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Zhang P, Liu X, Liu Y, Zhu H, Zheng C, Ling Q, Yan F, He Q, Zhu H, Yuan T, Yang B. VCP Promotes Cholangiocarcinoma Development by Mediating BAP1 Ubiquitination-Dependent Degradation. Cancer Sci 2025. [PMID: 40122668 DOI: 10.1111/cas.70061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 03/07/2025] [Accepted: 03/14/2025] [Indexed: 03/25/2025] Open
Abstract
Cholangiocarcinoma (CCA), recognized for its high malignancy, has been an enormous challenge due to lacking effective treatment therapy over the past decades. Recently, the targeted therapies, such as Pemigatinib and Ivosidenib, have provided new treatment options for patients carrying fibroblast growth factor receptor (FGFR) and isocitrate dehydrogenase 1/2 (IDH1/2) mutations, but only ~30% of patients harbor these mutants; it is urgent to explore novel targets and therapeutic therapies. The frequent downregulation of BAP1 has been observed in CCA, and the low expression of BAP1 is closely related to the poor prognosis of CCA. However, there are no effective interventions to re-activate BAP1 protein; blocking its degradation may provide a feasible strategy for BAP1-downregulation CCA treatment. In this study, we demonstrated the tumor-suppressive roles of BAP1 in CCA and identified VCP functions as the key upstream regulator mediated by BAP1 protein homeostasis. Mechanistically, VCP binds to BAP1 and promotes the latter's ubiquitination degradation via the ubiquitin-proteasome pathway, thus promoting cell proliferation and inhibiting cell apoptosis. Moreover, we found that VCP inhibitors inhibited CCA cell growth and promoted cell apoptosis by blocking BAP1 ubiquitination degradation. Collectively, our findings not only provided a novel mechanism underlying the aberrant low expression of BAP1 in CCA but also verified the anti-tumor effect of VCP inhibitors in CCA, offering a novel therapeutic target for CCA treatment.
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Affiliation(s)
- Peiying Zhang
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Xiangning Liu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yue Liu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hongdao Zhu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Churun Zheng
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Qi Ling
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fangjie Yan
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China
| | - Qiaojun He
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hong Zhu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China
| | - Tao Yuan
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China
| | - Bo Yang
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
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Cammarota A, Balsano R, Pressiani T, Bozzarelli S, Rimassa L, Lleo A. The Immune-Genomics of Cholangiocarcinoma: A Biological Footprint to Develop Novel Immunotherapies. Cancers (Basel) 2025; 17:272. [PMID: 39858054 PMCID: PMC11763448 DOI: 10.3390/cancers17020272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/11/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
Cholangiocarcinoma (CCA) represents approximately 3% of all gastrointestinal cancers and is a highly heterogeneous and aggressive malignancy originating from the epithelial cells of the biliary tree. CCA is classified by anatomical location into intrahepatic (iCCA), extrahepatic (eCCA), gallbladder cancer (GBC), and ampullary cancers. Although considered a rare tumor, CCA incidence has risen globally, particularly due to the increased diagnosis of iCCA. Genomic and immune profiling studies have revealed significant heterogeneity within CCA, leading to the identification of molecular subtypes and actionable genetic alterations in 40-60% of cases, particularly in iCCA. Among these, FGFR2 rearrangements or fusions (7-15%) and IDH1 mutations (10-20%) are common in iCCA, while HER2 amplifications/overexpression are more frequent in eCCA and GBC. The tumor-immune microenvironment (TIME) of CCAs plays an active role in the pathogenesis and progression of the disease, creating a complex and plastic environment dominated by immune-suppressive populations. Among these, cancer-associated fibroblasts (CAFs) are a key component of the TIME and are associated with worse survival due to their role in maintaining a poorly immunogenic landscape through the deposition of stiff extracellular matrix and release of pro-tumor soluble factors. Improved understanding of CCA tumor biology has driven the development of novel treatments. Combination therapies of cisplatin and gemcitabine with immune checkpoint inhibitors (ICIs) have replaced the decade-long standard doublet chemotherapy, becoming the new standard of care in patients with advanced CCA. However, the survival improvements remain modest prompting research into more effective ways to target the TIME of CCAs. As key mechanisms of immune evasion in CCA are uncovered, novel immune molecules emerge as potential therapeutic targets. Current studies are exploring strategies targeting multiple immune checkpoints, angiogenesis, and tumor-specific antigens that contribute to immune escape. Additionally, the success of ICIs in advanced CCA has led to interest in their application in earlier stages of the disease, such as in adjuvant and neoadjuvant settings. This review offers a comprehensive overview of the immune biology of CCAs and examines how this knowledge has guided clinical drug development, with a focus on both approved and emergent treatment strategies.
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Affiliation(s)
- Antonella Cammarota
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (R.B.); (L.R.)
| | - Rita Balsano
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (R.B.); (L.R.)
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (T.P.); (S.B.)
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (T.P.); (S.B.)
| | - Silvia Bozzarelli
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (T.P.); (S.B.)
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (R.B.); (L.R.)
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (T.P.); (S.B.)
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (R.B.); (L.R.)
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
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Cantallops Vilà P, Ravichandra A, Agirre Lizaso A, Perugorria MJ, Affò S. Heterogeneity, crosstalk, and targeting of cancer-associated fibroblasts in cholangiocarcinoma. Hepatology 2024; 79:941-958. [PMID: 37018128 DOI: 10.1097/hep.0000000000000206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 11/25/2022] [Indexed: 04/06/2023]
Abstract
Cholangiocarcinoma (CCA) comprises diverse tumors of the biliary tree and is characterized by late diagnosis, short-term survival, and chemoresistance. CCAs are mainly classified according to their anatomical location and include diverse molecular subclasses harboring inter-tumoral and intratumoral heterogeneity. Besides the tumor cell component, CCA is also characterized by a complex and dynamic tumor microenvironment where tumor cells and stromal cells crosstalk in an intricate network of interactions. Cancer-associated fibroblasts, one of the most abundant cell types in the tumor stroma of CCA, are actively involved in cholangiocarcinogenesis by participating in multiple aspects of the disease including extracellular matrix remodeling, immunomodulation, neo-angiogenesis, and metastasis. Despite their overall tumor-promoting role, recent evidence indicates the presence of transcriptional and functional heterogeneous CAF subtypes with tumor-promoting and tumor-restricting properties. To elucidate the complexity and potentials of cancer-associated fibroblasts as therapeutic targets in CCA, this review will discuss the origin of cancer-associated fibroblasts, their heterogeneity, crosstalk, and role during tumorigenesis, providing an overall picture of the present and future perspectives toward cancer-associated fibroblasts targeting CCA.
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Affiliation(s)
| | - Aashreya Ravichandra
- Medical Clinic and Polyclinic II, Klinikum Rechts Der Isar, Technical University Munich, Munich, Germany
| | - Aloña Agirre Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain
- CIBERehd, Institute of Health Carlos III, Madrid, Spain
- Department of Medicine, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Leioa, Spain
| | - Silvia Affò
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
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Chen Z, Kang F, Xie C, Liao C, Li G, Wu Y, Lin H, Zhu S, Hu J, Lin C, Huang Y, Tian Y, Huang L, Wang Z, Chen S. A Novel Trojan Horse Nanotherapy Strategy Targeting the cPKM-STMN1/TGFB1 Axis for Effective Treatment of Intrahepatic Cholangiocarcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2303814. [PMID: 37789644 PMCID: PMC10646249 DOI: 10.1002/advs.202303814] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 08/21/2023] [Indexed: 10/05/2023]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is characterized by its dense fibrotic microenvironment and highly malignant nature, which are associated with chemotherapy resistance and very poor prognosis. Although circRNAs have emerged as important regulators in cancer biology, their role in ICC remains largely unclear. Herein, a circular RNA, cPKM is identified, which is upregulated in ICC and associated with poor prognosis. Silencing cPKM in ICC cells reduces TGFB1 release and stromal fibrosis, inhibits STMN1 expression, and suppresses ICC growth and metastasis, moreover, it also leads to overcoming paclitaxel resistance. This is regulated by the interactions of cPKM with miR-199a-5p or IGF2BP2 and by the ability of cPKM to stabilize STMN1/TGFB1 mRNA. Based on these findings, a Trojan horse nanotherapy strategy with co-loading of siRNA against cPKM (si-cPKM) and paclitaxel (PTX) is developed. The siRNA/PTX co-loaded nanosystem (Trojan horse) efficiently penetrates tumor tissues, releases si-cPKM and paclitaxel (soldiers), promotes paclitaxel sensitization, and suppresses ICC proliferation and metastasis in vivo. Furthermore, it alleviates the fibrosis of ICC tumor stroma and reopens collapsed tumor vessels (opening the gates), thus enhancing the efficacy of the standard chemotherapy regimen (main force). This novel nanotherapy provides a promising new strategy for ICC treatment.
