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1
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-Like Lesions. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:842-946. [DOI: 10.1016/b978-0-7020-8228-3.00013-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Kodali S, Shetty A, Shekhar S, Victor DW, Ghobrial RM. Management of Intrahepatic Cholangiocarcinoma. J Clin Med 2021; 10:jcm10112368. [PMID: 34072277 PMCID: PMC8198953 DOI: 10.3390/jcm10112368] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/20/2021] [Accepted: 05/22/2021] [Indexed: 01/04/2023] Open
Abstract
Cholangiocarcinoma is a tumor that arises as a result of differentiation of the cholangiocytes and can develop from anywhere in the biliary tree. Subtypes of cholangiocarcinoma are differentiated based on their location in the biliary tree. If diagnosed early these can be resected, but most cases of intrahepatic cholangiocarcinoma present late in the disease course where surgical resection is not an option. In these patients who are poor candidates for resection, a combination of chemotherapy, locoregional therapies like ablation, transarterial chemo and radioembolization, and in very advanced and metastatic disease, external radiation are the available options. These modalities can improve overall disease-free and progression-free survival chances. In this review, we will discuss the risk factors and clinical presentation of intrahepatic cholangiocarcinoma, diagnosis, available therapeutic options, and future directions for management options.
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Affiliation(s)
- Sudha Kodali
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA; (S.K.); (A.S.); (R.M.G.)
- Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Akshay Shetty
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA; (S.K.); (A.S.); (R.M.G.)
- Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Soumya Shekhar
- Texas A&M College of Medicine, Houston Campus, Houston, TX 77030, USA;
| | - David W. Victor
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA; (S.K.); (A.S.); (R.M.G.)
- Houston Methodist Research Institute, Houston, TX 77030, USA
- Correspondence:
| | - Rafik M. Ghobrial
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA; (S.K.); (A.S.); (R.M.G.)
- Houston Methodist Research Institute, Houston, TX 77030, USA
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Izzo P, Izzo S, DI Cello P, D'Amata G, Cardi M, Polistena A, Messineo D, Izzo L. Role of Leptin in Neoplastic and Biliary Tree Disease. In Vivo 2020; 34:2485-2490. [PMID: 32871776 DOI: 10.21873/invivo.12064] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/07/2020] [Accepted: 07/08/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND/AIM Leptin is a small hormone of protein nature, it is strongly involved in the regulation of lipid metabolism and its functioning mechanism is not yet well known or whether or not it is actually secreted by cholangiocytes, nor if the biliary tree expresses its receptors. In the past, various studies have tried to correlate leptin levels with certain neoplasms. The aim of this study was to demonstrate that serum leptin values can become a new sensitive and specific serum marker for cholangiocarcinoma. MATERIALS AND METHODS Seventy-two patients with gallbladder stones, hepatolithiasis with benign biliary stenosis, cholangiocarcinoma, and a group of patients without hepato-biliary diseases were enrolled in the study. In all cases blood and bile samples were collected for evaluation of leptin levels and liver biopsies were performed to confirm diagnosis. In all patients, both ultrasound and cholangio-magnetic resonance imaging (MRI) were performed to complete the diagnostic procedure. RESULTS Twenty-two patients were affected by cholangiocarcinoma, 50 by benign biliary disease (35 cholelithiasis and 6 hepatolithiasis and 9 by inflammatory biliary stenosis). The mean values of serum leptin in patients with cholangiocarcinoma were 19.28±8.76 ng/ml, significantly higher than those observed in non-neoplastic biliary diseases. CONCLUSION Serum leptin levels might be a useful marker to differentiate patients with cholangiocarcinoma from those with biliary lithiasis and inflammatory stenosis.
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Affiliation(s)
- Paolo Izzo
- Department of Surgery "Pietro Valdoni", Policlinico Umberto I, Università degli studi "La Sapienza", Rome, Italy
| | - Sara Izzo
- Unit of Colorectal Surgery, Department of Medical, Surgical, Neurologic, Metabolic and Ageing Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | | | - Gabriele D'Amata
- ASL Roma 5 UOC Chirurgia Generale Ospedale di Colleferro, Rome, Italy
| | - Maurizio Cardi
- Department of Surgery "Pietro Valdoni", Policlinico Umberto I, Università degli studi "La Sapienza", Rome, Italy
| | - Andrea Polistena
- Department of Surgery "Pietro Valdoni", Policlinico Umberto I, Università degli studi "La Sapienza", Rome, Italy
| | - Daniela Messineo
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Università degli Studi "La Sapienza", Rome, Italy
| | - Luciano Izzo
- Department of Surgery "Pietro Valdoni", Policlinico Umberto I, Università degli studi "La Sapienza", Rome, Italy
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Fruscione M, Pickens RC, Baker EH, Martinie JB, Iannitti DA, Hwang JJ, Vrochides D. Conversion therapy for intrahepatic cholangiocarcinoma and tumor downsizing to increase resection rates: A systematic review. Curr Probl Cancer 2020; 45:100614. [PMID: 32622478 DOI: 10.1016/j.currproblcancer.2020.100614] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/29/2020] [Accepted: 06/02/2020] [Indexed: 12/14/2022]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a devastating malignant neoplasm with dismal outcomes. Several therapeutic modalities have been used with variable success to downsize these tumors for resection. Neoadjuvant therapy such as chemoembolization and radioembolization offer promising options to manage tumor burden prior to resection. A systematic review of the literature was performed with a focus on conversion therapy for ICC and tumor downsizing to increase resection rates among patients who have an initially unresectable tumor. Of 132 patients with initially unresectable ICC, we identified 27 who underwent conversion therapy with surgical resection. Adequate tumor downsizing was achieved with chemotherapy, chemoembolization, radioembolization, or combination thereof. Although negative tumor margins were possible in some patients, recurrence rates and survival outcomes were inconsistently reported. Twenty-three of 27 patients were alive at last reported follow-up. Conversion therapy for initially unresectable ICC may offer adequate tumor downsizing for resection.
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Affiliation(s)
- Mike Fruscione
- Department of Surgery, Division of Hepatopancreatobiliary Surgery, Carolinas Medical Center, Charlotte, NC
| | - Ryan C Pickens
- Department of Surgery, Division of Hepatopancreatobiliary Surgery, Carolinas Medical Center, Charlotte, NC
| | - Erin H Baker
- Department of Surgery, Division of Hepatopancreatobiliary Surgery, Carolinas Medical Center, Charlotte, NC
| | - John B Martinie
- Department of Surgery, Division of Hepatopancreatobiliary Surgery, Carolinas Medical Center, Charlotte, NC
| | - David A Iannitti
- Department of Surgery, Division of Hepatopancreatobiliary Surgery, Carolinas Medical Center, Charlotte, NC
| | - Jimmy J Hwang
- Department of Medical Oncology, Levine Cancer Institute, Carolinas Medical Center, Charlotte, NC
| | - Dionisios Vrochides
- Department of Surgery, Division of Hepatopancreatobiliary Surgery, Carolinas Medical Center, Charlotte, NC.
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Chang CW, Yeh CN, Chung YH, Chen YR, Tien SW, Chen TW, Farn SS, Huang YC, Yu CS. Synthesis and evaluation of ortho-[ 18F] fluorocelecoxib for COX-2 cholangiocarcinoma imaging. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:1467-1478. [PMID: 29872269 PMCID: PMC5973465 DOI: 10.2147/dddt.s161718] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background An 18F-tagged NSAID analog was prepared for use as a probe for COX-2 expression, which is associated with tumor development. Methods The in vivo uptake of celecoxib was monitored with ortho-[18F]fluorocelecoxib using positron emission tomography (PET). The binding affinity of ortho-[18F]fluorocelecoxib to COX-1 and COX-2 enzymes were assessed using the competitor celecoxib. Results The IC50 values were 0.039 μM and 0.024 μM, respectively. A selectivity index of 1.63 was obtained (COX-2 vs COX-1). COX-2 overexpressed cholangiocarcinoma (CCA) murine cells took up more ortho-[18F]fluorocelecoxib than that by usual CCA cells from 10 to 60 minutes post incubation. Competitive inhibition (blocking) of the tracer uptake of ortho-[18F]fluorocelecoxib in the presence of celecoxib by the COX-2 overexpressed CCA cells and the usual CCA cells gave the IC50 values of 0.5 μM and 46.5 μM, respectively. Based on the in vitro accumulation data and in vivo metabolism half-life (30 min), PET scanning was performed 30–60 min after the administration of ortho-[18F]fluorocelecoxib through the tail vein. Study of ortho-[18F]F-celecoxib in the CCA rats showed a tumor to normal ratio (T/N) of 1.38±0.23 and uptake dose of 1.14±0.25 (%ID/g). Conclusion The inferior in vivo blocking results of 1.48±0.20 (T/N) and 1.18±0.22 (%ID/g) suggests that the nonspecificity is associated with the complex role of peroxidase or the binding to carbonic anhydrase.
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Affiliation(s)
- Chi-Wei Chang
- Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chun-Nan Yeh
- Department of Surgery, Liver Research Center, Chang-Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Hsiu Chung
- Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yong-Ren Chen
- Department of Biomedical Engineering and Environmental Sciences, National Tsinghua University, Hsinchu, Taiwan
| | - Shi-Wei Tien
- Department of Biomedical Engineering and Environmental Sciences, National Tsinghua University, Hsinchu, Taiwan
| | - Tsung-Wen Chen
- Department of Surgery, Liver Research Center, Chang-Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
| | - Shiou-Shiow Farn
- Department of Biomedical Engineering and Environmental Sciences, National Tsinghua University, Hsinchu, Taiwan.,Isotope Application Division, Institute of Nuclear Energy Research, Taoyuan, Taiwan
| | - Ying-Cheng Huang
- Department of Neurosurgery, Chang-Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
| | - Chung-Shan Yu
- Department of Biomedical Engineering and Environmental Sciences, National Tsinghua University, Hsinchu, Taiwan.,Institute of Nuclear Engineering and Science, National Tsinghua University, Hsinchu, Taiwan
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-like Lesions of the Liver. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:780-879. [DOI: 10.1016/b978-0-7020-6697-9.00013-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Synthesis and characterization of boron fenbufen and its F-18 labeled homolog for boron neutron capture therapy of COX-2 overexpressed cholangiocarcinoma. Eur J Pharm Sci 2017; 107:217-229. [PMID: 28728977 DOI: 10.1016/j.ejps.2017.07.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 06/16/2017] [Accepted: 07/16/2017] [Indexed: 12/30/2022]
Abstract
Boron neutron capture therapy (BNCT) is a binary therapy that employs neutron irradiation on the boron agents to release high-energy helium and alpha particles to kill cancer cells. An optimal response to BNCT depends critically on the time point of maximal 10B accumulation and highest tumor to normal ratio (T/N) for performing the neutron irradiation. The aggressive cholangiocarcinoma (CCA) representing a liver cancer that overexpresses COX-2 enzyme is aimed to be targeted by COX-2 selective boron carrier, fenbufen boronopinacol (FBPin). Two main works were performed including: 1) chemical synthesis of FBPin as the boron carrier and 2) radiochemical labeling with F-18 to provide the radiofluoro congener, m-[18F]fluorofenbufen ester boronopinacol (m-[18F]FFBPin), to assess the binding affinity, cellular accumulation level and distribution profile in CCA rats. FBPin was prepared from bromofenbufen via 3 steps with 82% yield. The binding assay employed [18F]FFBPin to compete FBPin for binding to COX-1 (IC50=0.91±0.68μM) and COX-2 (IC50=0.33±0.24μM). [18F]FFBPin-derived 60-min dynamic PET scans predict the 10B-accumulation of 0.8-1.2ppm in liver and 1.2-1.8ppm in tumor and tumor to normal ratio=1.38±0.12. BNCT was performed 40-55min post intravenous administration of FBPin (20-30mg) in the CCA rats. CCA rats treated with BNCT display more tumor reduction than that by NCT with respect of 2-[18F]fluoro-2-deoxy glucose uptake in the tumor region of interest, 20.83±3.00% (n=12) vs. 12.83±3.79% (n=10), P=0.05. The visualizing agent [18F]FFBPin resembles FBPin to generate the time-dependent boron concentration profile. Optimal neutron irradiation period is thus determinable for BNCT. A boron-substituted agent based on COX-2-binding features has been prepared. The moderate COX-2/COX-1 selectivity index of 2.78 allows a fair tumor selectivity index of 1.38 with a mild cardiovascular effect. The therapeutic effect from FBPin with BNCT warrants a proper COX-2 targeting of boron NSAIDs.
