore, a cell-lineage visualization system using tamoxifen-inducible Cre-loxP demonstrated that the ICCs did not originate from hepatocytes but from cholangiocytes. Our data suggest that mice carrying liver-specific Kras activation in combination with homozygous Pten deletion should be useful for the investigation of therapeutic strategies for human ICC.
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27
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Wei M, Lü L, Lin P, Chen Z, Quan Z, Tang Z. Multiple cellular origins and molecular evolution of intrahepatic cholangiocarcinoma. Cancer Lett 2016; 379:253-61. [PMID: 26940139 DOI: 10.1016/j.canlet.2016.02.038] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2016] [Revised: 02/18/2016] [Accepted: 02/19/2016] [Indexed: 12/12/2022]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy associated with unfavorable prognosis and for which no effective treatments are available. Its molecular pathogenesis is poorly understood. Genome-wide sequencing and high-throughput technologies have provided critical insights into the molecular basis of ICC while sparking a heated debate on the cellular origin. Cancer exhibits variabilities in origin, progression and cell biology. Recent evidence suggests that ICC has multiple cellular origins, including differentiated hepatocytes; intrahepatic biliary epithelial cells (IBECs)/cholangiocytes; pluripotent stem cells, such as hepatic stem/progenitor cells (HPCs) and biliary tree stem/progenitor cells (BTSCs); and peribiliary gland (PBG). However, both somatic mutagenesis and epigenomic features are highly cell type-specific. Multiple cellular origins may have profoundly different genomic landscapes and key signaling pathways, driving phenotypic variation and thereby posing significant challenges to personalized medicine in terms of achieving the optimal drug response and patient outcome. Considering this information, we have summarized the latest experimental evidence and relevant literature to provide an up-to-date view of the cellular origin of ICC, which will contribute to establishment of a hierarchical model of carcinogenesis and allow for improvement of the anatomical-based classification of ICC. These new insights have important implications for both the diagnosis and treatment of ICC patients.
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Affiliation(s)
- Miaoyan Wei
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Lisheng Lü
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Peiyi Lin
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Zhisheng Chen
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Zhiwei Quan
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Zhaohui Tang
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
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28
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Lemaigre FP. Determining the fate of hepatic cells by lineage tracing: facts and pitfalls. Hepatology 2015; 61:2100-3. [PMID: 25503476 DOI: 10.1002/hep.27659] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 12/10/2014] [Indexed: 12/19/2022]
Abstract
Slow renewal of the epithelial cells by proliferation ensures homeostasis of the liver, but extensive proliferation may occur upon injury. When proliferation is impaired, transdifferentiation of mature cells or differentiation of stem cells allows production of new hepatocytes and cholangiocytes. While lineage tracings using cyclization recombinase (Cre) recombinase-mediated cell labeling represent the gold standard for defining cell fate, there are more variables than was initially realized. This led to controversies about the capacity of liver cells to switch their fate. Here, I review how cells are traced in the liver and highlight the experimental pitfalls that may cause misinterpretations and controversies.
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29
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Abstract
Biliary tract cancers are a heterogeneous group of cancers that arise in either the intra- or extrahepatic bile ducts or the gallbladder. Local therapy with surgical resection and perhaps radiation therapy is used for localized disease. There is no known effective adjuvant therapy, although various combinations have been used clinically without definitive data showing a benefit. The most standard chemotherapy for metastatic disease is gemcitabine plus cisplatin based on a single positive randomized trial. Genetic mutations that may lead to better, targeted therapy choices are being identified, albeit with variable frequency. Early studies of targeted agents have been negative, but these were in unselected patients where it was unknown whether the target was activated in any individual patient. Careful selection of patients enrolling onto trials of targeted agents will make the subsets of biliary tract cancers even smaller but is likely necessary to improve outcomes from these deadly diseases.
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Affiliation(s)
- Emily Chan
- All authors: Vanderbilt University, Nashville, TN.
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30
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Kongpetch S, Jusakul A, Ong CK, Lim WK, Rozen SG, Tan P, Teh BT. Pathogenesis of cholangiocarcinoma: From genetics to signalling pathways. Best Pract Res Clin Gastroenterol 2015; 29:233-44. [PMID: 25966424 DOI: 10.1016/j.bpg.2015.02.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 02/07/2015] [Indexed: 01/31/2023]
Abstract
Cholangiocarcinoma (CCA) is a malignant tumour of bile duct epithelial cells with dismal prognosis and rising incidence. Chronic inflammation resulting from liver fluke infection, hepatitis and other inflammatory bowel diseases is a major contributing factor to cholangiocarcinogenesis, likely through accumulation of serial genetic and epigenetic alterations resulting in aberration of oncogenes and tumour suppressors. Recent studies making use of advances in high-throughput genomics have revealed the genetic landscape of CCA, greatly increasing our understanding of its underlying biology. A series of highly recurrent mutations in genes such as TP53, KRAS, SMAD4, BRAF, MLL3, ARID1A, PBRM1 and BAP1, which are known to be involved in cell cycle control, cell signalling pathways and chromatin dynamics, have led to investigations of their roles, through molecular to mouse modelling studies, in cholangiocarcinogenesis. This review focuses on the landscape genetic alterations in CCA and its functional relevance to the formation and progression of CCA.