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Affiliation(s)
- Zhi‐Wen Chen
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
| | - Feng‐Ping Kang
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
| | - Cheng‐Ke Xie
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
| | - Cheng‐Yu Liao
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
| | - Ge Li
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary SurgeryFujian Medical University Union HospitalFuzhou350001China
| | - Yong‐Ding Wu
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
| | - Hong‐Yi Lin
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
| | - Shun‐Cang Zhu
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
| | - Jian‐Fei Hu
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
| | - Cai‐Feng Lin
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
- Department of Hepatobiliary SurgeryJinshan Branch of Fujian Provincial HospitalFuzhou350001China
| | - Yi Huang
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
- Center for Experimental Research in Clinical MedicineFujian Provincial HospitalFuzhou350001China
| | - Yi‐Feng Tian
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
- Department of Hepatopancreatobiliary SurgeryFujian Provincial HospitalFuzhou350001China
| | - Long Huang
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
- Department of Hepatopancreatobiliary SurgeryFujian Provincial HospitalFuzhou350001China
| | - Zu‐Wei Wang
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
- Department of Hepatopancreatobiliary SurgeryFujian Provincial HospitalFuzhou350001China
| | - Shi Chen
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
- Department of Hepatopancreatobiliary SurgeryFujian Provincial HospitalFuzhou350001China
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Ohaegbulam KC, Koethe Y, Fung A, Mayo SC, Grossberg AJ, Chen EY, Sharzehi K, Kardosh A, Farsad K, Rocha FG, Thomas CR, Nabavizadeh N. The multidisciplinary management of cholangiocarcinoma. Cancer 2023; 129:184-214. [PMID: 36382577 DOI: 10.1002/cncr.34541] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/11/2022] [Accepted: 10/14/2022] [Indexed: 11/17/2022]
Abstract
Cholangiocarcinoma is a lethal malignancy of the biliary epithelium that can arise anywhere along the biliary tract. Surgical resection confers the greatest likelihood of long-term survivability. However, its insidious onset, difficult diagnostics, and resultant advanced presentation render the majority of patients unresectable, highlighting the importance of early detection with novel biomarkers. Developing liver-directed therapies and emerging targeted therapeutics may offer improved survivability for patients with unresectable or advanced disease. In this article, the authors review the current multidisciplinary standards of care in resectable and unresectable cholangiocarcinoma, with an emphasis on novel biomarkers for early detection and nonsurgical locoregional therapy options.
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Affiliation(s)
- Kim C Ohaegbulam
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Yilun Koethe
- Department of Interventional Radiology, Oregon Health & Science University, Portland, Oregon, USA
| | - Alice Fung
- Department of Diagnostic Radiology, Oregon Health & Science University, Portland, Oregon, USA
| | - Skye C Mayo
- Department of Surgical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Aaron J Grossberg
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Emerson Y Chen
- Division of Hematology/Medical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Kaveh Sharzehi
- Division of Gastroenterology and Hepatology, Oregon Health & Science University, Portland, Oregon, USA
| | - Adel Kardosh
- Division of Hematology/Medical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Khashayar Farsad
- Department of Interventional Radiology, Oregon Health & Science University, Portland, Oregon, USA
| | - Flavio G Rocha
- Department of Surgical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Charles R Thomas
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA.,Department of Radiation Oncology, Dartmouth School of Medicine, Hanover, New Hampshire, USA
| | - Nima Nabavizadeh
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA
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Song F, Lu CL, Wang CG, Hu CW, Zhang Y, Wang TL, Han L, Chen Z. Uncovering the mechanism of Kang-ai injection for treating intrahepatic cholangiocarcinoma based on network pharmacology, molecular docking, and in vitro validation. Front Pharmacol 2023; 14:1129709. [PMID: 36937833 PMCID: PMC10017963 DOI: 10.3389/fphar.2023.1129709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 02/20/2023] [Indexed: 03/06/2023] Open
Abstract
Objective: Kang-ai injection (KAI) has been a popular adjuvant treatment for solid tumors, but its anti-tumor mechanism in intrahepatic cholangiocarcinoma (ICC) remains poorly understood. This study applied a network pharmacology-based approach to unveil KAI's anti-tumor activity, key targets, and potential pharmacological mechanism in ICC by integrating molecular docking and in vitro validation. Methods: The KAI-compound-target-ICC network was constructed to depict the connections between active KAI compounds and ICC-related targets based on the available data sources. The crucial ingredients, potential targets, and signaling pathways were screened using GO, KEGG enrichment analysis, and the PPI network. Molecular docking was performed to visualize the interactions between hub targets and components. In vitro experiments were carried out to validate the findings. Results: Among the 87 active components of KAI and 80 KAI-ICC-related targets, bioinformatics analysis identified quercetin as a possible candidate. GO and KEGG enrichment analysis indicated that the PI3K-AKT signaling pathway might be essential in ICC pharmacotherapy. The PPI network and its sub-networks screened 10 core target genes, including AKT1 and IL1β. Molecular docking results showed stable binding between AKT1 and IL1β with KAI active ingredients. The in vitro experiments confirmed that KAI might suppress the proliferation of ICC cell lines by inhibiting the PI3K/AKT signaling pathway, consistent with the network pharmacology approach and molecular docking predictions. Conclusion: The study sheds light on KAI's biological activity, potential targets, and molecular mechanisms in treating ICC and provides a promising strategy for understanding the scientific basis and therapeutic mechanisms of herbal treatments for ICC. This research has important implications for developing new, targeted therapies for ICC and highlights the importance of network pharmacology-based approaches in investigating complex herbal formulations.
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Affiliation(s)
- Fei Song
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Chang-Liang Lu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Cheng-Gui Wang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Chen-Wei Hu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Yu Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Tian-Lun Wang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Lu Han
- Jiangsu Vocational College of Medicine, Yancheng, China
| | - Zhong Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
- *Correspondence: Zhong Chen,
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Peng H, Zhu E, Zhang Y. Advances of cancer-associated fibroblasts in liver cancer. Biomark Res 2022; 10:59. [PMID: 35971182 PMCID: PMC9380339 DOI: 10.1186/s40364-022-00406-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 08/01/2022] [Indexed: 12/24/2022] Open
Abstract
Liver cancer is one of the most common malignant tumors worldwide, it is ranked sixth in incidence and fourth in mortality. According to the distinct origin of malignant tumor cells, liver cancer is mainly divided into hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Since most cases are diagnosed at an advanced stage, the prognosis of liver cancer is poor. Tumor growth depends on the dynamic interaction of various cellular components in the tumor microenvironment (TME). As the most abundant components of tumor stroma, cancer-associated fibroblasts (CAFs) have been involved in the progression of liver cancer. The interplay between CAFs and tumor cells, immune cells, or vascular endothelial cells in the TME through direct cell-to-cell contact or indirect paracrine interaction, affects the initiation and development of tumors. Additionally, CAFs are not a homogeneous cell population in liver cancer. Recently, single-cell sequencing technology has been used to help better understand the diversity of CAFs in liver cancer. In this review, we mainly update the knowledge of CAFs both in HCC and CCA, including their cell origins, chemoresistance, tumor stemness induction, tumor immune microenvironment formation, and the role of tumor cells on CAFs. Understanding the context-dependent role of different CAFs subsets provides new strategies for precise liver cancer treatment.
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Affiliation(s)
- Hao Peng
- Medical School, Southeast University, Nanjing, 210009, China
| | - Erwei Zhu
- The Second People's Hospital of Lianyungang (The Oncology Hospital of Lianyungang), Lianyungang, 222006, China
| | - Yewei Zhang
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210009, China.
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Deenonpoe R, Sa-Ngiamwibool P, Watcharadetwittaya S, Thanee M, Intuyod K, Kongpan T, Padthaisong S, Nutalai R, Chamgramol Y, Pairojkul C. Fluorescence in situ hybridization detection of chromosome 7 and/or 17 polysomy as a prognostic marker for cholangiocarcinoma. Sci Rep 2022; 12:8441. [PMID: 35589822 PMCID: PMC9119972 DOI: 10.1038/s41598-022-11945-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 05/03/2022] [Indexed: 11/09/2022] Open
Abstract
Cholangiocarcinoma (CCA) is highly endemic in the Northeast Thailand. Recently, chromosome aberrations provided new insights into pathogenesis of CCA. Therefore, chromosome aberration might be used as a prognostic factor and therapeutic planning of this cancer. This aim of this study is to examine the correlation between an increase of chromosome 7 (C7) and/or 17 (C17) copy number variants (CNVs) with clinicopathological data and the overall survival time (OS) of CCA patients using fluorescence in situ hybridization (FISH) assays. C7 and C17 CNVs were examined using FISH form 157 formalin-fixed paraffin-embedded (FFPE) tissues of CCA patients from Khon Kaen, Thailand between 2011 and 2015. OS was visualized using Kaplan-Meier plot. Univariate and multivariate analyses were used to determine the ability of the clinicopathological parameters to predict OS. C17 > trisomy (odd ratio, 6.944, P < 0.001), C7/17 trisomy (odd ratio; 4.488, P = 0.019), and C7/17 > trisomy (odd ratio; 6.723, P < 0.001) were independently predictive factors for lymph node metastasis. Interestingly, an increase of C7, C17, and C7/17 CNVs in both trisomy and > trisomy was independently correlated with short median OS. An increased of C7 and/or 17 have a potential as a poor prognostic marker in CCA patients.