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Aberrant DNA Methylation as a Biomarker and a Therapeutic Target of Cholangiocarcinoma. Int J Mol Sci 2017; 18:ijms18061111. [PMID: 28545228 PMCID: PMC5485935 DOI: 10.3390/ijms18061111] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 05/16/2017] [Accepted: 05/18/2017] [Indexed: 12/31/2022] Open
Abstract
Cholangiocarcinoma is an epithelial malignancy arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile duct. The effect of current chemotherapy regimens against cholangiocarcinoma is limited, and the prognosis of patients with cholangiocarcinoma is poor. Aberrant DNA methylation and histone modification induce silencing of tumor suppressor genes and chromosomal instability during carcinogenesis. Studies have shown that the tumor suppressor genes and microRNAs (miRNAs) including MLH1, p14, p16, death-associated protein kinase (DAPK), miR-370 and miR-376c are frequently methylated in cholangiocarcinoma. Silencing of these tumor suppressor genes and miRNAs plays critical roles in the initiation and progression of cholangiocarcinoma. In addition, recent studies have demonstrated that DNA methylation inhibitors induce expression of endogenous retroviruses and exert the anti-tumor effect of via an anti-viral immune response. Aberrant DNA methylation of tumor suppressor genes and miRNAs could be a powerful biomarker for the diagnosis and treatment of cholangiocarcinoma. Epigenetic therapy with DNA methylation inhibitors holds considerable promise for the treatment of cholangiocarcinoma through the reactivation of tumor suppressor genes and miRNAs as well as the induction of an anti-viral immune response.
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Rahnemai-Azar AA, Weisbrod A, Dillhoff M, Schmidt C, Pawlik TM. Intrahepatic cholangiocarcinoma: Molecular markers for diagnosis and prognosis. Surg Oncol 2017; 26:125-137. [PMID: 28577718 DOI: 10.1016/j.suronc.2016.12.009] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 12/24/2016] [Accepted: 12/29/2016] [Indexed: 02/08/2023]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver tumor with increasing incidence worldwide. The outcome of patients with iCCA is dismal owing to tumor's aggressiveness, late diagnosis and lack of effective treatment options. Detection of the tumor at early stages may make surgical resection, as only potential curative treatment, more feasible. Unfortunately, despite recent developments in imaging modalities and laboratory tests, the diagnosis of iCCA remains challenging and patients often present in advanced stages when surgery cannot be offered. Moreover, accurate assessment of disease burden is critical to optimize management strategy, including the use of adjuvant therapies and clinical trials. Identifying iCCA specific diagnostic and prognostic biomarkers has been a focus of interest among many investigators with a progressive increase in data on iCCA related to advances in "omics" technologies. We herein summarize iCCA biomarkers and define the molecular mechanisms underlying iCCA carcinogenesis, as well as highlight potential diagnostic and prognostic application of molecular biomarkers.
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Affiliation(s)
- Amir A Rahnemai-Azar
- Department of Surgery, University of Washington Medical Center, Seattle, WA, USA
| | - Allison Weisbrod
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Mary Dillhoff
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Carl Schmidt
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.
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Sawanyawisuth K, Tantapotinan N, Wongkham C, Riggins GJ, Kraiklang R, Wongkham S, Puapairoj A. Suppression of trophoblast cell surface antigen 2 enhances proliferation and migration in liver fluke-associated cholangiocarcinoma. Ann Hepatol 2016; 15:71-81. [PMID: 26626643 DOI: 10.5604/16652681.1184223] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIM Trophoblast cell surface antigen 2 (TROP2) or tumor-associated calcium signal transducer 2 (TACSTD2) is a 36-kDa type I transmembrane glycoprotein and exerts dual functions as an oncogene and tumor suppressor in cancer cells. In this study, we investigated the expression and functions of TROP2 in liver fluke-associated cholangiocarcinoma (CCA). MATERIAL AND METHODS TROP2 expression in 85 CCA tissues was detected by using immunohistochemistry. The methylation status of TROP2 promoter was studied in 15 matched pairs of normal and CCA formalin fixed paraffin embedded (FFPE) tissues using the bisulfite genomic sequencing (BGS) method. The functions of TROP2 on cancer cell behavior were investigated using siRNA in CCA cell lines. Proliferation, migration and invasion assays were performed. A PCR array was used to evaluate the impact of TROP2 knockdown on the gene expression profiles. RESULTS TROP2 was highly expressed in all normal bile duct epithelia, but significantly down-regulated in CCA cells. Sixty percent of CCA revealed promoter hypermethylation compared to the corresponding adjacent normal tissues. TROP2 knockdown significantly enhanced the proliferation and migration in CCA cell lines, and altered the expressions of MARCK, EMP1 and FILIP1L. CONCLUSION We provide new evidence that TROP2 is epigenetically down-regulated and operates as a negative regulator of cell proliferation and migration in liver fluke-associated CCA.
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Affiliation(s)
- Kanlayanee Sawanyawisuth
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Nattawat Tantapotinan
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Chaisiri Wongkham
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Gregory J Riggins
- Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, USA
| | - Ratthaphol Kraiklang
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sopit Wongkham
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Anucha Puapairoj
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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Lee CH, Wang HE, Seo SY, Kim SH, Kim IH, Kim SW, Lee ST, Kim DG, Han MK, Lee SO. Cancer related gene alterations can be detected with next-generation sequencing analysis of bile in diffusely infiltrating type cholangiocarcinoma. Exp Mol Pathol 2016; 101:150-156. [PMID: 27460275 DOI: 10.1016/j.yexmp.2016.07.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 05/25/2016] [Accepted: 07/22/2016] [Indexed: 01/30/2023]
Abstract
Genome-wide association study in diffusely infiltrating type cholangiocarcinoma (CC) can be limited due to the difficulty of obtaining tumor tissue. We aimed to evaluate the genomic alterations of diffusely infiltrating type CC using next-generation sequencing (NGS) of bile and to compare the variations with those of mass-forming type CC. A total of 24 bile samples obtained during endoscopic retrograde cholangiopancreatography (ERCP) and 17 surgically obtained tumor tissue samples were evaluated. Buffy coat and normal tissue samples were used as controls for a somatic mutation analysis. After extraction of genomic DNA, NGS analysis was performed for 48 cancer related genes. There were 27 men and 14 women with a mean age of 65.0±11.8years. The amount of extracted genomic DNA from 3cm(3) of bile was 66.0±84.7μg and revealed a high depth of sequencing coverage. All of the patients had genomic variations, with an average number of 19.4±2.8 and 22.3±3.3 alterations per patient from the bile and tumor tissue, respectively. After filtering process, damaging SNPs (8 sites for each type of CC) were predicted by analyzing tools, and their target genes showed relevant differences between the diffusely infiltrating and mass-forming type CC. Finally, in somatic mutation analysis, tumor-normal paired 14 tissue and 6 bile samples were analyzed, genomic alterations of EGFR, FGFR1, ABL1, PIK3CA, and CDKN2A gene were seen in the diffusely infiltrating type CC, and TP53, KRAS, APC, GNA11, ERBB4, ATM, SMAD4, BRAF, and IDH1 were altered in the mass-forming type CC group. STK11, GNAQ, RB1, KDR, and SMO genes were revealed in both groups. The NGS analysis was feasible with bile sample and diffusely infiltrating type CC revealed genetic differences compared with mass-forming type CC. Genome-wide association study could be performed using bile sample in the patients with CC undergoing ERCP and a different genetic approach for accurate diagnosis, pathogenesis study, and targeted therapy will be needed in diffusely infiltrating type CC.
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Affiliation(s)
- Chang Hun Lee
- Division of Gastroenterology, Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Republic of Korea; Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea
| | - Hong En Wang
- Department of Medical Science, The Graduate School, Chonbuk National University, Jeonju, Republic of Korea; Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea
| | - Seung Young Seo
- Division of Gastroenterology, Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Republic of Korea; Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea
| | - Seong Hun Kim
- Division of Gastroenterology, Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Republic of Korea; Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea
| | - In Hee Kim
- Division of Gastroenterology, Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Republic of Korea; Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea
| | - Sang Wook Kim
- Division of Gastroenterology, Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Republic of Korea; Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea
| | - Soo Teik Lee
- Division of Gastroenterology, Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Republic of Korea; Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea
| | - Dae Ghon Kim
- Division of Gastroenterology, Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Republic of Korea; Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea
| | - Myung Kwan Han
- Department of Microbiology, Chonbuk National University Medical School, Jeonju, Republic of Korea; Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea.
| | - Seung Ok Lee
- Division of Gastroenterology, Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Republic of Korea; Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea; Research Institute of Clinical Medicine, Chonbuk National University, Jeonju, Republic of Korea.
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12
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Genetic Abnormalities in Biliary Brush Samples for Distinguishing Cholangiocarcinoma from Benign Strictures in Primary Sclerosing Cholangitis. Gastroenterol Res Pract 2016; 2016:4381513. [PMID: 27127503 PMCID: PMC4834158 DOI: 10.1155/2016/4381513] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 02/22/2016] [Indexed: 12/14/2022] Open
Abstract
Background. Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and is strongly associated with cholangiocarcinoma (CCA). The lack of efficient diagnostic methods for CCA is a major problem. Testing for genetic abnormalities may increase the diagnostic value of cytology. Methods. We assessed genetic abnormalities for CDKN2A, TP53, ERBB2, 20q, MYC, and chromosomes 7 and 17 and measures of genetic clonal diversity in brush samples from 29 PSC patients with benign biliary strictures and 12 patients with sporadic CCA or PSC-associated CCA. Diagnostic performance of cytology alone and in combination with genetic markers was evaluated by sensitivity, specificity, and area under the curve analysis. Results. The presence of MYC gain and CDKN2A loss as well as a higher clonal diversity was significantly associated with malignancy. MYC gain increased the sensitivity of cytology from 50% to 83%. However, the specificity decreased from 97% to 76%. The diagnostic accuracy of the best performing measures of clonal diversity was similar to the combination of cytology and MYC. Adding CDKN2A loss to the panel had no additional benefit. Conclusion. Evaluation of MYC abnormalities and measures of clonal diversity in brush cytology specimens may be of clinical value in distinguishing CCA from benign biliary strictures in PSC.