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Affiliation(s)
- Sarinya Kongpetch
- Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore; Department of Pharmacology, Faculty of Medicine and Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, Thailand; Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore.
| | - Apinya Jusakul
- Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore; Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore.
| | - Choon Kiat Ong
- Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore; Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore.
| | - Weng Khong Lim
- Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore; Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore.
| | - Steven G Rozen
- Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore; Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore.
| | - Patrick Tan
- Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore; Genome Institute of Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
| | - Bin Tean Teh
- Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore; Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
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31
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Lunardi A, Webster KA, Papa A, Padmani B, Clohessy JG, Bronson RT, Pandolfi PP. Role of aberrant PI3K pathway activation in gallbladder tumorigenesis. Oncotarget 2015; 5:894-900. [PMID: 24658595 PMCID: PMC4011591 DOI: 10.18632/oncotarget.1808] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The PI3K/AKT pathway governs a plethora of cellular processes, including cell growth, proliferation, and metabolism, in response to growth factors and cytokines. By acting as a unique lipid phosphatase converting phosphatidylinositol-3,4,5,-trisphosphate (PIP3) to phosphatidylinositol-4,5,-bisphosphate (PIP2), phosphatase and tensin homolog (PTEN) acts as the major cellular suppressor of PI3K signaling and AKT activation. Recently, PI3K mutations and loss/mutation of PTEN have been characterized in human gallbladder tumors; whether aberrant PTEN/PI3K pathway plays a causal role in gallbladder carcinogenesis, however, remains unknown. Herein we show that in mice, deregulation of PI3K/AKT signaling is sufficient to transform gallbladder epithelial cells and trigger fully penetrant, highly proliferative gallbladder tumors characterized by high levels of phospho-AKT. Histopathologically, these mouse tumors faithfully resemble human adenomatous gallbladder lesions. The identification of PI3K pathway deregulation as both an early event in the neoplastic transformation of the gallbladder epithelium and a main mechanism of tumor growth in Pten heterozygous and Pten mutant mouse models provides a new framework for studying in vivo the efficacy of target therapies directed against the PI3K pathway, as advanced metastatic tumors are often addicted to “trunkular” mutations.
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32
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Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma. Oncotarget 2015; 5:2372-89. [PMID: 24796583 PMCID: PMC4058012 DOI: 10.18632/oncotarget.1706] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
The PI3K/Akt/mTOR pathway is overactivated and heat shock protein (HSP) 90 is overexpressed in common cancers. We hypothesized that targeting both pathways can kill intrahepatic cholangiocarcinoma (CCA) cells. HSP90 and PTEN protein expression was evaluated by immunohistochemical staining of samples from 78 patients with intrahepatic CCA. CCA cell lines and a thioacetamide (TAA)-induced CCA animal model were treated with NVP-AUY922 (an HSP90 inhibitor) and NVP-BEZ235 (a PI3K/mTOR inhibitor) alone or in combination. Both HSP90 overexpression and loss of PTEN were poor prognostic factors in patients with intrahepatic CCA. The combination of the HSP90 inhibitor NVP-AUY922 and the PI3K/mTOR inhibitor NVP-BEZ235 was synergistic in inducing cell death in CCA cells. A combination of NVP-AUY922 and NVP-BEZ235 caused tumor regression in CCA rat animal model. This combination not only inhibited the PI3K/Akt/mTOR pathway but also induced ROS, which may exacerbate the vicious cycle of ER stress. Our data suggest simultaneous targeting of the PI3K/mTOR and HSP pathways for CCA treatment.