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Affiliation(s)
- Raksawan Deenonpoe
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand. .,Cholangiocarcinoma Research Institute (CARI), Khon Kaen University, Khon Kaen, Thailand.
| | - Prakasit Sa-Ngiamwibool
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute (CARI), Khon Kaen University, Khon Kaen, Thailand
| | - Sasithorn Watcharadetwittaya
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute (CARI), Khon Kaen University, Khon Kaen, Thailand
| | - Malinee Thanee
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute (CARI), Khon Kaen University, Khon Kaen, Thailand
| | - Kitti Intuyod
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand
| | - Thachanan Kongpan
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand
| | - Sureerat Padthaisong
- Faculty of Allied Health Sciences, Burapha University, Chonburi, 20131, Thailand
| | - Rungtiwa Nutalai
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand.,Nuffield Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Yaovalux Chamgramol
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand
| | - Chawalit Pairojkul
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand
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9
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Chang YC, Li CH, Chan MH, Chen MH, Yeh CN, Hsiao M. Regorafenib inhibits epithelial-mesenchymal transition and suppresses cholangiocarcinoma metastasis via YAP1-AREG axis. Cell Death Dis 2022; 13:391. [PMID: 35449153 PMCID: PMC9023529 DOI: 10.1038/s41419-022-04816-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 03/24/2022] [Accepted: 03/31/2022] [Indexed: 12/22/2022]
Abstract
Cholangiocarcinoma (CCA) is a subtype of bile duct cancer usually diagnosed late with a low survival rate and no satisfactorily systemic treatment. Recently, regorafenib has been accepted as a second-line treatment for CCA patients. In this study, we investigated the potential signal transduction pathways mediated by regorafenib. We established a transcriptomic database for regorafenib-treated CCA cells using expression microarray chips. Our data indicate that regorafenib inhibits yes-associated protein 1 (YAP1) activity in various CCA cells. In addition, we demonstrated that YAP1 regulates epithelial-mesenchymal transition (EMT)-related genes, including E-cadherin and SNAI2. We further examined YAP1 activity, phosphorylation status, and expression levels of YAP1 downstream target genes in the regorafenib model. We found that regorafenib dramatically suppressed these events in CCA cells. Moreover, in vivo results revealed that regorafenib could significantly inhibit lung foci formation and tumorigenicity. Most importantly, regorafenib and amphiregulin (AREG) neutralize antibody exhibited synergistic effects against CCA cells. In a clinical setting, patients with high YAP1 and EMT expression had a worse survival rate than patients with low YAP1, and EMT expression did. In addition, we found that YAP1 upregulated the downstream target amphiregulin in CCA. Our findings suggest that AREG neutralizing antibody antibodies combined with regorafenib can reverse the CCA metastatic phenotype and EMT in vitro and in vivo. These findings provide novel therapeutic strategies to combat the metastasis of CCA.
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10
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Matricellular proteins in intrahepatic cholangiocarcinoma. Adv Cancer Res 2022; 156:249-281. [DOI: 10.1016/bs.acr.2022.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Ravichandra A, Bhattacharjee S, Affò S. Cancer-associated fibroblasts in intrahepatic cholangiocarcinoma progression and therapeutic resistance. Adv Cancer Res 2022; 156:201-226. [DOI: 10.1016/bs.acr.2022.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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12
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Brindley PJ, Bachini M, Ilyas SI, Khan SA, Loukas A, Sirica AE, Teh BT, Wongkham S, Gores GJ. Cholangiocarcinoma. Nat Rev Dis Primers 2021; 7:65. [PMID: 34504109 PMCID: PMC9246479 DOI: 10.1038/s41572-021-00300-2] [Citation(s) in RCA: 411] [Impact Index Per Article: 102.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/03/2021] [Indexed: 02/08/2023]
Abstract
Cholangiocarcinoma (CCA) is a highly lethal adenocarcinoma of the hepatobiliary system, which can be classified as intrahepatic, perihilar and distal. Each anatomic subtype has distinct genetic aberrations, clinical presentations and therapeutic approaches. In endemic regions, liver fluke infection is associated with CCA, owing to the oncogenic effect of the associated chronic biliary tract inflammation. In other regions, CCA can be associated with chronic biliary tract inflammation owing to choledocholithiasis, cholelithiasis, or primary sclerosing cholangitis, but most CCAs have no identifiable cause. Administration of the anthelmintic drug praziquantel decreases the risk of CCA from liver flukes, but reinfection is common and future vaccination strategies may be more effective. Some patients with CCA are eligible for potentially curative surgical options, such as resection or liver transplantation. Genetic studies have provided new insights into the pathogenesis of CCA, and two aberrations that drive the pathogenesis of non-fluke-associated intrahepatic CCA, fibroblast growth factor receptor 2 fusions and isocitrate dehydrogenase gain-of-function mutations, can be therapeutically targeted. CCA is a highly desmoplastic cancer and targeting the tumour immune microenvironment might be a promising therapeutic approach. CCA remains a highly lethal disease and further scientific and clinical insights are needed to improve patient outcomes.
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Affiliation(s)
- Paul J. Brindley
- Department of Microbiology, Immunology & Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA
| | | | - Sumera I. Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Shahid A. Khan
- Liver Unit, Division of Digestive Diseases, Imperial College London, London, UK
| | - Alex Loukas
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia
| | - Alphonse E. Sirica
- Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Bin Tean Teh
- Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre, Singapore, Singapore
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA,
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13
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Rojas-Pintor KP, Arizmendi-Villarreal MA, Aparicio-Salas JE, Moreno-Peña DP, Hernández-Barajas D, Cordero-Pérez P, Muñoz-Espinosa LE. Differences in the presentation and treatment of primary liver tumors at a hepatology center and an oncology center. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2021; 86:370-377. [PMID: 34384724 DOI: 10.1016/j.rgmxen.2021.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 08/05/2020] [Indexed: 10/20/2022]
Abstract
INTRODUCTION AND AIMS Primary liver cancer is a public health problem in Mexico and the world. Liver transplantation (LT) is the ideal treatment for early hepatocellular carcinoma (HCC). Our aim was to evaluate the characteristics of patients with HCC and cholangiocarcinoma (CC) at two centers and identify transplantation candidates. MATERIALS AND METHODS A retrospective observational study was conducted at the Hepatology Center (HC) and the University Center Against Cancer (UCAC), within the time frame of 2012-2018. HCC or intrahepatic CC was confirmed in 109 patients. Staging classifications, transplant selection models, and a predictive model for post-LT recurrence were applied to the HCC patients. RESULTS Of the total population, 93% (n=102) presented with cirrhosis, 86% (n=94) had HCC (HC: 58%, UCAC: 42%), and 14% (n=15) had intrahepatic CC (HC: 40%, UCAC: 60%). Of the HC patients with HCC, Okuda I-II, BCLC A-B, and AFP levels <100ng/m predominated, whereas Okuda II-III, BCLC C-D, and AFP levels >1000ng/mL predominated in the UCAC patients. Half of the HC population with HCC met the criteria for LT, in contrast to 23% of the UCAC patients. Fifteen patients were evaluated for LT, and at present, six have undergone transplantation. CONCLUSIONS The most frequent primary liver tumor was HCC. Patients from the HC presented with earlier-stage disease and a high number of them met the criteria for LT. Only patients from the HC underwent transplantation.
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Affiliation(s)
- K P Rojas-Pintor
- Centro de Hepatología, Medicina Interna, Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - M A Arizmendi-Villarreal
- Centro de Hepatología, Medicina Interna, Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - J E Aparicio-Salas
- Centro de Hepatología, Medicina Interna, Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - D P Moreno-Peña
- Centro de Hepatología, Medicina Interna, Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - D Hernández-Barajas
- Centro Universitario Contra el Cáncer, Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - P Cordero-Pérez
- Centro de Hepatología, Medicina Interna, Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - L E Muñoz-Espinosa
- Centro de Hepatología, Medicina Interna, Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey, Mexico.
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14
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Li H, Li J, Xiao W, Zhang Y, Lv Y, Yu X, Zheng J. The Therapeutic Potential of Galectin-3 in the Treatment of Intrahepatic Cholangiocarcinoma Patients and Those Compromised With COVID-19. Front Mol Biosci 2021; 8:666054. [PMID: 34109213 PMCID: PMC8180910 DOI: 10.3389/fmolb.2021.666054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 05/07/2021] [Indexed: 11/13/2022] Open
Abstract
The novel coronavirus pneumonia COVID-19 is characterized by all age susceptibility, which imposes a dramatic threat to the human species all over the world. According to current available data, the cytokine storm appears to be the most life-threatening symptom of severe COVID-19 cases accompanied with lung fibrosis. Galectin-3 (Gal-3), a member of soluble β-galactoside-binding lectin families, has been implicated as a key regulator in various inflammation conditions in addition to its well-documented roles in cancer. The pro-inflammatory activity of Gal-3 in the inflammatory response and lung fibrosis of COVID-19 has been proposed by emerging studies, which suggested that inhibition of Gal-3 may represent a novel treatment approach for COVID-19 patients. Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with poor prognosis. ICC accounts for 10-25% of primary liver cancers with limited therapeutic options, which has higher incidence in Asian countries, particularly in China. Cancer patients, including ICC patients, are highly vulnerable to COVID-19 due to their impaired immune system. It is thus undoubtedly a challenge for our oncology department to establish effective treatment strategies under the influence of the COVID-19 crisis. According to our management procedures in the COVID-19 era, emergency treatment will be applied to ICC patients who are under life-threatening conditions, despite the COVID-19 infection. To the best of our knowledge, the modulatory function of Gal-3 in ICC is still barely explored to date. In order to evaluate the therapeutic potential of Gal-3 for ICC patients or those comprised with COVID-19, we herein report our preliminary investigation into roles of Gal-3 in ICC. Our results exhibited that the expression of Gal-3 was significantly up-regulated in ICC tissues, and a significant correlation was observed between its overexpression and malignant progression of ICC cells. We further discussed the activity and possible molecular mechanisms of Gal-3 in ICC, which may pave the ways for further exploring the possibility of Gal-3 as a potential therapeutic target for treating ICC patients or those with COVID-19-related conditions.