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Abstract
Cholangiocarcinomas (CCAs) are associated with poor overall survival, and majority of the tumors are unresectable at the time of diagnosis. Early diagnosis at a resectable stage is essential for improved outcomes. Noninvasive imaging plays an important role in evaluating patients with biliary obstruction, but is limited due to the lack of tissue sampling and in many cases due to the absence of a mass, especially for extrahepatic CCAs. Endoscopic diagnosis is needed in majority of patients with CCA and the diagnostic yield depends on the tumor location as well as the expertise and experience of the endoscopist. Endoscopic retrograde cholangiopancreatography and endoscopic ultrasound remain the most common endoscopic diagnostic tools although newer technologies including fluorescence in situ hybridization, single-operator cholangioscopy, confocal laser endomicroscopy, and intraductal ultrasound are being increasing used. Traditionally, the role of endoscopy has been mainly palliative and limited to biliary drainage in patients with obstructive jaundice, however, newer treatment options like photodynamic therapy and radiofrequency ablation have shown promise toward improved patient survival. Multidisciplinary approach that involves medical oncology, gastroenterology, radiology, and surgical oncology teams is imperative for improved outcomes. In this review, we will first review the diagnostic approach to CCAs including imaging and endoscopic methods followed by a discussion of different endoscopic techniques in management of patients after a diagnosis of CCA.
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Affiliation(s)
- Ajaypal Singh
- Center for Endoscopic Research and Therapeutics (CERT), University of Chicago Medical Center, Chicago, IL
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Abstract
Liver cancer is an extraordinarily heterogeneous malignant disease among the tumors that have so far been identified. Hepatocellular carcinoma (HCC) arises most frequently in the setting of chronic liver inflammation and fibrosis, and takes a variety of course in individual patients to process to tumor. The risk factors such as HBV and/or HCV infections, aflatoxin infection, abuse alcohol intake, metabolic syndrome, obesity and diabetes are closely related to the environmental and genetic susceptibilities to HCC. The consequent resulting genomic instability, molecular and signal transduction network disorders and microenvironmental discrepancies are characterized by the extraordinary heterogeneity of liver cancer. The histology-based definition of the morphological heterogeneity of liver cancer has been modified and refined to treat patients with targeted therapies, but this still cannot solve all the problems. Lack of consistent outcome for anticancer agents and conventional therapies in liver cancer treatment calls for assessing the benefits of new molecularly targeted drugs and combined therapy, under the heterogeneity condition of tumor. The present review article will provide the complex mechanism and phenotype of liver cancer heterogeneity, and help us to execute precision medicine in a really personalized manner.
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Affiliation(s)
- Liang Li
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer, Shanghai, China
| | - Hongyang Wang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer, Shanghai, China; National Laboratory for Oncogenes and Related Genes, Cancer Institute, RenJi Hospital, Shanghai Jiao Tong University, Shanghai 200441, China.
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15
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Oyasiji T, Zhang J, Kuvshinoff B, Iyer R, Hochwald SN. Molecular Targets in Biliary Carcinogenesis and Implications for Therapy. Oncologist 2015; 20:742-51. [PMID: 26025932 DOI: 10.1634/theoncologist.2014-0442] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 03/27/2015] [Indexed: 12/19/2022] Open
Abstract
UNLABELLED Biliary tract cancers (BTCs) encompass a group of invasive carcinomas, including cholangiocarcinoma (intrahepatic, perihilar, or extrahepatic), and gallbladder carcinoma. Approximately 90% of patients present with advanced, unresectable disease and have a poor prognosis. The latest recommendation is to treat advanced or metastatic disease with gemcitabine and cisplatin, although chemotherapy has recorded modest survival benefits. Comprehension of the molecular basis of biliary carcinogenesis has resulted in experimental trials of targeted therapies in BTCs, with promising results. This review addresses the emerging role of targeted therapy in the treatment of BTCs. Findings from preclinical studies were reviewed and correlated with the outcomes of clinical trials that were undertaken to translate the laboratory discoveries. IMPLICATIONS FOR PRACTICE Biliary tract cancers are rare. Approximately 90% of patients present with advanced, unresectable disease and have a poor prognosis. Median overall and progression-free survival are 12 and 8 months, respectively. Because chemotherapy has recorded modest survival benefits, targeted therapies are being explored for personalized treatment of these cancers. A comprehensive review of targeted therapies in biliary tract cancers was undertaken to present emerging evidence from laboratory and/or molecular studies as they translate to clinical trials and outcomes. The latest evidence on this topic is presented to clinicians and practitioners to guide decisions on treatment of this disease.
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Affiliation(s)
- Tolutope Oyasiji
- Departments of Surgical Oncology and Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Jianliang Zhang
- Departments of Surgical Oncology and Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Boris Kuvshinoff
- Departments of Surgical Oncology and Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Renuka Iyer
- Departments of Surgical Oncology and Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Steven N Hochwald
- Departments of Surgical Oncology and Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
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16
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Yao L, Han C, Song K, Zhang J, Lim K, Wu T. Omega-3 Polyunsaturated Fatty Acids Upregulate 15-PGDH Expression in Cholangiocarcinoma Cells by Inhibiting miR-26a/b Expression. Cancer Res 2015; 75:1388-98. [PMID: 25691459 DOI: 10.1158/0008-5472.can-14-2561] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 01/26/2015] [Indexed: 12/19/2022]
Abstract
Prostaglandin E2 (PGE2) is a proinflammatory lipid mediator that promotes cancer growth. The 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes oxidation of the 15(S)-hydroxyl group of PGE2, leading to its inactivation. Therefore, 15-PGDH induction may offer a strategy to treat cancers that are driven by PGE2, such as human cholangiocarcinoma. Here, we report that omega-3 polyunsaturated fatty acids (ω-3 PUFA) upregulate 15-PGDH expression by inhibiting miR-26a and miR-26b, thereby contributing to ω-3 PUFA-induced inhibition of human cholangiocarcinoma cell growth. Treatment of human cholangiocarcinoma cells (CCLP1 and TFK-1) with ω-3 PUFA (DHA) or transfection of these cells with the Fat-1 gene (encoding Caenorhabditis elegans desaturase, which converts ω-6 PUFA to ω-3 PUFA) significantly increased 15-PGDH enzymes levels, but with little effect on the activity of the 15-PGDH gene promoter. Mechanistic investigations revealed that this increase in 15-PGDH levels in cells was mediated by a reduction in the expression of miR-26a and miR-26b, which target 15-PGDH mRNA and inhibit 15-PGDH translation. These findings were extended by the demonstration that overexpressing miR-26a or miR-26b decreased 15-PGDH protein levels, reversed ω-3 PUFA-induced accumulation of 15-PGDH protein, and prevented ω-3 PUFA-induced inhibition of cholangiocarcinoma cell growth. We further observed that ω-3 PUFA suppressed miR-26a and miR-26b by inhibiting c-myc, a transcription factor that regulates miR-26a/b. Accordingly, c-myc overexpression enhanced expression of miR-26a/b and ablated the ability of ω-3 PUFA to inhibit cell growth. Taken together, our results reveal a novel mechanism for ω-3 PUFA-induced expression of 15-PGDH in human cholangiocarcinoma and provide a preclinical rationale for the evaluation of ω-3 PUFA in treatment of this malignancy.
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Affiliation(s)
- Lu Yao
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Chang Han
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Kyoungsub Song
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Jinqiang Zhang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Kyu Lim
- Department of Biochemistry, College of Medicine, Cancer Research Institute and Infection Signaling, Network Research Center, Chungnam National University, Daejeon, Korea
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
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17
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Raggi C, Invernizzi P, Andersen JB. Impact of microenvironment and stem-like plasticity in cholangiocarcinoma: molecular networks and biological concepts. J Hepatol 2015; 62:198-207. [PMID: 25220250 DOI: 10.1016/j.jhep.2014.09.007] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 08/30/2014] [Accepted: 09/03/2014] [Indexed: 12/13/2022]
Abstract
Clinical complexity, anatomic diversity and molecular heterogeneity of cholangiocarcinoma (CCA) represent a major challenge in the assessment of effective targeted therapies. Molecular and cellular mechanisms underlying the diversity of CCA growth patterns remain a key issue of clinical concern. Crucial questions comprise the nature of the CCA-origin, the initial target for cellular transformation as well as the relationship with the cancer stem cells (CSC) concept. Additionally, since CCA often develops in the context of an inflammatory milieu (cirrhosis and cholangitis), the stromal compartment or tumour microenvironment (TME) likely promotes initiation and progression of this malignancy, contributing to its heterogeneity. This review will emphasize the dynamic interplay between stem-like intrinsic and TME-extrinsic pathways, which may represent novel options for multi-targeted therapies in CCA.
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Affiliation(s)
- Chiara Raggi
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy.
| | - Pietro Invernizzi
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Jesper B Andersen
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
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18
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Maroni L, Pierantonelli I, Banales JM, Benedetti A, Marzioni M. The significance of genetics for cholangiocarcinoma development. ANNALS OF TRANSLATIONAL MEDICINE 2014; 1:28. [PMID: 25332972 DOI: 10.3978/j.issn.2305-5839.2012.10.04] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Accepted: 10/15/2012] [Indexed: 12/15/2022]
Abstract
Cholangiocarcinoma (CCA) is a rare malignancy of the liver, arising from bile ducts. The incidence is increasing worldwide, but the prognosis has remained dismal and virtually unchanged in the past 30 years. Although several risk factors have been associated with the development of this cancer, none of them are normally identified in most patients. Diagnosis in advanced stages of the disease and limited therapeutic options contribute to poor survival rates. The recent analysis of genetic and epigenetic alterations occurring in CCA has shed new light in the understanding of the molecular mechanisms leading to the malignant transformation of biliary cells. Further studies in this direction may foster new diagnostic, prognostic and therapeutic approaches. This review provides a global overview of recent advances in CCA and describes the most important genetic mutations and epigenetic alterations so far reported in CCA.