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33
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Plk1-targeted therapies in TP53- or RAS-mutated cancer. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2014; 761:31-39. [PMID: 24630986 DOI: 10.1016/j.mrrev.2014.02.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 02/27/2014] [Accepted: 02/27/2014] [Indexed: 11/23/2022]
Abstract
Despite advances in treatment, prognosis for many types of carcinoma remains poor. Polo-like kinase 1 (Plk1) has been explored as a target for the development of anticancer drugs. As a mitotic master Ser/Thr kinase, Plk1 is involved in centrosomal maturation, microtubule nucleation, chromosomal segregation, and cytokinesis. Additional functions in interphase and in response to DNA damage have been revealed. The multiple locations of Plk1 correspond to distinct functions, mediated by phosphorylation of multiple substrates. Since it is highly expressed in several carcinomas, and expression of Plk1 is inversely correlated with the survival rate of patients in non-small cell lung, head and neck, and esophageal cancer, Plk1 is recognized as a valid prognostic marker. Connections between Plk1 and p53 or KRAS in carcinoma provide a rationale and several possible routes to the development of therapies. Tumors with both p53-deficiency and high Plk1 expression may be particularly sensitive to Plk1 inhibitors, although some controversial data exist. In KRAS-mutant cancers, on the other hand, Plk1 may be essential for tumor cell survival, but detailed studies as to whether Plk1 inhibitors are more effective in KRAS-mutant cancers must be performed in order to determine whether this is the case. Here, we present evidence for Plk1 as a prognostic marker and potentially effective target for the treatment of patients with carcinoma, to demonstrate the value of Plk1 as a target for the development of cancer treatment, especially for patients with solid tumors. In addition, the effects of Plk1 inhibition in p53- or KRAS-mutated cancer are discussed with respect to clinical implications. Structural specifics of Plk1 are presented, as well as current strategies for discovering new Plk1 inhibitors by targeting the conserved ATP binding site or polo-box domain of Plk1, in order to develop Plk1-specific anticancer drugs.
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Davies EJ, Marsh Durban V, Meniel V, Williams GT, Clarke AR. PTEN loss and KRAS activation leads to the formation of serrated adenomas and metastatic carcinoma in the mouse intestine. J Pathol 2014; 233:27-38. [PMID: 24293351 DOI: 10.1002/path.4312] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 11/22/2013] [Accepted: 11/26/2013] [Indexed: 12/15/2022]
Abstract
Mutation or loss of the genes PTEN and KRAS have been implicated in human colorectal cancer (CRC), and have been shown to co-occur despite both playing a role in the PI3' kinase (PI3'K) pathway. We investigated the role of these genes in intestinal tumour progression in vivo, using genetically engineered mouse models, with the aim of generating more representative models of human CRC. Intestinal-specific deletion of Pten and activation of an oncogenic allele of Kras was induced in wild-type (WT) mice and mice with a predisposition to adenoma development (Apc(fl/+) ). The animals were euthanized when they became symptomatic of a high tumour burden. Histopathological examination of the tissues was carried out, and immunohistochemistry used to characterize signalling pathway activation. Mutation of Pten and Kras resulted in a significant life-span reduction of mice predisposed to adenomas. Invasive adenocarcinoma was observed in these animals, with evidence of activation of the PI3'K pathway but no metastasis. However, mutation of Pten and Kras in WT animals not predisposed to adenomas led to perturbed homeostasis of the intestinal epithelium and the development of hyperplastic polyps, dysplastic sessile serrated adenomas and metastasizing adenocarcinomas with serrated features. These studies demonstrate synergism between Pten and Kras mutations in intestinal tumour progression, in an autochthonous and immunocompetent murine model, with potential application to preclinical drug testing. In particular, they show that Pten and Kras mutations alone predispose mice to the spectrum of serrated lesions that reflect the serrated pathway of CRC progression in humans.
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Affiliation(s)
- Emma J Davies
- Cardiff School of Biosciences, Cardiff University, UK
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Liu C, Li G, Chen R, Yang X, Zhao X, Zhao H. A novel PTEN gene promoter mutation and untypical Cowden syndrome. Chin J Cancer Res 2013; 25:306-11. [PMID: 23825907 DOI: 10.3978/j.issn.1000-9604.2013.06.02] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Accepted: 05/25/2013] [Indexed: 12/13/2022] Open
Abstract
Cowden syndrome (CS), an autosomal dominant disorder, is one of a spectrum of clinical disorders that have been linked to germline mutations in the phosphatase and tensin homolog (PTEN) gene. Although 70-80% of patients with CS have an identifiable germline PTEN mutation, the clinical diagnosis presents many challenges because of the phenotypic and genotypic variations. In the present study, we sequenced the exons and the promoter of PTEN gene, mutations and variations in the promoter and exons were identified, and a PTEN protein expression negative region was determined by immunohistochemistry (IHC). In conclusion, a novel promoter mutation we found in PTEN gene may turn off PTEN protein expression occasionally, leading to the disorder of PTEN and untypical CS manifestations.
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Affiliation(s)
- Chen Liu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; ; Peking Union Medical College, Beijing 100730, China
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