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Affiliation(s)
- Hao Li
- Biliary Tract Surgery Laboratory, Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, China.,Hunan Research Center of Biliary Disease, the First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Jianmin Li
- Department of Pulmonary and Critical Care Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Wei Xiao
- Department of Medical Administration, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Yujing Zhang
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Yuan Lv
- The Key Laboratory of Molecular Epidemiology in Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Xing Yu
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Jiao Zheng
- Department of Drug Clinical Trial, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
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15
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Lin J, Cao Y, Yang X, Li G, Shi Y, Wang D, Long J, Song Y, Mao J, Xie F, Bai Y, Zhang L, Yang X, Wan X, Wang A, Guan M, Zhao L, Hu K, Pan J, Huo L, Lu X, Mao Y, Sang X, Zhang H, Wang K, Wang X, Zhao H. Mutational spectrum and precision oncology for biliary tract carcinoma. Theranostics 2021; 11:4585-4598. [PMID: 33754015 PMCID: PMC7978308 DOI: 10.7150/thno.56539] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 02/18/2021] [Indexed: 12/20/2022] Open
Abstract
Background: The genomic spectrum of biliary tract carcinoma (BTC) has been characterized and is associated with distinct anatomic and etiologic subtypes, yet limited studies have linked genomic alterations with personalized therapies in BTC patients. Methods: This study analyzed 803 patients with BTC:164 with gallbladder cancer, 475 with intrahepatic cholangiocarcinoma (ICC) and 164 with extrahepatic cholangiocarcinoma. We determined genomic alterations, mutational signatures related to etiology and histopathology and prognostic biomarkers. Personalized targeted therapies for patients harboring potentially actionable targets (PATs) were investigated. Results: The median tumor mutation burden (TMB) was 1.23 Mut/Mb, with 4.1% of patients having hypermutated BTCs. Unlike the results obtained from the Western population, the most frequently altered cancer-related genes in our cohort included TP53 (53%), KRAS (26%), ARID1A (18%), LRP1B (14%) and CDKN2A (14%). Germline mutations occurred mostly in DNA damage repair genes. Notably, 35.8% of the ICCs harbored aristolochic acid related signatures and an elevated TMB. TP53 and KRAS mutations and amplified 7q31.2 were demonstrated to negatively affect patient prognosis. Moreover, 19 genes were proposed to be PATs in BTCs, with 25.4% of patients harboring these PATs. Forty-six patients received PAT-matched targeted therapies, achieving a 26.1% objective response rate; the median progression-free survival (PFS) was 5.0 months, with 56.8% of patients obtaining PFS benefits. Conclusions: Extensive genomic diversity and heterogeneity were observed among BTC patients, with contributions according to potential etiology exposures, anatomical subtypes and clinicopathological characteristics. We also demonstrated that patients with refractory BTCs who have PATs can derive considerable benefit from receiving a matched therapy, initiating further prospective clinical trials guided by molecular profiling among this aggressive cancer.
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Affiliation(s)
- Jianzhen Lin
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University; Pancreas Institute, Nanjing Medical University, Nanjing 210000, China
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Yinghao Cao
- Institute of Basic Medical Sciences (IBMS), Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing 100730, China
| | - Xu Yang
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Guangyu Li
- Institute of Basic Medical Sciences (IBMS), Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing 100730, China
| | - Yang Shi
- School of Mathematical Sciences, Peking University, Beijing 100871, China
| | - Dongxu Wang
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Junyu Long
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Yang Song
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Jinzhu Mao
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Fucun Xie
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Yi Bai
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Lei Zhang
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Xiaobo Yang
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Xueshuai Wan
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Anqiang Wang
- Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Mei Guan
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Lin Zhao
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Ke Hu
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Jie Pan
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Li Huo
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Xin Lu
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Yilei Mao
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Xinting Sang
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
| | - Henghui Zhang
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing; Genecast Precision Medicine Technology Institute, Beijing 100089, China
| | - Kai Wang
- OrigiMed Co. Ltd, Shanghai 201114, China
| | - Xiaoyue Wang
- Institute of Basic Medical Sciences (IBMS), Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing 100730, China
| | - Haitao Zhao
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China
- Multidisciplinary Molecular Tumor Board of Hepatobiliary Tumors (Departments of Liver Surgery, Medical Oncology, Radiology, Radiotherapy and Nuclear Medicine), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing, China
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16
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Rojas-Pintor KP, Arizmendi-Villarreal MA, Aparicio-Salas JE, Moreno-Peña DP, Hernández-Barajas D, Cordero-Pérez P, Muñoz-Espinosa LE. Differences in the presentation and treatment of primary liver tumors at a hepatology center and an oncology center. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2021; 86:S0375-0906(21)00002-1. [PMID: 33676785 DOI: 10.1016/j.rgmx.2020.08.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 07/30/2020] [Accepted: 08/05/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION AND AIMS Primary liver cancer is a public health problem in Mexico and the world. Liver transplantation (LT) is the ideal treatment for early hepatocellular carcinoma (HCC). Our aim was to evaluate the characteristics of patients with HCC and cholangiocarcinoma (CC) at two centers and identify transplantation candidates. MATERIALS AND METHODS A retrospective observational study was conducted at the Hepatology Center (HC) and the University Center Against Cancer (UCAC), within the time frame of 2012-2018. HCC or intrahepatic CC was confirmed in 109 patients. Staging classifications, transplant selection models, and a predictive model for post-LT recurrence were applied to the HCC patients. RESULTS Of the total population, 93% (n = 102) presented with cirrhosis, 86% (n = 94) had HCC (HC: 58%, UCAC: 42%), and 14% (n = 15) had intrahepatic CC (HC: 40%, UCAC: 60%). Of the HC patients with HCC, Okuda I-II, BCLC A-B, and AFP levels < 100 ng/m predominated, whereas Okuda II-III, BCLC C-D, and AFP levels > 1,000 ng/mL predominated in the UCAC patients. Half of the HC population with HCC met the criteria for LT, in contrast to 23% of the UCAC patients. Fifteen patients were evaluated for LT, and at present, six have undergone transplantation. CONCLUSIONS The most frequent primary liver tumor was HCC. Patients from the HC presented with earlier-stage disease and a high number of them met the criteria for LT. Only patients from the HC underwent transplantation.
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Affiliation(s)
- K P Rojas-Pintor
- Centro de Hepatología, Medicina Interna, Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey, México
| | - M A Arizmendi-Villarreal
- Centro de Hepatología, Medicina Interna, Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey, México
| | - J E Aparicio-Salas
- Centro de Hepatología, Medicina Interna, Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey, México
| | - D P Moreno-Peña
- Centro de Hepatología, Medicina Interna, Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey, México
| | - D Hernández-Barajas
- Centro Universitario Contra el Cáncer, Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey, México
| | - P Cordero-Pérez
- Centro de Hepatología, Medicina Interna, Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey, México
| | - L E Muñoz-Espinosa
- Centro de Hepatología, Medicina Interna, Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey, México.
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17
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Sirica AE, Strazzabosco M, Cadamuro M. Intrahepatic cholangiocarcinoma: Morpho-molecular pathology, tumor reactive microenvironment, and malignant progression. Adv Cancer Res 2020; 149:321-387. [PMID: 33579427 PMCID: PMC8800451 DOI: 10.1016/bs.acr.2020.10.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a relatively rare, but highly lethal and biologically complex primary biliary epithelial cancer arising within liver. After hepatocellular carcinoma, iCCA is the second most common primary liver cancer, accounting for approximately 10-20% of all primary hepatic malignancies. Over the last 10-20 years, iCCA has become the focus of increasing concern largely due to its rising incidence and high mortality rates in various parts of the world, including the United States. The challenges posed by iCCA are daunting and despite recent progress in the standard of care and management options for iCCA, the prognosis for this cancer continues to be dismal. In an effort to provide a framework for advancing our understanding of iCCA malignant aggressiveness and therapy resistance, this review will highlight key etiological, biological, molecular, and microenvironmental factors hindering more effective management of this hepatobiliary cancer. Particular focus will be on critically reviewing the cell origins and morpho-molecular heterogeneity of iCCAs, providing mechanistic insights into high risk fibroinflammatory cholangiopathies associated with iCCA development, and notably discussing the deleterious role played by the tumor reactive desmoplastic stroma in regulating iCCA malignant progression, lymphangiogenesis, and tumor immunobiology.
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Affiliation(s)
- Alphonse E Sirica
- Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA, United States.
| | - Mario Strazzabosco
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States
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18
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Chen C, Zhang R, Ma L, Li Q, Zhao YL, Zhang GJ, Zhang D, Li WZ, Cao S, Wang L, Geng ZM. Neuropilin-1 is up-regulated by cancer-associated fibroblast-secreted IL-8 and associated with cell proliferation of gallbladder cancer. J Cell Mol Med 2020; 24:12608-12618. [PMID: 32951327 PMCID: PMC7686964 DOI: 10.1111/jcmm.15825] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 07/22/2020] [Accepted: 08/13/2020] [Indexed: 01/04/2023] Open
Abstract
We previously demonstrated that cancer‐associated fibroblasts (CAFs) promoted the proliferation of gallbladder cancer (GBC) cells, but the mechanism is not clear. Neuropilin‐1 (NRP‐1) plays an important role in various malignancies as transmembrane glycoprotein. Our goal was to reveal the relationship between CAFs and NRP‐1 and their potential functions in GBC. In this study, we found NRP‐1 was overexpressed in GBC tissue, associated with poor survival and was up‐regulated by CAFs. The cytokine array cluster analysis revealed IL‐8 secreted by CAFs facilitated the up‐regulation of NRP‐1 in tumour cells. NRP‐1 knockdown suppressed tumour growth in vivo. Gene expression microarray analysis showed 581 differentially regulated genes under NRP‐1 knockdown conditions. Ingenuity pathway analysis demonstrated that NRP‐1 knockdown may inhibit tumour progression by affecting cell proliferation. We then confirmed that NRP‐1 knockdown in NOZ and GBC‐SD cells significantly inhibited cell proliferation. Additionally, the IL‐8 mediated MDM2 and CCNA2 expression were affected by NRP‐1 knockdown. Our findings suggested that NRP‐1 was up‐regulated by CAF‐secreted IL‐8, which subsequently promoted GBC cell proliferation, and these molecules may serve as useful prognostic biomarkers and therapeutic targets for GBC.