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Affiliation(s)
- Luca Maroni
- 1 Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy ; 2 Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands ; 3 Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria ; 4 Division of Hepatology and Gastroenterology, Biodonostia Research Institute (Donostia University Hospital), CIBERehd, University of Basque Country, San Sebastián, Spain - IKERBASQUE (Basque Foundation of Science), and "Asociación Española Contra el Cáncer, (AECC)"
| | - Irene Pierantonelli
- 1 Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy ; 2 Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands ; 3 Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria ; 4 Division of Hepatology and Gastroenterology, Biodonostia Research Institute (Donostia University Hospital), CIBERehd, University of Basque Country, San Sebastián, Spain - IKERBASQUE (Basque Foundation of Science), and "Asociación Española Contra el Cáncer, (AECC)"
| | - Jesus M Banales
- 1 Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy ; 2 Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands ; 3 Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria ; 4 Division of Hepatology and Gastroenterology, Biodonostia Research Institute (Donostia University Hospital), CIBERehd, University of Basque Country, San Sebastián, Spain - IKERBASQUE (Basque Foundation of Science), and "Asociación Española Contra el Cáncer, (AECC)"
| | - Antonio Benedetti
- 1 Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy ; 2 Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands ; 3 Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria ; 4 Division of Hepatology and Gastroenterology, Biodonostia Research Institute (Donostia University Hospital), CIBERehd, University of Basque Country, San Sebastián, Spain - IKERBASQUE (Basque Foundation of Science), and "Asociación Española Contra el Cáncer, (AECC)"
| | - Marco Marzioni
- 1 Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy ; 2 Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands ; 3 Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria ; 4 Division of Hepatology and Gastroenterology, Biodonostia Research Institute (Donostia University Hospital), CIBERehd, University of Basque Country, San Sebastián, Spain - IKERBASQUE (Basque Foundation of Science), and "Asociación Española Contra el Cáncer, (AECC)"
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19
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Moehler M, Maderer A, Schimanski C, Kanzler S, Denzer U, Kolligs FT, Ebert MP, Distelrath A, Geissler M, Trojan J, Schütz M, Berie L, Sauvigny C, Lammert F, Lohse A, Dollinger MM, Lindig U, Duerr EM, Lubomierski N, Zimmermann S, Wachtlin D, Kaiser AK, Schadmand-Fischer S, Galle PR, Woerns M. Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme. Eur J Cancer 2014; 50:3125-35. [PMID: 25446376 DOI: 10.1016/j.ejca.2014.09.013] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 09/13/2014] [Accepted: 09/22/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study. PATIENTS AND METHODS 102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0-2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks+1-week rest followed by once 3-weeks+1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA). RESULTS Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P=0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P=0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P=0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRβ expression correlated with longer PFS. CONCLUSION The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.
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Affiliation(s)
- M Moehler
- Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany.
| | - A Maderer
- Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany
| | - C Schimanski
- Department of Internal Medicine, Marienhospital Darmstadt, Darmstadt, Germany
| | - S Kanzler
- 2nd Department of Medicine, Leopoldina Hospital, Schweinfurt, Germany
| | - U Denzer
- 1st Department of Medicine, University Hospital Hamburg, Hamburg, Germany
| | - F T Kolligs
- Department of Medicine II, University Hospital Munich, Munich, Germany
| | - M P Ebert
- 2nd Department of Medicine, University Hospital Mannheim, Mannheim, Germany
| | - A Distelrath
- Tumor Department, Hospital Fulda, Fulda, Germany
| | - M Geissler
- Department of Internal Medicine, Hospital Esslingen, Esslingen, Germany
| | - J Trojan
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany
| | - M Schütz
- Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany
| | - L Berie
- Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany
| | - C Sauvigny
- Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany
| | - F Lammert
- Department of Internal Medicine II, University Hospital Homburg, Homburg, Germany
| | - A Lohse
- 1st Department of Medicine, University Hospital Hamburg, Hamburg, Germany
| | - M M Dollinger
- Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany
| | - U Lindig
- Department of Internal Medicine II, University Hospital Jena, Jena, Germany
| | - E M Duerr
- Department of Medicine II, University Hospital Munich, Munich, Germany
| | - N Lubomierski
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany
| | - S Zimmermann
- Department of Internal Medicine II, University Hospital Homburg, Homburg, Germany
| | - D Wachtlin
- Interdisciplinary Center for Clinical Trials of the University Medical Center Mainz, Germany
| | - A-K Kaiser
- Interdisciplinary Center for Clinical Trials of the University Medical Center Mainz, Germany
| | - S Schadmand-Fischer
- Department of Radiology, Johannes Gutenberg-University of Mainz, Mainz, Germany
| | - P R Galle
- Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany
| | - M Woerns
- Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany
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20
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Rasch S, Algül H. A clinical perspective on the role of chronic inflammation in gastrointestinal cancer. Clin Exp Gastroenterol 2014; 7:261-72. [PMID: 25143751 PMCID: PMC4134025 DOI: 10.2147/ceg.s43457] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Chronic inflammation has been identified as an important risk factor for the development of malignancy, and knowledge about its molecular and cellular mechanisms is increasing. Several chronic inflammatory diseases of the gastrointestinal tract are important as risk factors for malignancy and have been studied in detail. In this review, we summarize important molecular mechanisms in chronic inflammation and highlight established and potential links between chronic inflammation and gastrointestinal cancer. In addition, we present the role of chronic inflammation in numerous tumors within the gastrointestinal tract as well as the relevant pathways or epidemiologic observations linking the pathogenesis of these tumors to inflammation.
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Affiliation(s)
- Sebastian Rasch
- II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Hana Algül
- II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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21
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Takahashi H, Ojima H, Shimizu H, Furuse J, Furukawa H, Shibata T. Axitinib (AG-013736), an oral specific VEGFR TKI, shows potential therapeutic utility against cholangiocarcinoma. Jpn J Clin Oncol 2014; 44:570-8. [PMID: 24755544 DOI: 10.1093/jjco/hyu045] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Cholangiocarcinoma is a refractory cancer whose incidence has been increasing worldwide in recent years. Neoangiogenesis plays an important role in the growth of various solid cancers, including cholangiocarcinoma. Vascular endothelial growth factor plays an important role in tumor-induced angiogenesis and its expression is associated with the progression and prognosis of cholangiocarcinoma. This study examined whether axitinib (AG-013736, INLYTA(®)), a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, could be a potentially useful therapeutic agent for cholangiocarcinoma. METHODS We performed expression profiling of angiogenesis-related molecules in eight cholangiocarcinoma cell lines and found that three of them showed high vascular endothelial growth factor expression. Among them, we examined the in vivo anti-tumor effect of axitinib on NCC-BD1 (a gemcitabine-sensitive extra-hepatic cholangiocarcinoma cell line) and TKKK (a gemcitabine-resistant intra-hepatic cholangiocarcinoma cell line) using subcutaneous xenograft models. RESULTS Oral administration of axitinib significantly inhibited the growth of TKKK xenografts at a dose of 6 mg kg(-1) day(-1) (P<0.05), and the growth of NCC-BD1 xenografts at 30 mg kg(-1)day(-1) (P<0.05). Treated tumors showed a significant decrease of microvessel density and the tumor cell proliferation index and a mild but significant increase of the apoptotic index in comparison with untreated tumors. CONCLUSIONS Our results suggest that axitinib should be a promising therapy for vascular endothelial growth factor-expressing cholangiocarcinoma, irrespective of tumor origin and gemcitabine sensitivity.
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Affiliation(s)
- Hiroyuki Takahashi
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo Division of Gastroenterologic and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa
| | - Hidenori Ojima
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo
| | - Hiroko Shimizu
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo
| | - Junji Furuse
- Department of Internal Medicine, Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan
| | - Hiroyuki Furukawa
- Division of Gastroenterologic and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa
| | - Tatsuhiro Shibata
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo
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22
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Zhang J, Han C, Zhu H, Song K, Wu T. miR-101 inhibits cholangiocarcinoma angiogenesis through targeting vascular endothelial growth factor (VEGF). THE AMERICAN JOURNAL OF PATHOLOGY 2014; 182:1629-39. [PMID: 23608225 DOI: 10.1016/j.ajpath.2013.01.045] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Revised: 01/10/2013] [Accepted: 01/24/2013] [Indexed: 12/14/2022]
Abstract
Recent evidence has suggested an important role of miRNAs in liver biology and diseases, although the implication of miRNAs in cholangiocarcinoma remains to be defined further. This study was designed to examine the biological function and molecular mechanism of miR-101 in cholangiocarcinogenesis and tumor progression. In situ hybridization and quantitative RT-PCR were performed to determine the expression of miR-101 in human cholangiocarcinoma tissues and cell lines. Compared with noncancerous biliary epithelial cells, the expression of miR-101 is decreased in 43.5% of human cholangiocarcinoma specimens and in all three cholangiocarcinoma cell lines used in this study. Forced overexpression of miR-101 significantly inhibited cholangiocarcinoma growth in severe combined immunodeficiency mice. miR-101-overexpressed xenograft tumor tissues showed decreased capillary densities and decreased levels of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). The VEGF and COX-2 mRNAs were identified as the bona fide targets of miR-101 in cholangiocarcinoma cells by both computational analysis and experimental assays. miR-101 inhibits cholangiocarcinoma angiogenesis by direct targeting of VEGF mRNA 3'untranslated region and by repression of VEGF gene transcription through inhibition of COX-2. This study established a novel tumor-suppressor role of miR-101 in cholangiocarcinoma and it suggests the possibility of targeting miR-101 and related signaling pathways for future therapy.
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Affiliation(s)
- Jinqiang Zhang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
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23
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Chen CP, Haas-Kogan D. Neoplasms of the hepatobiliary system: clinical presentation, molecular pathways and diagnostics. Expert Rev Mol Diagn 2014; 10:883-95. [DOI: 10.1586/erm.10.76] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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24
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Sia D, Tovar V, Moeini A, Llovet JM. Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies. Oncogene 2013; 32:4861-70. [PMID: 23318457 PMCID: PMC3718868 DOI: 10.1038/onc.2012.617] [Citation(s) in RCA: 182] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Revised: 11/08/2012] [Accepted: 11/15/2012] [Indexed: 02/07/2023]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with very poor prognosis. Genome-wide, high-throughput technologies have made major advances in understanding the molecular basis of this disease, although important mechanisms are still unclear. Recent data have revealed specific genetic mutations (for example, KRAS, IDH1 and IDH2), epigenetic silencing, aberrant signaling pathway activation (for example, interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3), tyrosine kinase receptor-related pathways) and molecular subclasses with unique alterations (for example, proliferation and inflammation subclasses). In addition, some ICCs share common genomic traits with hepatocellular carcinoma. All this information provides the basis to explore novel targeted therapies. Currently, surgery at early stage is the only effective therapy. At more advanced stages, chemotherapy regimens are emerging (that is, cisplatin plus gemcitabine), along with molecular targeted agents tested in several ongoing clinical trials. Nonetheless, a first-line conclusive treatment remains an unmet need. Similarly, there are no studies assessing tumor response related with genetic alterations. This review explores the recent advancements in the knowledge of the molecular alterations underlying ICC and the future prospects in terms of therapeutic strategies leading towards a more personalized treatment of this neoplasm.