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Affiliation(s)
- Chen Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Rui Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Li Ma
- Department of Emergency, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Qi Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Ya-Ling Zhao
- Department of of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University, Health Science Center, Xi'an, Shaanxi Province, China
| | - Guan-Jun Zhang
- Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Dong Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Wen-Zhi Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Sheng Cao
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Lin Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Zhi-Min Geng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
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19
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Wappler J, Arts M, Röth A, Heeren RMA, Peter Neumann U, Olde Damink SW, Soons Z, Cramer T. Glutamine deprivation counteracts hypoxia-induced chemoresistance. Neoplasia 2019; 22:22-32. [PMID: 31765939 PMCID: PMC6883317 DOI: 10.1016/j.neo.2019.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 10/12/2019] [Accepted: 10/14/2019] [Indexed: 12/29/2022] Open
Abstract
The microenvironment of solid tumors is a key determinant of therapy efficacy. The co-occurrence of oxygen and nutrient deprivation is a common phenomenon of the tumor microenvironment and associated with treatment resistance. Cholangiocarcinoma (CCA) is characterized by a very poor prognosis and pronounced chemoresistance. A better understanding of the underlying molecular mechanisms is urgently needed to improve therapy strategies against CCA. We sought to investigate the importance of the conditionally essential amino acid glutamine, a centrally important nutrient for a variety of solid tumors, for CCA. Glutamine levels were strongly decreased in CCA samples and the growth of established human CCA cell lines was highly dependent on glutamine. Using gradual reduction of external glutamine, we generated derivatives of CCA cell lines which were able to grow without external glutamine (termed glutamine-depleted (GD)). To analyze the effects of coincident oxygen and glutamine deprivation, GD cells were treated with cisplatin or gemcitabine under normoxia and hypoxia. Strikingly, the well-established phenomenon of hypoxia-induced chemoresistance was completely reversed in GD cells. In order to better understand the underlying mechanisms, we focused on the oncogene c-Myc. The combination of cisplatin and hypoxia led to sustained c-Myc protein expression in wildtype cells. In contrast, c-Myc expression was reduced in response to the combinatorial treatment in GD cells, suggesting a functional importance of c-Myc in the process of hypoxia-induced chemoresistance. In summary, these findings indicate that the mechanisms driving adaption to tumor microenvironmental changes and their relevance for the response to therapy are more complex than expected.
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Affiliation(s)
- Jessica Wappler
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany
| | - Martijn Arts
- Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Anjali Röth
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany; ESCAM - European Surgery Center Aachen Maastricht, Aachen, Germany; ESCAM - European Surgery Center Aachen Maastricht, Maastricht, the Netherlands
| | - Ron M A Heeren
- The Maastricht MultiModal Molecular Imaging Institute (M4I), Division of Imaging Mass Spectrometry, Maastricht University, Maastricht, the Netherlands
| | - Ulf Peter Neumann
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany; Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands; ESCAM - European Surgery Center Aachen Maastricht, Aachen, Germany; ESCAM - European Surgery Center Aachen Maastricht, Maastricht, the Netherlands
| | - Steven W Olde Damink
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany; Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands; ESCAM - European Surgery Center Aachen Maastricht, Aachen, Germany; ESCAM - European Surgery Center Aachen Maastricht, Maastricht, the Netherlands; NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Zita Soons
- Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands; NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Thorsten Cramer
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany; Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands; ESCAM - European Surgery Center Aachen Maastricht, Aachen, Germany; ESCAM - European Surgery Center Aachen Maastricht, Maastricht, the Netherlands; NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.
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20
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Liu S, Jiang J, Huang L, Jiang Y, Yu N, Liu X, Lv Y, Li H, Zou L, Peng C, Yu X, Jiang B. iNOS is associated with tumorigenicity as an independent prognosticator in human intrahepatic cholangiocarcinoma. Cancer Manag Res 2019; 11:8005-8022. [PMID: 31692584 PMCID: PMC6716572 DOI: 10.2147/cmar.s208773] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 07/12/2019] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Inducible nitric oxide synthase (iNOS) has supposed to implicate in inflammation, infection, liver cirrhosis, and neoplastic diseases. This study was designed to explore the biological and clinical function of iNOS in intrahepatic cholangiocarcinoma (ICC). METHODS RT-PCR (Real-time quantitative PCR) and immunohistochemical staining were used to analyze the expression of iNOS in ICC and adjacent tissues. CCK8, transwell assays, flow cytometry were conducted to detect the proliferation, apoptosis, cell cycle. Western blotting was performed to detect the expression of target proteins. Multivariate analyses were conducted to analysis associates between clinicopathological values and survival. RESULTS We found that levels of iNOS mRNA and protein were dramatically increased in ICC samples and positively correlated with complicated bile duct stone, differentiation, pathology T, pathology M, Wip1, MMP-2, and MMP-9. iNOS expression was significantly correlated with the poor survival of ICC patients. Furthermore, iNOS was high expression in ICC cell lines (QBC-939, ICC-9810, SSP-25) compare with human normal biliary epithelium cell line (HIBEpic); both iNOS knockdown and iNOS inhibitor (1400 W) suppressed cell proliferation, invasion, and migration though nitric oxide production in ICC cells. Down-regulation of iNOS also induced G0/G1 cell cycle arrest and ICC cell apoptosis. Moreover, iNOS knockdown treatment significantly decreased Wip1, MMP-9, and MMP-2 gene expression. CONCLUSION Lowly expressed iNOS-inhibited proliferation yet promoted apoptosis of ICC cells. Our data show targeted inhibition of iNOS in ICC may have therapeutic value.
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Affiliation(s)
- Sulai Liu
- Department of Hepatobiliary Surgery, Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, People's Republic of China
| | - Jinqiong Jiang
- Department of Oncology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, People’s Republic of China
| | - Linsheng Huang
- Department of Hepatopancreatobiliary Surgery, Taihe Hospital, Hubei University of Medicine, Wuhan, Hubei, People’s Republic of China
| | - Yu Jiang
- Hunan Provincial Institute of Emergency Medicine, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, People’s Republic of China
| | - Nanhui Yu
- Hunan Provincial Institute of Emergency Medicine, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, People’s Republic of China
| | - Xiehong Liu
- Hunan Provincial Institute of Emergency Medicine, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, People’s Republic of China
| | - Yuan Lv
- Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, People’s Republic of China
| | - Hao Li
- Department of Hepatobiliary Surgery, Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, People's Republic of China
| | - Lianhong Zou
- Hunan Provincial Institute of Emergency Medicine, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, People’s Republic of China
| | - Chuang Peng
- Department of Hepatobiliary Surgery, Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, People's Republic of China
| | - Xing Yu
- School of Medicine, Hunan Normal University, Changsha, People’s Republic of China
- Institute for Glycomics, Griffith University, Southport, Queensland, Australia
| | - Bo Jiang
- Department of Hepatobiliary Surgery, Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, People's Republic of China
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21
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Ma KW, Cheung TT, She WH, Chok KSH, Chan ACY, Dai WC, Chiu WH, Lo CM. Diagnostic and Prognostic Role of 18-FDG PET/CT in the Management of Resectable Biliary Tract Cancer. World J Surg 2018; 42:823-834. [PMID: 28905105 DOI: 10.1007/s00268-017-4192-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Role of 18-FDG PET/CT had been well established in other more prevalent malignancies such as colorectal and lung cancer; however, this is not as well defined in cholangiocarcinoma. Literature focusing on the prognostic values of preoperative PET/CT for resectable cholangiocarcinoma is scarce. METHOD This is a retrospective cohort of 66 consecutive patients who had received curative resection for cholangiocarcinoma from 2010 to 2015. All patients had preoperative 18-FDG PET/CT performed. Accuracy of metastatic lymph node detection of PET/CT and the prognostic value of maximum standard uptake value (SUV-max) was explored. RESULTS There were 38 male and 28 female recruited, and the median age was 66. Intrahepatic cholangiocarcinoma (ICC) constituted the majority (59.1%) of the cases, followed by hilar cholangiocarcinoma (22.8%), gallbladder cancer (13.6%) and common bile duct cancer (4.5%). The 3-year disease-free survival (DFS) and overall survival (OS) of the whole population were 27.1 and 39.2%, respectively. The median follow-up duration was 27 months. The accuracy of PET/CT in metastatic lymph node detection was 72.7% (P = 0.005, 95% CI 0.583-0.871) and 81.8% (P = 0.011, 95% CI 0.635-0.990) in whole population and ICC subgroup analysis, respectively. SUV-max was shown by multivariate analysis to be an independent factor for DFS (P = 0.007 OR 1.16, 95% CI 1.04-1.29) and OS (P = 0.012 OR 1.145, 95% CI 1.030-1.273) after resection. SUV-max of 8 was shown to be a discriminant cut-off for poor oncological outcomes in patients with early cholangiocarcinoma (TNM stage I or II) after curative resection (3-year DFS: 21.2 vs. 63.2%, P = 0.004, and 3-year OS: 29 vs. 74% P = 0.048, respectively). CONCLUSION PET/CT is a reliable imaging modality for metastatic lymph node detection in cholangiocarcinoma. Tumour SUV-max is an independent factor for oncological outcomes in patients with resectable disease. For patients who have TNM stage I or II cholangiocarcinoma, tumour SUV-max over 8 is associated with significantly inferior disease-free and overall survival even after curative resection.
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Affiliation(s)
- Ka Wing Ma
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China
| | - Tan To Cheung
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China.
| | - Wong Hoi She
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China
| | - Kenneth Siu Ho Chok
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China
| | - Albert Chi Yan Chan
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China
| | - Wing Chiu Dai
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China
| | - Wan Hang Chiu
- Department of Radiology, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China
| | - Chung Mau Lo
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China.,State Key Laboratory for Liver Research, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China
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22
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Chang PMH, Cheng CT, Wu RC, Chung YH, Chiang KC, Yeh TS, Liu CY, Chen MH, Chen MH, Yeh CN. Nab-paclitaxel is effective against intrahepatic cholangiocarcinoma via disruption of desmoplastic stroma. Oncol Lett 2018; 16:566-572. [PMID: 29963132 DOI: 10.3892/ol.2018.8690] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 02/02/2018] [Indexed: 12/18/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (IH-CCA) is the second predominant hepatic malignancy worldwide. However, effective treatment strategies for IH-CCA have not yet been developed. Nab-paclitaxel may be an effective drug against IH-CCA, a type of desmoid-like tumor, and its antitumor effects may be attributable to its ability to disrupt the cancer-associated fibroblasts. In the present study, MTT and Annexin-V apoptosis detection kits were used to evaluate the efficacy of paclitaxel and nab-paclitaxel against human cholangiocarcinoma KKU-100 and KKU-213 cell lines. A rat model of thioacetamide-induced spontaneous desmoplastic IH-CCA was used to compare the treatment response of four different drug regimens: Control, paclitaxel, nab-paclitaxel and gemcitabine/oxaliplatin. Positron emission tomography and immunofluorescence analysis were used to measure the tumor volume and to study the resected tumor, respectively. In vitro, paclitaxel and nab-paclitaxel induced anti-proliferative effects in KKU-100 and KKU-M213 cells. With regards to the treatment regimes, only nab-paclitaxel and gemcitabine/oxaliplatin induced antitumor effects in the rat model of thioacetamide-induced IH-CCA. The immunofluorescence study indicated that nab-paclitaxel was more efficient in disrupting cancer-associated fibroblasts than paclitaxel. In conclusion, nab-paclitaxel is effective against IH-CCA owing to its ability to markedly disrupt the desmoplastic stroma.
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Affiliation(s)
- Peter Mu-Hsin Chang
- Department of Oncology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei 112, Taiwan, R.O.C.,School of Medicine, National Yang-Ming University, Taipei 112, Taiwan, R.O.C
| | - Chi-Tung Cheng
- Department of Surgery and Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, R.O.C
| | - Ren-Chin Wu
- Department of Pathology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, R.O.C
| | - Yi-Hsiu Chung
- Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, R.O.C
| | - Kun-Chun Chiang
- Department of Surgery and Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, R.O.C
| | - Ta-Sen Yeh
- Department of Surgery and Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, R.O.C
| | - Chun-Yu Liu
- Department of Oncology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei 112, Taiwan, R.O.C.,School of Medicine, National Yang-Ming University, Taipei 112, Taiwan, R.O.C
| | - Ming-Han Chen
- School of Medicine, National Yang-Ming University, Taipei 112, Taiwan, R.O.C
| | - Ming-Huang Chen
- Department of Oncology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei 112, Taiwan, R.O.C.,School of Medicine, National Yang-Ming University, Taipei 112, Taiwan, R.O.C
| | - Chun-Nan Yeh
- Department of Surgery and Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, R.O.C
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23
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Bai JG, Tang RF, Shang JF, Qi S, Yu GD, Sun C. Upregulation of long non‑coding RNA CCAT2 indicates a poor prognosis and promotes proliferation and metastasis in intrahepatic cholangiocarcinoma. Mol Med Rep 2018; 17:5328-5335. [PMID: 29393466 DOI: 10.3892/mmr.2018.8518] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 11/02/2017] [Indexed: 11/06/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (IHCC) is an aggressive cancer with a poor survival rate and is the second most common type of primary cancer of the hepatobiliary system. At present, the molecular mechanisms of IHCC initiation and progression remain unclear. Recent evidence has indicated that long non‑coding RNAs (lncRNAs) serve a crucial role in cancer development; however, the functional role of lncRNAs in IHCC has not been investigated in detail. In the present study, a marked overexpression of lncRNA colon cancer‑associated transcript 2 (CCAT2) was observed in IHCC cell lines and clinical specimens. Statistical analysis of IHCC clinicopathological characteristics and CCAT2 expression data revealed that high CCAT2 expression levels correlated with microvascular invasion, differentiation grade, tumor (T), lymph node (N), metastasis (M) and overall TNM stages of IHCC (P<0.05). Kaplan‑Meier analysis demonstrated that CCAT2 upregulation was associated with poor overall survival and progression‑free survival in IHCC. Furthermore, high CCAT2 expression was identified as an independent risk factor of IHCC poor prognosis in both univariate and multivariate Cox regression analyses. The role of CCAT2 in promoting IHCC cell proliferation, motility and invasion was further confirmed with in vitro assays. Therefore, CCAT2 may promote IHCC progression and metastasis, and may be a promising prognostic biomarker and therapeutic target in IHCC.
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Affiliation(s)
- Jian-Guo Bai
- Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Rui-Feng Tang
- Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Jun-Feng Shang
- Department of General Surgery, The People's Hospital of Daming, Handan, Hebei 056900, P.R. China
| | - Shuai Qi
- Second Department of Surgery, The People's Hospital of Luancheng, Shijiazhuang, Hebei 051430, P.R. China
| | - Guo-Dong Yu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Chao Sun
- Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
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24
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Utaijaratrasmi P, Vaeteewoottacharn K, Tsunematsu T, Jamjantra P, Wongkham S, Pairojkul C, Khuntikeo N, Ishimaru N, Sirivatanauksorn Y, Pongpaibul A, Thuwajit P, Thuwajit C, Kudo Y. The microRNA-15a-PAI-2 axis in cholangiocarcinoma-associated fibroblasts promotes migration of cancer cells. Mol Cancer 2018; 17:10. [PMID: 29347950 PMCID: PMC5773154 DOI: 10.1186/s12943-018-0760-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 01/04/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA) has an abundance of tumor stroma which plays an important role in cancer progression via tumor-promoting signals. This study aims to explore the microRNA (miRNA) profile of CCA-associated fibroblasts (CCFs) and the roles of any identified miRNAs in CCA progression. METHODS miRNA expression profiles of CCFs and normal skin fibroblasts were compared by microarray. Identified downregulated miRNAs and their target genes were confirmed by real-time PCR. Their binding was confirmed by a luciferase reporter assay. The effects of conditioned-media (CM) of miRNA mimic- and antagonist-transfected CCFs were tested in CCA migration in wound healing assays. Finally, the levels of miRNA and their target genes were examined by real-time PCR and immunohistochemistry in clinical CCA samples. RESULTS miR-15a was identified as a downregulated miRNA in CCFs. Moreover, PAI-2 was identified as a novel target gene of miR-15a. Recombinant PAI-2 promoted migration of CCA cells. Moreover, CM from miR-15a mimic-transfected CCFs suppressed migration of CCA cells. Lower expression of miR-15a and higher expression of PAI-2 were observed in human CCA samples compared with normal liver tissues. Importantly, PAI-2 expression correlated with poor prognosis in CCA patients. CONCLUSIONS These findings highlight the miR-15a/PAI-2 axis as a potential therapeutic target in CCA patients.
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Affiliation(s)
- Penkhae Utaijaratrasmi
- Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kulthida Vaeteewoottacharn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Takaaki Tsunematsu
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Pranisa Jamjantra
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Chawalit Pairojkul
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Narong Khuntikeo
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Naozumi Ishimaru
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Yongyut Sirivatanauksorn
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Ananya Pongpaibul
- Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Peti Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Chanitra Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
| | - Yasusei Kudo
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.
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25
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Xia XL, Xue D, Xiang TH, Xu HY, Song DK, Cheng PG, Wang JQ. Overexpression of long non-coding RNA CRNDE facilitates epithelial-mesenchymal transition and correlates with poor prognosis in intrahepatic cholangiocarcinoma. Oncol Lett 2018; 15:4105-4112. [PMID: 29556285 PMCID: PMC5844116 DOI: 10.3892/ol.2018.7815] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 09/20/2017] [Indexed: 01/01/2023] Open
Abstract
The clinical significance and essential role of long non-coding RNA colorectal neoplasia differentially expressed (lncRNA CRNDE) have been well illuminated in various cancers. However, the function of CRNDE in intrahepatic cholangiocarcinoma (IHCC) has not been reported at present. The aim of the present study was to investigate the role of CRNDE in IHCC. Firstly, the relative expression of CRNDE was observed to be upregulated in IHCC cell lines and tissues. And high CRNDE expression was statistically associated with IHCC differentiation grade, lymph node metastasis, tumor-nodes-metastasis (TNM) stage and size. Survival analysis identified that high CRNDE expression is a predictor of worse overall survival (OS) and progression-free survival (PFS) in patients with IHCC. Moreover, high CRNDE expression was identified as an independent risk factor of IHCC poor OS and PFS. Further studies of in vitro assays suggested that CRNDE silencing could suppress the proliferation of HuCCT1 cells following CCK-8 and colony formation assays, while CRNDE ectopic expression in HCCC9810 cells promoted proliferation. Moreover, the migration and invasion of HuCCT1 cells were greatly repressed with CRNDE deficiency following Transwell and Matrigel assays. Accordingly, the motility of HCCC9810 cells was notably accelerated with CRNDE overexpression. Mechanistically, CRNDE was revealed to facilitate the epithelial-mesenchymal transition (EMT) of IHCC cells. In conclusion, these observations indicated that CRNDE could promote the clinical progression and metastasis of IHCC by facilitating EMT. CRNDE may be a novel prognostic marker and therapeutic target in IHCC.