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Affiliation(s)
- D Sia
- HCC Translational Research Laboratory, Liver Unit, Barcelona-Clinic Liver Cancer Group, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Catalonia, Spain
- Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Milan, Italy
| | - V Tovar
- HCC Translational Research Laboratory, Liver Unit, Barcelona-Clinic Liver Cancer Group, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Catalonia, Spain
| | - A Moeini
- HCC Translational Research Laboratory, Liver Unit, Barcelona-Clinic Liver Cancer Group, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Catalonia, Spain
| | - JM Llovet
- HCC Translational Research Laboratory, Liver Unit, Barcelona-Clinic Liver Cancer Group, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Catalonia, Spain
- Mount Sinai Liver Cancer Program [Divisions of Liver Diseases], Department of Medicine, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain
- University of Barcelona, Barcelona, Catalonia, Spain
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25
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Wu JW, Li T, Li JJ, Meng YP, Chai XQ. Expression of RASSF1A and Cyclin A2 in intrahepatic cholangiocarcinoma. Shijie Huaren Xiaohua Zazhi 2013; 21:2038-2044. [DOI: 10.11569/wcjd.v21.i21.2038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the expression of RASSF1A and CyclinA2 in intrahepatic cholangiocarcinoma (ICC) and to analyze their relationship with the biological behavior of ICC.
METHODS: Thirty ICC specimens and 18 tumor-adjacent tissue specimens were collected from January 2010 to September 2011 in Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. The expression of RASSF1A and CyclinA2 in these specimens was detected by immunohistochemistry. The relationship between the expression of RASSF1A and CyclinA2 and clinicopathologic parameters of ICC was then analyzed.
RESULTS: The positive rate of expression of RASSF1A in ICC was significantly lower than that in tumor-adjacent tissue (36.67% vs 83.33%, P < 0.05), while the positive rate of expression of Cyclin A2 in ICC was significantly higher than that in tumor-adjacent tissue (73.33% vs 11.11%, P < 0.05). There was a negative correlation between the expression of RASSF1A and that of Cyclin A2 in ICC (P < 0.01, r = 0.54).
CONCLUSION: RASSF1A and CyclinA2 may be involved in the occurrence and development of ICC. Inactivation of RASSF1A may contribute to the invasion and metastasis of ICC. CyclinA2 may play a significant role in the tumor inhibition mechanism mediated by RASSF1A.
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Reappraisal of the therapeutic role of celecoxib in cholangiocarcinoma. PLoS One 2013; 8:e69928. [PMID: 23922859 PMCID: PMC3724720 DOI: 10.1371/journal.pone.0069928] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 06/13/2013] [Indexed: 01/01/2023] Open
Abstract
Cholangiocarcinoma (CCA), a lethal disease, affects many thousands worldwide yearly. Surgical resection provides the best chance for a cure; however, only one-third of CCA patients present with a resectable tumour at the time of diagnosis. Currently, no effective chemotherapy is available for advanced CCA. Cyclooxygenase-2 (COX-2) is a potential oncogene expressing in human CCA tissues and represents a candidate target for treatment; however, COX-2 inhibitors increase the risk of negative cardiovascular events as application for chemoprevention aim. Here, we re-evaluated the effectiveness and safety of celecoxib, one widely used COX-2 inhibitor, in treating CCA. We demonstrated that celecoxib exhibited an anti-proliferative effect on CGCCA cells via cell cycle arrest at G2 phase and apoptosis induction. Treatment for 5 weeks high dose celecoxib (160 mg/kg) significantly repressed thioacetamide-induced CCA tumour growth in rats as monitored by animal positron emission tomography through apoptosis induction. No obviously observable side effects were noted during the therapeutic period. As retrospectively reviewing 78 intrahepatic mass-forming CCA patients, their survival was strongly and negatively associated with a positive resection margin and high COX-2 expression. Based on our result, we concluded that short-term high dose celecoxib may be a promising therapeutic regimen for CCA. Yet its clinical application still needs more studies to prove its safety.
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Yang ZQ, Fan LF. EGFR signaling pathway and targeted therapy for cholangiocarcinoma. Shijie Huaren Xiaohua Zazhi 2013; 21:514-520. [DOI: 10.11569/wcjd.v21.i6.514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma has a poor prognosis and is difficult to detect in early stage. Overexpression of epidermal growth factor receptor (EGFR) plays an important role in the evolution of malignant tumors, and EGFR-targeted therapy has become a hotspot in cancer treatment. Various monoclonal antibodies and small molecule tyrosine kinase inhibitors targeting EGFR have been developed. Currently, there have been only very few reported clinical trials that assessed the efficacy of EGFR-targeted drugs in the management of cholangiocarcinoma. A comprehensive description of the EGFR signaling pathway and EGFR-targeted treatment for cholangiocarcinoma has great significance for the treatment of this malignancy.
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Oishi N, Kumar MR, Roessler S, Ji J, Forgues M, Budhu A, Zhao X, Andersen JB, Ye QH, Jia HL, Qin LX, Yamashita T, Woo HG, Kim YJ, Kaneko S, Tang ZY, Thorgeirsson SS, Wang XW. Transcriptomic profiling reveals hepatic stem-like gene signatures and interplay of miR-200c and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma. Hepatology 2012; 56:1792-803. [PMID: 22707408 PMCID: PMC3458130 DOI: 10.1002/hep.25890] [Citation(s) in RCA: 190] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2011] [Accepted: 05/19/2012] [Indexed: 12/14/2022]
Abstract
UNLABELLED Intrahepatic cholangiocellular carcinoma (ICC) is the second most common type of primary liver cancer. However, its tumor heterogeneity and molecular characteristics are largely unknown. In this study, we conducted transcriptomic profiling of 23 ICC and combined hepatocellular cholangiocarcinoma tumor specimens from Asian patients using Affymetrix messenger RNA (mRNA) and NanoString microRNA microarrays to search for unique gene signatures linked to tumor subtypes and patient prognosis. We validated the signatures in an additional 68 ICC cases derived from Caucasian patients. We found that both mRNA and microRNA expression profiles could independently classify Asian ICC cases into two main subgroups, one of which shared gene expression signatures with previously identified hepatocellular carcinoma (HCC) with stem cell gene expression traits. ICC-specific gene signatures could predict survival in Asian HCC cases and independently in Caucasian ICC cases. Integrative analyses of the ICC-specific mRNA and microRNA expression profiles revealed that a common signaling pathway linking miR-200c signaling to epithelial-mesenchymal transition (EMT) was preferentially activated in ICC with stem cell gene expression traits. Inactivation of miR-200c resulted in an induction of EMT, whereas activation of miR-200c led to a reduction of EMT including a reduced cell migration and invasion in ICC cells. We also found that miR-200c and neural cell adhesion molecule 1 (NCAM1) expression were negatively correlated and their expression levels were predictive of survival in ICC samples. NCAM1, a known hepatic stem/progenitor cell marker, was experimentally demonstrated to be a direct target of miR-200c. CONCLUSION Our results indicate that ICC and HCC share common stem-like molecular characteristics and poor prognosis. We suggest that the specific components of EMT may be exploited as critical biomarkers and clinically relevant therapeutic targets for an aggressive form of stem cell-like ICC.
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Affiliation(s)
- Naoki Oishi
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Mia R. Kumar
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Stephanie Roessler
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Junfang Ji
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Marshonna Forgues
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Anuradha Budhu
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Xuelian Zhao
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jesper B. Andersen
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Qing-Hai Ye
- Liver Cancer Institute, Fudan University, Shanghai, China
| | - Hu-Liang Jia
- Liver Cancer Institute, Fudan University, Shanghai, China
| | - Lun-Xiu Qin
- Liver Cancer Institute, Fudan University, Shanghai, China
| | - Taro Yamashita
- Liver Disease Center and Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan
| | - Hyun Goo Woo
- Department of Physiology, Ajou University School of Medicine, Suwon
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Shuichi Kaneko
- Liver Disease Center and Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan
| | - Zhao-You Tang
- Liver Cancer Institute, Fudan University, Shanghai, China
| | - Snorri S. Thorgeirsson
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA,Address reprint request to: Xin Wei Wang, National Cancer Institute, 37 Convent Drive, Building 37, Room 3044A, Bethesda, MD 20892;
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Zhang J, Han C, Wu T. MicroRNA-26a promotes cholangiocarcinoma growth by activating β-catenin. Gastroenterology 2012; 143:246-56.e8. [PMID: 22484120 PMCID: PMC3668336 DOI: 10.1053/j.gastro.2012.03.045] [Citation(s) in RCA: 148] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 02/18/2012] [Accepted: 03/21/2012] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS MicroRNAs (miRNAs) have been implicated in the development and progression of human cancers. We investigated the roles and mechanisms of miR-26a in human cholangiocarcinoma. METHODS We used in situ hybridization and quantitative reverse transcriptase polymerase chain reaction to measure expression of miR-26a in human cholangiocarcinoma tissues and cell lines (eg, CCLP1, SG231, HuCCT1, TFK1). Human cholangiocarcinoma cell lines were transduced with lentiviruses that expressed miR-26a1 or a scrambled sequence (control); proliferation and colony formation were analyzed. We analyzed growth of human cholangiocarcinoma cells that overexpress miR-26a or its inhibitor in severe combined immune-deficient mice. Immunoblot, immunoprecipitation, DNA pull-down, immunofluorescence, and luciferase reporter assays were used to measure expression and activity of glycogen synthase kinase (GSK)-3β, β-catenin, and related signaling molecules. RESULTS Human cholangiocarcinoma tissues and cell lines had increased levels of miR-26a compared with the noncancerous biliary epithelial cells. Overexpression of miR-26a increased proliferation of cholangiocarcinoma cells and colony formation in vitro, whereas miR-26 depletion reduced these parameters. In severe combined immune-deficient mice, overexpression of miR-26a by cholangiocarcinoma cells increased tumor growth and overexpression of the miR-26a inhibitor reduced it. GSK-3β messenger RNA was identified as a direct target of miR-26a by computational analysis and experimental assays. miR-26a-mediated reduction of GSK-3β resulted in activation of β-catenin and induction of several downstream genes including c-Myc, cyclinD1, and peroxisome proliferator-activated receptor δ. Depletion of β-catenin partially prevented miR-26a-induced tumor cell proliferation and colony formation. CONCLUSIONS miR-26a promotes cholangiocarcinoma growth by inhibition of GSK-3β and subsequent activation of β-catenin. These signaling molecules might be targets for prevention or treatment of cholangiocarcinoma.