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Affiliation(s)
- Xiu-Liang Xia
- Department of General Surgery, The People's Hospital of Binzhou, Binzhou, Shandong 256610, P.R. China
| | - Dong Xue
- Department of General Surgery, The People's Hospital of Binzhou, Binzhou, Shandong 256610, P.R. China
| | - Ting-Hai Xiang
- Department of General Surgery, The People's Hospital of Binzhou, Binzhou, Shandong 256610, P.R. China
| | - Huai-Yong Xu
- Department of General Surgery, The People's Hospital of Binzhou, Binzhou, Shandong 256610, P.R. China
| | - De-Kun Song
- Department of General Surgery, The People's Hospital of Binzhou, Binzhou, Shandong 256610, P.R. China
| | - Pei-Guang Cheng
- Department of General Surgery, The People's Hospital of Binzhou, Binzhou, Shandong 256610, P.R. China
| | - Jian-Qiang Wang
- Department of General Surgery, The People's Hospital of Binzhou, Binzhou, Shandong 256610, P.R. China
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26
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Manzanares MÁ, Campbell DJW, Maldonado GT, Sirica AE. Overexpression of periostin and distinct mesothelin forms predict malignant progression in a rat cholangiocarcinoma model. Hepatol Commun 2017; 2:155-172. [PMID: 29404524 PMCID: PMC5796331 DOI: 10.1002/hep4.1131] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 11/14/2017] [Accepted: 11/14/2017] [Indexed: 12/27/2022] Open
Abstract
Periostin and mesothelin have each been suggested to be predictors of poor survival for patients with intrahepatic cholangiocarcinoma, although the clinical prognostic value of both of these biomarkers remains uncertain. The aim of the current study was to investigate these biomarkers for their potential to act as tumor progression factors when assessed in orthotopic tumor and three-dimensional culture models of rat cholangiocarcinoma progression. Using our orthotopic model, we demonstrated a strong positive correlation between tumor and serum periostin and mesothelin and increasing liver tumor mass and associated peritoneal metastases that also reflected differences in cholangiocarcinoma cell aggressiveness and malignant grade. Periostin immunostaining was most prominent in the desmoplastic stroma of larger sized more aggressive liver tumors and peritoneal metastases. In comparison, mesothelin was more highly expressed in the cholangiocarcinoma cells; the slower growing more highly differentiated liver tumors exhibited a luminal cancer cell surface immunostaining for this biomarker, and the rapidly growing less differentiated liver and metastatic tumor masses largely showed cytoplasmic mesothelin immunoreactivity. Two molecular weight forms of mesothelin were identified, one at ∼40 kDa and the other, a more heavily glycosylated form, at ∼50 kDa. Increased expression of the 40-kDa mesothelin over that of the 50 kDa form predicted increased malignant progression in both the orthotopic liver tumors and in cholangiocarcinoma cells of different malignant potential in three-dimensional culture. Moreover, coculturing of cancer-associated myofibroblasts with cholangiocarcinoma cells promoted overexpression of the 40-kDa mesothelin, which correlated with enhanced malignant progression in vitro. Conclusion: Periostin and mesothelin are useful predictors of tumor progression in our rat desmoplastic cholangiocarcinoma models. This supports their relevance to human intrahepatic cholangiocarcinoma. (Hepatology Communications 2018;2:155-172).
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Affiliation(s)
- Miguel Á Manzanares
- Division of Cellular and Molecular Pathogenesis, Department of Pathology Virginia Commonwealth University School of Medicine Richmond VA
| | - Deanna J W Campbell
- Division of Cellular and Molecular Pathogenesis, Department of Pathology Virginia Commonwealth University School of Medicine Richmond VA
| | - Gabrielle T Maldonado
- Division of Cellular and Molecular Pathogenesis, Department of Pathology Virginia Commonwealth University School of Medicine Richmond VA
| | - Alphonse E Sirica
- Division of Cellular and Molecular Pathogenesis, Department of Pathology Virginia Commonwealth University School of Medicine Richmond VA
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Kovalenko YA, Zharikov YO. [Portal cholangiocarcinoma: epidemiology, staging principles and aspects of tumor biology]. Khirurgiia (Mosk) 2017:85-91. [PMID: 29186104 DOI: 10.17116/hirurgia20171185-91] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
| | - Yu O Zharikov
- A.V. Vishnevsky Institute of Surgery, Moscow, Russia
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Kwon H, Song K, Han C, Zhang J, Lu L, Chen W, Wu T. Epigenetic Silencing of miRNA-34a in Human Cholangiocarcinoma via EZH2 and DNA Methylation: Impact on Regulation of Notch Pathway. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:2288-2299. [PMID: 28923203 DOI: 10.1016/j.ajpath.2017.06.014] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 06/19/2017] [Indexed: 12/12/2022]
Abstract
Aberrant expression and regulation of miRNAs have been implicated in multiple stages of tumorigenic processes. The current study was designed to explore the biological function and epigenetic regulation of miR-34a in human cholangiocarcinoma (CCA). Our data show that the expression of miR-34a is decreased significantly in CCA cells compared with non-neoplastic biliary epithelial cells. Forced overexpression of miR-34a in CCA cells inhibited their proliferation and clonogenic capacity in vitro, and suppressed tumor xenograft growth in severe combined immunodeficiency mice. We identified three key components of the Notch pathway, Notch1, Notch2, and Jagged 1, as direct targets of miR-34a. Our further studies show that down-regulation of miR-34a is caused by Enhancer of zeste homolog 2 (EZH2)-mediated H3 lysine 27 trimethylation as well as DNA methylation. Accordingly, treatment with the EZH2 inhibitor, selective S-adenosyl-methionine-competitive small-molecule (GSK126), or the DNA methylation inhibitor, 5-Aza-2'-deoxycytidine, partially restored miR-34a levels in human CCA cells. Immunohistochemical staining and Western blot analyses showed increased EZH2 expression in human CCA tissues and cell lines. We observed that GSK126 significantly reduced CCA cell growth in vitro and intrahepatic metastasis in vivo. Our findings provide novel evidence that miR-34a expression is silenced epigenetically by EZH2 and DNA methylation, which promotes CCA cell growth through activation of the Notch pathway. Consequently, these signaling cascades may represent potential therapeutic targets for effective treatment of human CCA.
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Affiliation(s)
- Hyunjoo Kwon
- 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
| | - Chang Han
- 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
| | - Lu Lu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Weina Chen
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
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29
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He J, Chen X, Li B, Zhou W, Xiao J, He K, Zhang J, Xiang G. Chaetocin induces cell cycle arrest and apoptosis by regulating the ROS-mediated ASK-1/JNK signaling pathways. Oncol Rep 2017; 38:2489-2497. [PMID: 28849240 DOI: 10.3892/or.2017.5921] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Accepted: 08/07/2017] [Indexed: 12/11/2022] Open
Abstract
The present study demonstrated that chaetocin, a natural small-molecule product produced by Chaetomium fungal species and a potential anticancer agent, inhibited the viability and invasive ability of the human intrahepatic cholangio-carcinoma cell line CCLP-1 in vivo and in vitro as revealed by CCK-8 and Transwell invasion assays and mouse xenograft tumor experiments. As determined using flow cytometry and intracellular ROS assays, chaetocin was found to induce cell cycle arrest and oxidative stress, leading to CCLP-1 cell apoptosis. Cell apoptosis can be initiated via different apoptotic signaling pathways under oxidative stress. As determined by western blot analysis, expression levels of the apoptosis signal-regulating kinase 1 (ASK-1) signalosome and its downstream c-Jun N-terminal kinase (JNK) signaling pathway were increased under oxidative stress stimulation. These findings indicate that chaetocin arrests the cell cycle and induces apoptosis by regulating the reactive oxygen species-mediated ASK-1/JNK signaling pathways.
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Affiliation(s)
- Jingliang He
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Xiaoxun Chen
- Department of Gastrointestinal Surgery, The Guigang City People's Hospital, Guigang, Guangxi 537100, P.R. China
| | - Bowei Li
- The Third Clinical Medical College of Southern Medical University, Guangzhou, Guangdong 510317, P.R. China
| | - Wenjie Zhou
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Jinfeng Xiao
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Ke He
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Jinqian Zhang
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Guoan Xiang
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
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Chinchilla-López P, Aguilar-Olivos N, García-Gómez J, Hernández-Alejandro K, Chablé-Montero F, Motola-Kuba D, Patel T, Méndez-Sánchez N. Prevalence, Risk Factors, and Survival of Patients with Intrahepatic Cholangiocarcinoma. Ann Hepatol 2017; 16:565-568. [PMID: 28611259 DOI: 10.5604/01.3001.0010.0293] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
PURPOSE To investigate the prevalence, related risk factors, and survival of intrahepatic cholangiocarcinoma in a Mexican population. MATERIAL AND METHODS We conducted a cross-sectional study at Medica Sur Hospital in Mexico City with approval of the local research ethics committee. We found cases by reviewing all clinical records of in-patients between October 2005 and January 2016 who had been diagnosed with malignant liver tumors. Clinical characteristics and comorbidities were obtained to evaluate the probable risk factors and the Charlson index. The cases were staged based on the TNM staging system for bile duct tumors used by the American Joint Committee on Cancer and median patient survival rates were calculated using the Kaplan-Meier method. RESULTS We reviewed 233 cases of hepatic cancer. Amongst these, hepatocellular carcinomas represented 19.3% (n = 45), followed by intrahepatic cholangiocarcinomas, which accounted for 7.7% (n = 18). The median age of patients with intrahepatic cholangiocarcinoma was 63 years, and most of them presented with cholestasis and intrahepatic biliary ductal dilation. Unfortunately, 89% (n = 16) of them were in an advanced stage and 80% had multicentric tumors. Median survival was 286 days among patients with advanced stage tumors (25th-75th interquartile range, 174-645 days). No correlation was found between the presence of comorbidities defined by the Charlson index, and survival. We evaluated the presence of definite and probable risk factors for the development of intrahepatic cholangiocarcinoma, that is, smoking, alcohol consumption, and primary sclerosing cholangitis. DISCUSSION We found an overall prevalence of intrahepatic cholangiocarcinoma of 7.7%; unfortunately, these patients were diagnosed at advanced stages. Smoking and primary sclerosing cholangitis were the positive risk factors for its development in this population.