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Larbcharoensub N, Sornmayura P, Sirachainan E, Wilasrusmee C, Wanmoung H, Janvilisri T. Prognostic value of ABCG2 in moderately and poorly differentiated intrahepatic cholangiocarcinoma. Histopathology 2012; 59:235-46. [PMID: 21884202 DOI: 10.1111/j.1365-2559.2011.03935.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
AIMS Intrahepatic cholangiocarcinoma (ICC) is a primary hepatic malignancy derived from cholangiocytes. The survival rate of ICC patients is very low, and conventional chemotherapy is not effective in prolonging long-term survival. Adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporters mediate the transport of various substances in several cellular processes. The expression of ABCB1, ABCC1 and ABCG2 has been implicated in multidrug resistance and poor prognosis in several types of cancer. The aim of this study was to examine their expression in normal cholangiocytes and ICC tissues. METHODS AND RESULTS Immunohistochemistry was employed to evaluate the expression of these transporters in 60 cases of ICC with respect to clinicopathological features and patient outcome. The proportions of cases with loss of ABCB1, ABCC1 and ABCG2 expression were 93.3%, 68.3% and 50%, respectively. Only the loss of ABCG2 was related to a worse prognosis (P = 0.031), and was associated with lymph node involvement (P = 0.003) and higher tumour grade (P = 0.028). Furthermore, multivariate analysis showed that the loss of ABCG2 expression was an independent prognostic factor in patients with moderately or poorly differentiated ICC (P = 0.02). CONCLUSIONS These results suggest that ABCG2 may be involved in cholangiocarcinogenesis; the loss of its expression may enhance tumour progression and contribute to aggressive growth of ICC.
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Affiliation(s)
- Noppadol Larbcharoensub
- Department of Pathology Oncology Unit, Faculty of Medicine at Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Goodman ZD, Terracciano LM, Wee A. Tumours and tumour-like lesions of the liver. MACSWEEN'S PATHOLOGY OF THE LIVER 2012:761-851. [DOI: 10.1016/b978-0-7020-3398-8.00014-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Yoon HA, Noh MH, Kim BG, Han JS, Jang JS, Choi SR, Jeong JS, Chun JH. Clinicopathological significance of altered Notch signaling in extrahepatic cholangiocarcinoma and gallbladder carcinoma. World J Gastroenterol 2011; 17:4023-30. [PMID: 22046092 PMCID: PMC3199562 DOI: 10.3748/wjg.v17.i35.4023] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2010] [Revised: 01/11/2011] [Accepted: 01/18/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role and clinicopathological significance of aberrant expression of Notch receptors and Delta-like ligand-4 (DLL4) in extrahepatic cholangiocarcinoma and gallbladder carcinoma.
METHODS: One hundred and ten patients had surgically resected extrahepatic cholangiocarcinoma (CC) and gallbladder carcinoma specimens examined by immunohistochemistry of available paraffin blocks. Immunohistochemistry was performed using anti-Notch receptors 1-4 and anti-DLL4 antibodies. We scored the immunopositivity of Notch receptors and DLL4 expression by percentage of positive tumor cells with cytoplasmic expression and intensity of immunostaining. Coexistent nuclear localization was evaluated. Clinicopathological parameters and survival data were compared with the expression of Notch receptors 1-4 and DLL4.
RESULTS: Notch receptor proteins showed in the cytoplasm with or without nuclear expression in cancer cells, as well as showing weak cytoplasmic expression in non-neoplastic cells. By semiquantitative evaluation, positive immunostaining of Notch receptor 1 was detected in 96 cases (87.3%), Notch receptor 2 in 97 (88.2%), Notch receptor 3 in 97 (88.2%), Notch receptor 4 in 103 (93.6), and DLL4 in 84 (76.4%). In addition, coexistent nuclear localization was noted [Notch receptor 1; 18 cases (18.8%), Notch receptor 2; 40 (41.2%), Notch receptor 3; 32 (33.0%), Notch receptor 4; 99 (96.1%), DLL4; 48 (57.1%)]. Notch receptor 1 expression was correlated with advanced tumor, node, metastasis (TNM) stage (P = 0.043), Notch receptor 3 with advanced T stage (P = 0.017), tendency to express in cases with nodal metastasis (P = 0.065) and advanced TNM stage (P = 0.052). DLL4 expression tended to be related to less histological differentiation (P = 0.095). Coexistent nuclear localization of Notch receptor 3 was related to no nodal metastasis (P = 0.027) and Notch receptor 4 with less histological differentiation (P = 0.036), while DLL4 tended to be related inversely with T stage (P = 0.053). Coexistent nuclear localization of DLL4 was related to poor survival (P = 0.002).
CONCLUSION: Aberrant expression of Notch receptors 1 and 3 play a role during cancer progression, and cytoplasmic nuclear coexistence of DLL4 expression correlates with poor survival in extrahepatic CC and gallbladder carcinoma.
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Charbel H, Al-Kawas FH. Cholangiocarcinoma: epidemiology, risk factors, pathogenesis, and diagnosis. Curr Gastroenterol Rep 2011; 13:182-7. [PMID: 21271364 DOI: 10.1007/s11894-011-0178-8] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Cholangiocarcinoma (CCA) is a rare tumor arising from the epithelium of the intrahepatic or the extrahepatic bile ducts. It is rarely diagnosed before 40 years of age except in patients with primary sclerosing cholangitis. CCA is usually clinically silent until the tumor obstructs the bile ducts. Carbohydrate antigen 19-9 is the most commonly used tumor marker, and magnetic resonance cholangiopancreatography is the best available imaging modality for CCA. Endoscopic retrograde cholangiopancreatography and cholangioscopy allow tissue acquisition. Positron emission tomography may play a role in identifying occult metastases. Tissue diagnosis is obtained by brush cytology or bile duct biopsy.
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Affiliation(s)
- Halim Charbel
- Division of Gastroenterology, Georgetown University Hospital, Second Floor, Main Hospital, M2025, 3800 Reservoir Road NW, Washington, DC 20007, USA.
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Lu D, Han C, Wu T. Microsomal prostaglandin E synthase-1 inhibits PTEN and promotes experimental cholangiocarcinogenesis and tumor progression. Gastroenterology 2011; 140:2084-94. [PMID: 21354147 PMCID: PMC3109169 DOI: 10.1053/j.gastro.2011.02.056] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2010] [Revised: 01/27/2011] [Accepted: 02/06/2011] [Indexed: 01/29/2023]
Abstract
BACKGROUND & AIMS Microsomal prostaglandin E synthase-1 (mPGES-1) is a rate-limiting enzyme that is coupled with cyclooxygenase (COX)-2 in the synthesis of prostaglandin E2. Although COX-2 is involved in the development and progression of various human cancers, the role of mPGES-1 in carcinogenesis has not been determined. We investigated the role of mPGES-1 in human cholangiocarcinoma growth. METHODS We used immunohistochemical analyses to examine the expression of mPGES-1 in formalin-fixed, paraffin-embedded human cholangiocarcinoma tissues. The effects of mPGES-1 on human cholangiocarcinoma cells were determined in vitro and in SCID mice. Immunoblotting and immunoprecipitation assays were performed to determine the levels of PTEN and related signaling molecules in human cholangiocarcinoma cells with overexpression or knockdown of mPGES-1. RESULTS mPGES-1 is overexpressed in human cholangiocarcinoma tissues. Overexpression of mPGES-1 in human cholangiocarcinoma cells increased tumor cell proliferation, migration, invasion, and colony formation; in contrast, RNA interference knockdown of mPGES-1 inhibited tumor growth parameters. In SCID mice with tumor xenografts, mPGES-1 overexpression accelerated tumor formation and increased tumor weight (P<.01), whereas mPGES-1 knockdown delayed tumor formation and reduced tumor weight (P<.01). mPGES-1 inhibited the expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), leading to activation of the epidermal growth factor/phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathways in cholangiocarcinoma cells. mPGES-1-mediated inhibition of PTEN is regulated through blocking of early growth response-1 sumoylation and binding to the 5'-untranslated region of the PTEN gene. CONCLUSIONS mPGES-1 promotes experimental cholangiocarcinogenesis and tumor progression by inhibiting PTEN.
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Affiliation(s)
- Dongdong Lu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, Tongji University School of Life Science and Technology, Shanghai 200092, China
| | - Chang Han
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112
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Hashim AbdAlla MS, Taylor-Robinson SD, Sharif AW, Williams HRT, Crossey MME, Badra GA, Thillainayagam AV, Bansi DS, Thomas HC, Waked IA, Khan SA. Differences in phosphatidylcholine and bile acids in bile from Egyptian and UK patients with and without cholangiocarcinoma. HPB (Oxford) 2011; 13:385-90. [PMID: 21609370 PMCID: PMC3103094 DOI: 10.1111/j.1477-2574.2011.00296.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Cholangiocarcinoma (CC) is a fatal malignancy, the incidence of which is increasing worldwide, with substantial regional variation. Current diagnostic techniques to distinguish benign from malignant biliary disease are unsatisfactory. Metabolic profiling of bile may help to differentiate benign from malignant disease. No previous studies have compared the metabolic profiles of bile from two geographically and racially distinct groups of CC patients. OBJECTIVES This study aimed to compare metabolic profiles of bile, using in vitro proton magnetic resonance spectroscopy, from CC patients from Egypt and the UK, and from patients with CC and patients with non-malignant biliary disease. METHODS A total of 29 bile samples, collected at cholangiography, were analysed using an 11.7-T system. Samples were from eight CC patients in either Egypt (n = 4) or the UK (n = 4) and 21 patients with benign biliary disease (choledocholithiasis [n = 8], sphincter of Oddi dysfunction [n = 8], primary sclerosing cholangitis [n = 5]). RESULTS Bile phosphatidylcholine (PtC) was significantly reduced in CC patients. Egyptian CC patients had significantly lower biliary PtC levels compared with UK patients. Taurine- and glycine-conjugated bile acids (H-26 and H-25 protons, respectively) were significantly elevated in bile from patients with CC compared with bile from patients with benign diseases (P = 0.013 and P < 0.01, respectively). CONCLUSIONS Biliary PtC levels potentially differentiate CC from benign biliary disease. Reduced biliary PtC in Egyptian compared with UK patients may reflect underlying carcinogenic mechanisms.
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Affiliation(s)
- Mohamed S Hashim AbdAlla
- Hepatology and Gastroenterology Section, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College LondonSt Mary's Hospital, London, UK,National Liver Institute, Menoufiya UniversityShebin El Khom, Egypt
| | - Simon D Taylor-Robinson
- Hepatology and Gastroenterology Section, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College LondonSt Mary's Hospital, London, UK
| | - Amar W Sharif
- Hepatology and Gastroenterology Section, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College LondonSt Mary's Hospital, London, UK
| | - Horace R T Williams
- Hepatology and Gastroenterology Section, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College LondonSt Mary's Hospital, London, UK
| | - Mary M E Crossey
- Hepatology and Gastroenterology Section, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College LondonSt Mary's Hospital, London, UK
| | - Gamal A Badra
- National Liver Institute, Menoufiya UniversityShebin El Khom, Egypt
| | - Andrew V Thillainayagam
- Hepatology and Gastroenterology Section, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College LondonSt Mary's Hospital, London, UK
| | - Devinder S Bansi
- Hepatology and Gastroenterology Section, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College LondonSt Mary's Hospital, London, UK
| | - Howard C Thomas
- Hepatology and Gastroenterology Section, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College LondonSt Mary's Hospital, London, UK
| | - Imam A Waked
- National Liver Institute, Menoufiya UniversityShebin El Khom, Egypt
| | - Shahid A Khan
- Hepatology and Gastroenterology Section, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College LondonSt Mary's Hospital, London, UK
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Kumar M, Zhao X, Wang XW. Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine? Cell Biosci 2011. [PMID: 21711594 DOI: 10.1186/2045-3701-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two major forms of primary liver cancers (PLC), accounting for approximately 90% and 5% respectively. The incidence of each is increasing rapidly in the western world, however our knowledge of the underlying mechanisms remains limited and the outcome, dismal. The etiologies of each vary geographically; nevertheless, chronic inflammation has been identified in more than 80% of the cases and appears to be a key mediator in altering the liver microenvironment, increasing the risk of carcinogenesis. However, since not all HCC and especially ICC cases have a recognized risk factor, there are currently two proposed models for liver carcinogenesis. The clonal evolution model demonstrates a multi-step process of tumor development from precancerous lesions to metastatic carcinoma, arising from the accumulation of genetic and epigenetic changes in a cell in the setting of chronic inflammation. While the majority of cases do occur as a consequence of chronic inflammation, most individuals with chronic infection do not develop PLC, suggesting the involvement of individual genetic and environmental factors. Further, since hepatocytes and cholangiocytes both have regenerative potential and arise from the same bi-potential progenitor cell, the more recently proposed cancer stem cell model is gaining its due attention. The integration of these models and the constant improvement in molecular profiling platforms is enabling a broader understanding of the mechanisms underlying these two devastating malignancies, perhaps moving us closer to a new world of molecularly-informed personalized medicine.
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Affiliation(s)
- Mia Kumar
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
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Kumar M, Zhao X, Wang XW. Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine? Cell Biosci 2011; 1:5. [PMID: 21711594 PMCID: PMC3116244 DOI: 10.1186/2045-3701-1-5] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Accepted: 01/24/2011] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two major forms of primary liver cancers (PLC), accounting for approximately 90% and 5% respectively. The incidence of each is increasing rapidly in the western world, however our knowledge of the underlying mechanisms remains limited and the outcome, dismal. The etiologies of each vary geographically; nevertheless, chronic inflammation has been identified in more than 80% of the cases and appears to be a key mediator in altering the liver microenvironment, increasing the risk of carcinogenesis. However, since not all HCC and especially ICC cases have a recognized risk factor, there are currently two proposed models for liver carcinogenesis. The clonal evolution model demonstrates a multi-step process of tumor development from precancerous lesions to metastatic carcinoma, arising from the accumulation of genetic and epigenetic changes in a cell in the setting of chronic inflammation. While the majority of cases do occur as a consequence of chronic inflammation, most individuals with chronic infection do not develop PLC, suggesting the involvement of individual genetic and environmental factors. Further, since hepatocytes and cholangiocytes both have regenerative potential and arise from the same bi-potential progenitor cell, the more recently proposed cancer stem cell model is gaining its due attention. The integration of these models and the constant improvement in molecular profiling platforms is enabling a broader understanding of the mechanisms underlying these two devastating malignancies, perhaps moving us closer to a new world of molecularly-informed personalized medicine.
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Affiliation(s)
- Mia Kumar
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
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Fava G. Molecular mechanisms of cholangiocarcinoma. World J Gastrointest Pathophysiol 2010; 1:12-22. [PMID: 21607138 PMCID: PMC3097940 DOI: 10.4291/wjgp.v1.i1.12] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Revised: 03/28/2010] [Accepted: 04/04/2010] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CC), the malignant tumor of the epithelial cells lining the biliary ducts, has undergone a worldwide increase in incidence and mortality. The malignant transformation of the biliary cells originates from a multistep process evolving through chronic inflammation of the biliary tract to CC. In the last few years several advances have been towards understanding and clarifying the molecular mechanisms implicated in the cholangiocarcinogenesis process. However, many pathophysiologic aspects governing the growth of CC are still undefined. The poor prognosis of this tumor underlines the urgent need to codify the underlying molecular mechanisms involved in the growth and progression of CC in order to design effective preventive measures and valid treatment regimens. This review reports on progresses made in the last few years in clarifying the molecular pathways involved in the process of cholangiocarcinogenesis.
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Poggi G, Amatu A, Montagna B, Quaretti P, Minoia C, Sottani C, Villani L, Tagliaferri B, Sottotetti F, Rossi O, Pozzi E, Zappoli F, Riccardi A, Bernardo G. OEM-TACE: a new therapeutic approach in unresectable intrahepatic cholangiocarcinoma. Cardiovasc Intervent Radiol 2010; 32:1187-92. [PMID: 19727937 DOI: 10.1007/s00270-009-9694-4] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2009] [Accepted: 07/22/2009] [Indexed: 12/30/2022]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a rare life-threatening disease, whose only treatment with potential for cure is surgical resection. However, only 27% of patients at most are suitable for surgery when first diagnosed. For patients with unresectable disease, therapeutic options are chemotherapy or chemoradiation. We evaluated the feasibility and safety of oxaliplatin-eluting microspheres transarterial chemoembolization (OEM-TACE) associated with chemotherapy (ChT) in patients affected by unresectable ICC. Between December 2005 and May 2008 we treated nine patients (six female and three male) with unresectable ICC. All patients had undergone OEM-TACE associated with chemotherapy with oxaliplatin and gemcitabine. A retrospective comparison was carried out with a historical group of 11 patients treated with ChT only, estimating the prevalence of adverse effects and the median survival of the two groups. A total of 30 TACEs were performed during the observational time (ranging from one to seven procedures per patient). OEM-TACEs were followed by few adverse effects (AEs), without G4 AEs, according to CTACAE 3.0. According to RECIST criteria, 44% (4/9) of patients achieved partial responses and 56% (5/9) stabilization of disease. Overall survival analysis in the two groups showed a significantly increased survival in patients treated with ChT and OEM-TACE, with respect to those treated with ChT (30 vs. 12.7 months; p=0.004). In conclusion, in our experience OEM-TACE associated with ChT in the treatment of advanced unresectable ICC is a safe and feasible treatment causing no major adverse events. Although RECIST criteria can underestimate the rate of responses in patients treated with locoregional therapies, we achieved very encouraging results. A randomized multicentric trial is warranted to assess the actual superiority of OEM-TACE associated with ChT compared to conventional chemotherapy.
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Affiliation(s)
- Guido Poggi
- Division of Medical Oncology II, Department of Interventional Radiology, IRCCS S. Maugeri Foundation, Maugeri Street 10, 27100 Pavia, Italy.
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Di Bisceglie AM, Befeler AS. Tumors and Cysts of the Liver. SLEISENGER AND FORDTRAN'S GASTROINTESTINAL AND LIVER DISEASE 2010:1569-1592.e6. [DOI: 10.1016/b978-1-4160-6189-2.00094-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Abbas G, Lindor KD. Cholangiocarcinoma in primary sclerosing cholangitis. J Gastrointest Cancer 2009; 40:19-25. [PMID: 19705300 DOI: 10.1007/s12029-009-9085-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2009] [Accepted: 08/12/2009] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Cholangiocarcinoma (CCA) is an aggressive and nearly always fatal tumor of the biliary tract. PURPOSE This review explores risk factors, epidemiology, current diagnostic approaches, and treatment of CCA arising in patients with primary sclerosing cholangitis (PSC). METHODS We review latest recommendations about screening strategies to enable the early detection of CCA in PSC, using CA 19-9 and ultrasound imaging, as well as fluorescent in situ hybridization techniques to enhance the accuracy of biliary cytology. We also review the emerging role of liver transplantation.
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Affiliation(s)
- Ghulam Abbas
- Division of Gastroenterology and Hepatology, Mayo Clinic, 20 First Street, SW, Rochester, MN 55905, USA
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Sawanyawisuth K, Wongkham C, Pairojkul C, Saeseow OT, Riggins GJ, Araki N, Wongkham S. Methionine aminopeptidase 2 over-expressed in cholangiocarcinoma: potential for drug target. Acta Oncol 2009; 46:378-85. [PMID: 17450475 DOI: 10.1080/02841860600871061] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Methionine aminopeptidases (MetAP) are proteases which remove the N-terminal methionine from newly synthesized proteins. Associations of MetAP2 with tumor progression of different cancers have been repeatedly reported. We aim to determine if MetAP2 is expressed in cholangiocarcinomas (CCA) and investigate to see if it would be a useful therapeutic target. We evaluated MetAP2 expression by immunohistochemistry in 82 patients of intrahepatic CCA. MetAP2 was expressed in bile ducts to various degrees. It was occasionally expressed with weak staining in normal bile duct epithelium but was strikingly over-expressed in dysplastic bile duct epithelia, primary and metastatic CCA tissues (p < 0.001). The increased expression of MetAP2 in proliferating bile duct was evident. All metastatic tumors had stronger expression of MetAP2 than the corresponding primary tumors. Fumagillin, a MetAP2 specific inhibitor, significantly inhibited cell proliferation in dose dependent manner and the degree of growth inhibition was dependent on the amount of cellular enzyme. The present study highlights the involvement of MetAP2 in an early event of carcinogenesis of CCA. The findings represent the first description of increased MetAP2 expression in CCA. The inhibition of enzyme activity using MetAP2 inhibitors may be a potential strategy for long-term control of tumor development and progression in CCA patients.
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Affiliation(s)
- Kanlayanee Sawanyawisuth
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
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Guedj N, Zhan Q, Perigny M, Rautou PE, Degos F, Belghiti J, Farges O, Bedossa P, Paradis V. Comparative protein expression profiles of hilar and peripheral hepatic cholangiocarcinomas. J Hepatol 2009; 51:93-101. [PMID: 19446907 DOI: 10.1016/j.jhep.2009.03.017] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2008] [Revised: 01/23/2009] [Accepted: 03/05/2009] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIMS Hepatic cholangiocarcinomas are tumors with poor prognosis and with increasing incidence worldwide. The aim of the study was to compare morphological features and protein profiles of hilar and peripheral cholangiocarcinomas. METHODS Clinicopathological data were collected from 111 cholangiocarcinomas (59 peripheral and 52 hilar). Protein expression, assessed on tissue samples using tissue microarray and protein array technologies, was compared between both types of tumors and with extrahepatic cholangiocarcinoma and hepatocholangiocarcinoma. RESULTS Hilar cholangiocarcinomas were smaller in size (mean: 2.7 vs. 8 cm, p<0.001), were more often well differentiated adenocarcinomas (65% vs. 36% well differentiated, p<0.01) and carried out stronger perineural invasion (83% vs. 42%, p<0.001) than peripheral cholangiocarcinomas. Regarding protein expression, hilar cholangiocarcinomas more often expressed MUC5AC (62% vs. 22%, p<0.0001), Akt2 (54% vs. 27%, p<0.001), CK8 (98% vs. 81%, p<0.005) and annexin II (92% vs. 66%, p<0.001). Interestingly, VEGF A expression was more frequently encountered in peripheral cholangiocarcinoma (69% vs. 25%, p<0.0001) and correlated with increased vascular density. Using protein array antibody, we identified filamin A as significantly overexpressed (>2-fold) in peripheral cholangiocarcinomas. CONCLUSIONS Our results show that hilar and peripheral cholangiocarcinomas display specific protein profiles, especially regarding VEGF expression. This suggests a potential benefit for anti-angiogenic therapies in peripheral hepatic CCs.
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Affiliation(s)
- Nathalie Guedj
- Department of Pathology, Beaujon Hospital, 100 boulevard du Général Leclerc, 92118 Clichy, France
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Sirica AE, Nathanson MH, Gores GJ, Larusso NF. Pathobiology of biliary epithelia and cholangiocarcinoma: proceedings of the Henry M. and Lillian Stratton Basic Research Single-Topic Conference. Hepatology 2008; 48:2040-6. [PMID: 18855901 PMCID: PMC3724356 DOI: 10.1002/hep.22623] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
In June 2008, the American Association for the Study of Liver Diseases (AASLD) sponsored the Henry M. and Lillian Stratton Basic Research Single-Topic Conference on the Pathobiology of Biliary Epithelia and Cholangiocarcinoma, which was held in Atlanta, GA. Attendees from 12 different countries participated in this conference, making it a truly international scientific event. Both oral and poster presentations were given by multidisciplinary experts, who highlighted important areas of current basic and translational research on biliary epithelial cell biology and pathophysiology, and on the etiology, cellular and molecular pathogenesis, and target-based therapy of cholangiocarcinoma. The specific goals and objectives of the conference were: (1) to advance knowledge of basic and molecular mechanisms underlying developmental and proliferative disorders of the biliary tract; (2) to foster a better and more comprehensive understanding of mechanisms regulating biliary epithelial (cholangiocyte) growth and transport, signaling, cell survival, and abnormalities that result in disease; and (3) to understand basic mechanisms of cholangiocarcinoma development and progression, with the added goal of identifying and exploiting potentially critical molecular pathways that may be targeted therapeutically. A number of interrelated themes emerged from the oral and poster sessions that affected current understandings of the complex organization of transcriptional and signaling mechanisms that regulate bile duct development, hepatic progenitor cell expansion, cholangiocyte secretory functions and proliferation, and mechanisms of cholangiocarcinogenesis and malignant cholangiocyte progression. Most notable were the critical questions raised as to how best to exploit aberrant signaling pathways associated with biliary disease as potential targets for therapy.
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Affiliation(s)
- Alphonse E Sirica
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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Song JS, Lee YJ, Kim KW, Huh J, Jang SJ, Yu E. Cholangiocarcinoma arising in von Meyenburg complexes: report of four cases. Pathol Int 2008; 58:503-12. [PMID: 18705771 DOI: 10.1111/j.1440-1827.2008.02264.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Although von Meyenburg complexes (VMC) are largely considered to be innocuous, neoplastic transformations have been described. The present report describes four cases of cholangiocarcinoma (CC) occurring on a background of VMC. The patients were all male and aged 69, 59, 68 and 75 years, respectively. While two patients were asymptomatic, the other two had a history of colon cancer. Radiologically the tumors measured 3, 4, 4.5 and 10 cm and were well enhanced from the arterial to delayed portal phase. Microscopically, the tumor consisted of multiple foci of characteristic VMC, and had a gradual transition from VMC to hyperplasia or dysplasia and well- to moderately differentiated adenocarcinomas. One patient had combined hepatocellular carcinoma (HCC) and CC, occurring in the high grade dysplastic nodule and VMC. On immunohistochemistry the epithelial cells of the VMC and CC were immunopositive for cytokeratin (CK) 7 in three patients, with another patient being focally positive only for CK19. The Ki-67 labeling indices increased from the VMC to the dysplastic areas and then to the carcinomas. As a potentially precancerous lesion, VMC should be carefully followed up in terms of any size increases. Thus, biopsies are essential to determine any proliferative epithelial changes including dysplasia and malignant transformation.
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Affiliation(s)
- Joon Seon Song
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Korea
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Wise C, Pilanthananond M, Perry BF, Alpini G, McNeal M, Glaser SS. Mechanisms of biliary carcinogenesis and growth. World J Gastroenterol 2008; 14:2986-9. [PMID: 18494047 PMCID: PMC2712163 DOI: 10.3748/wjg.14.2986] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma is a rare cancer originating from the neoplastic transformation of the epithelial cells (i.e. cholangiocytes) that line the biliary tract. The prognosis for patients with cholangiocarcinoma is grim due to lack of viable treatment options. The increase in world-wide incidence and mortality from cholangiocarcinoma highlights the importance of understanding the intracellular mechanisms that trigger the neoplastic transformation of cholangiocytes and the growth of biliary cancers. The purpose of the following review is to address what has been learned over the past decade concerning the molecular basis of cholangiocarcinogenesis. The material presented is divided into two sections: (1) mechanisms regulating neoplastic transformation of cholangiocytes; and (2) factors regulating cholangiocarcinoma growth. An understanding of the growth regulatory mechanisms of cholangiocarcinoma will lead to the identification of therapeutic targets for this devastating cancer.
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Mortensen FV, Jepsen P, Tarone RE, Funch-Jensen P, Jensen LS, Sørensen HT. Endoscopic sphincterotomy and long-term risk of cholangiocarcinoma: a population-based follow-up study. J Natl Cancer Inst 2008; 100:745-50. [PMID: 18477806 DOI: 10.1093/jnci/djn102] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Sphincterotomy of the ampulla of Vater--a common diagnostic and therapeutic procedure that is sometimes done during endoscopic retrograde cholangiography (ERC)--allows reflux of intestinal content into the biliary tree. The resulting inflammation may contribute to malignant transformation of the biliary epithelium and therefore increase the risk of cholangiocarcinoma. We used data from population-based Danish health-care registries to examine the incidence of cholangiocarcinoma after ERC for 10 690 ERC patients who underwent sphincterotomy between 1977 and 2003 and 10,690 ERC patients who did not undergo sphincterotomy. Patients with sphincterotomy were matched to patients without sphincterotomy by sex and age at, calendar year of, and indication for ERC. The cholangiocarcinoma incidence rate for sphincterotomy patients was 404 per 100,000 person-years during the first year after ERC and decreased progressively at later times after ERC (79, 42, and 27 per 100,000 person-years during years 2, 3-5, and > 5, respectively). The corresponding rates for patients without sphincterotomy were 458, 12, 10, and 19 per 100,000 person-years, respectively. The gradual decrease in cholangiocarcinoma rate over time after ERC for sphincterotomy patients indicates that some of these patients had a cholangiocarcinoma that was present at the time of ERC but not diagnosed until 2-5 years later. The similar rates at the latest times after ERC suggest the lack of a causal association between sphincterotomy and cholangiocarcinoma.
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Affiliation(s)
- Frank Viborg Mortensen
- Department of Surgical Gastroenterology L, Aarhus University Hospital, Noerrebrogade 44, 8000 Aarhus C, Denmark.
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Komori J, Marusawa H, Machimoto T, Endo Y, Kinoshita K, Kou T, Haga H, Ikai I, Uemoto S, Chiba T. Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma. Hepatology 2008; 47:888-96. [PMID: 18306229 DOI: 10.1002/hep.22125] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
UNLABELLED Chronic inflammation plays a critical role in oncogenesis in various human organs. Epidemiological studies have demonstrated that patients with primary sclerosing cholangitis have a predisposition to develop cholangiocarcinoma (CC). However, the molecular mechanisms that account for the development of bile duct carcinomas are not well defined. We recently provided evidence that activation-induced cytidine deaminase (AID), a member of the DNA/RNA editing enzyme family, is implicated in human tumorigenesis via its mutagenic activity. We found here that ectopic AID production is induced in response to tumor necrosis factor-alpha (TNF-alpha) stimulation via the IkappaB kinase-dependent nuclear factor-kappaB (NF-kappaB) activation pathway in human cholangiocarcinoma-derived cells. Aberrant expression of AID in biliary cells resulted in the generation of somatic mutations in tumor-related genes, including p53, c-myc, and the promoter region of the INK4A/p16 sequences. In human tissue specimens, real-time reverse transcription polymerase chain reaction (RT-PCR) analyses revealed that AID was increased significantly in 28 of 30 CC tissues (93%), whereas only trace amounts of AID were detected in the normal liver. Immunohistochemistry showed that all of the CC tissue samples examined showed overproduction of endogenous AID protein in cancer cells. Moreover, immunostaining for AID was detectable in 16 of 20 bile epithelia in the tissues underlying primary sclerosing cholangitis. CONCLUSION The proinflammatory cytokine-induced aberrant production of AID might link bile duct inflammation to an enhanced genetic susceptibility to mutagenesis, leading to cholangiocarcinogenesis.
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Affiliation(s)
- Junji Komori
- Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Lim K, Han C, Xu L, Isse K, Demetris AJ, Wu T. Cyclooxygenase-2-derived prostaglandin E2 activates beta-catenin in human cholangiocarcinoma cells: evidence for inhibition of these signaling pathways by omega 3 polyunsaturated fatty acids. Cancer Res 2008; 68:553-60. [PMID: 18199552 DOI: 10.1158/0008-5472.can-07-2295] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cholangiocarcinoma is a highly malignant neoplasm of the biliary tree. It has a high rate of mortality, and currently, there is no effective chemoprevention and treatment. This study was designed to investigate the potential effect of omega 3 polyunsaturated fatty acids (omega 3-PUFA) on human cholangiocarcinoma cell growth and to determine their mechanisms of actions. Treatment of three human cholangiocarcinoma cells (CCLP1, HuCCT1, SG231) with two omega 3-PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), for 12 to 72 h resulted in a dose- and time-dependent inhibition of cell growth; in contrast, arachidonic acid, a omega 6-PUFA, had no significant effect. The omega 3-PUFA effect is due to the induction of apoptosis, given that DHA induced the cleaved form of PARP, caspase-3, and caspase-9. DHA and EPA treatment caused dephosphorylation (and hence, the activation) of glycogen synthase kinase-3beta (GSK-3beta) with a decline of beta-catenin protein. Accordingly, DHA treatment also decreased the beta-catenin-mediated T cell factor/lymphoid enhancer factor (TCF/LEF) reporter activity, and inhibited the expression of c-Met, a beta-catenin-controlled downstream gene implicated in cholangiocarcinogenesis. The GSK-3beta inhibitor, SB216763, partially prevented DHA-induced reduction of beta-catenin protein and TCF/LEF reporter activity, and restored cell growth, suggesting the involvement of GSK-3beta dephosphorylation in omega 3-PUFA-induced beta-catenin degradation. In parallel, DHA treatment also induced the formation of the beta-catenin/Axin/GSK-3beta binding complex, further leading to beta-catenin degradation. Moreover, DHA inhibited the expression of cyclooxygenase-2 (COX-2) and enhanced the expression of 15-hydroxyprostaglandin dehydrogenase, a physiologic COX-2 antagonist, in human cholangiocarcinoma cells. These findings suggest that omega 3-PUFAs block cholangiocarcinoma cell growth at least in part through inhibition of Wnt/beta-catenin and COX-2 signaling pathways. Thus, utilization of omega 3-PUFAs may represent an effective and safe therapeutic approach for the chemoprevention and treatment of human cholangiocarcinoma.
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Affiliation(s)
- Kyu Lim
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
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