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Affiliation(s)
| | | | - Jaime García-Gómez
- Department of Radiology. Medica Sur Clinic & Foundation, Mexico City, Mexico
| | | | | | - Daniel Motola-Kuba
- Department of Oncology. Medica Sur Clinic & Foundation, Mexico City, Mexico
| | - Tushar Patel
- Department of Transplantation and Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
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Liu S, Jiang B, Li H, He Z, Lv P, Peng C, Wang Y, Cheng W, Xu Z, Chen W, Liu Z, Zhang B, Shen S, Xiang S. Wip1 is associated with tumorigenity and metastasis through MMP-2 in human intrahepatic cholangiocarcinoma. Oncotarget 2017; 8:56672-56683. [PMID: 28915621 PMCID: PMC5593592 DOI: 10.18632/oncotarget.18074] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Accepted: 04/26/2017] [Indexed: 12/21/2022] Open
Abstract
Wip1 has been shown to correlate with the metastasis/invasion of several tumors. This study was designed to investigate the clinical significance and biological function of Wip1 in intrahepatic cholangiocarcinoma (ICC). The expression of Wip1 was investigated in sixty human ICC biopsy samples by immunohistochemistry. Transient and stable knockdown of Wip1 in two human ICC cells (ICC-9810 and SSP25) were established using short hairpin RNA expression vector. Immunohistochemistry revealed that Wip1 was up-regulated in human ICC tissues (47/60, 78.3%). High levels of Wip1 in human ICC correlated with metastasis to the lymph metastasis (P=0.022). Genetic depletion of Wip1 in ICC cells resulted in significantly inhibited proliferation and invasion compared with controls. Most importantly, Wip1 down-regulation impaired tumor migration capacity of ICC cells in vivo. Subsequent investigations revealed that matrix metalloproteinase-2 (MMP-2) is an important target of Wip1. Consistently, in human ICC tissues, Wip1 level was positively correlated with MMP-2 expression. Taken together, our founding indicates that Wip1 may be a crucial regulator in the tumorigenicity and invasion of human ICC, Wip1 exerts its pro-invasion function at least in part through the MMP-2 signaling pathway, suggesting Wip1 as a potential therapeutic target for ICC.
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Affiliation(s)
- Sulai Liu
- Department of Hepatobiliary Surgery/Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, People's Republic of China
| | - Bo Jiang
- Department of Hepatobiliary Surgery/Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, People's Republic of China
| | - Hao Li
- Department of Hepatobiliary Surgery/Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, People's Republic of China
| | - Zili He
- Department of Hepatobiliary Surgery/Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, People's Republic of China
| | - Pin Lv
- Department of Hepatobiliary Surgery/Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, People's Republic of China
| | - Chuang Peng
- Department of Hepatobiliary Surgery/Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, People's Republic of China
| | - Yonggang Wang
- Department of Hepatobiliary Surgery/Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, People's Republic of China
| | - Wei Cheng
- Department of Hepatobiliary Surgery/Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, People's Republic of China
| | - Zhengquan Xu
- Department of Orthopaedics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China
| | - Wei Chen
- Department of Thoracic, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People's Republic of China
| | - Zhengkai Liu
- Department of Hepatobiliary Surgery/Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, People's Republic of China
| | - Bao Zhang
- Department of Hepatobiliary Surgery/Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, People's Republic of China
| | - Shengqian Shen
- Department of Hepatobiliary Surgery/Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, People's Republic of China
| | - Shuanglin Xiang
- Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, Hunan Province, People's Republic of China
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Zhang XF, Dong M, Pan YH, Chen JN, Huang XQ, Jin Y, Shao CK. Expression pattern of cancer-associated fibroblast and its clinical relevance in intrahepatic cholangiocarcinoma. Hum Pathol 2017; 65:92-100. [PMID: 28457731 DOI: 10.1016/j.humpath.2017.04.014] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 03/31/2017] [Accepted: 04/19/2017] [Indexed: 12/28/2022]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and lack of effective treatment, characterized by dense desmoplastic stroma rich in cancer-associated fibroblasts (CAFs), which have been indicated to facilitate tumor progression in several types of human cancer. However, the clinical relevance of CAFs in ICC has not been fully characterized. Here, we evaluated the histological phenotype of CAFs and immunohistochemical expressions of α-SMA, FSP-1, and PDGFRβ in 71 ICC cases, and found that immature CAF phenotype was significantly associated with lymph node metastasis (P=.045), advanced TNM stage (P=.025) and poor 5-year overall survival (OS) (38.5% versus 78.6%, P=.015). In addition, α-SMA, FSP-1, and PDGFRβ were positively expressed in stromal fibroblasts in 63.4% (45/71), 84.5% (60/71), and 78.9% (56/71) of patients, respectively. Positive expression of α-SMA was correlated with poor differentiation (P=.032); FSP-1 expression in stromal fibroblasts was linked with lymph node metastasis (P=.022) and immature phenotype (P=.048). What's more, positive expression of FSP-1 in cancer cells was observed in 22.5% (16/71) of cases and was correlated with worse 5-year OS (36.4% versus 76.7%, P=.014). Importantly, in multivariate analysis, histological CAF phenotype was an independent prognostic factor for OS in ICC. Our findings demonstrated histological categorization of CAFs was a useful predictor for prognosis, providing new evidence that CAFs play a crucial role in tumor progression and can serve as potential therapeutic targets in ICC.
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Affiliation(s)
- Xiao-Fang Zhang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Min Dong
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China; Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yu-Hang Pan
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Jian-Ning Chen
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Xiang-Qi Huang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Yi Jin
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Chun-Kui Shao
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
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Manzanares MÁ, Usui A, Campbell DJ, Dumur CI, Maldonado GT, Fausther M, Dranoff JA, Sirica AE. Transforming Growth Factors α and β Are Essential for Modeling Cholangiocarcinoma Desmoplasia and Progression in a Three-Dimensional Organotypic Culture Model. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:1068-1092. [PMID: 28315313 DOI: 10.1016/j.ajpath.2017.01.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 12/19/2016] [Accepted: 01/17/2017] [Indexed: 12/12/2022]
Abstract
To gain insight into the cellular and molecular interactions mediating the desmoplastic reaction and aggressive malignancy of mass-forming intrahepatic cholangiocarcinoma (ICC), we modeled ICC desmoplasia and progression in vitro. A unique three-dimensional (3D) organotypic culture model was established; within a dilute collagen-type I hydrogel, a novel clonal strain of rat cancer-associated myofibroblasts (TDFSM) was co-cultured with a pure rat cholangiocarcinoma cell strain (TDECC) derived from the same ICC type as TDFSM. This 3D organotypic culture model reproduced key features of desmoplastic reaction that closely mimicked those of the in situ tumor, as well as promoted cholangiocarcinoma cell growth and progression. Our results supported a resident liver mesenchymal cell origin of the TDFSM cells, which were not neoplastically transformed. Notably, 3D co-culturing of TDECC cells with TDFSM cells provoked the formation of a dense fibrocollagenous stroma in vitro that was associated with significant increases in both proliferative TDFSM myofibroblastic cells and TDECC cholangiocarcinoma cells accumulating within the gel matrix. This dramatic desmoplastic ICC-like phenotype, which was not observed in the TDECC or TDFSM controls, was highly dependent on transforming growth factor (TGF)-β, but not promoted by TGF-α. However, TGF-α was determined to be a key factor for promoting cholangiocarcinoma cell anaplasia, hyperproliferation, and higher malignant grading in this 3D culture model of desmoplastic ICC.
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Affiliation(s)
- Miguel Á Manzanares
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University, Richmond, Virginia
| | - Akihiro Usui
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University, Richmond, Virginia
| | - Deanna J Campbell
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University, Richmond, Virginia
| | - Catherine I Dumur
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University, Richmond, Virginia
| | - Gabrielle T Maldonado
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University, Richmond, Virginia
| | - Michel Fausther
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Jonathan A Dranoff
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Alphonse E Sirica
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University, Richmond, Virginia.
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Li L, Piontek K, Ishida M, Fausther M, Dranoff JA, Fu R, Mezey E, Gould SJ, Fordjour FK, Meltzer SJ, Sirica AE, Selaru FM. Extracellular vesicles carry microRNA-195 to intrahepatic cholangiocarcinoma and improve survival in a rat model. Hepatology 2017; 65:501-514. [PMID: 27474881 PMCID: PMC5258762 DOI: 10.1002/hep.28735] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 06/16/2016] [Accepted: 07/14/2016] [Indexed: 12/12/2022]
Abstract
UNLABELLED The cancer microenvironment plays a central role in cancer development, growth, and homeostasis. This paradigm suggests that cancer fibroblasts support cancers, probably in response to stimuli received from the cancer cells. We aimed at investigating whether extracellular vesicles (EVs) can shuttle microRNA (miR) species between cancer-associated fibroblasts (CAFs) and cancer cells. To this end, we extracted EVs according to published protocols. EVs were studied for their miR content by quantitative reverse-transcription polymerase chain reaction. EVs were transfected with select miR species and utilized in vitro as well as in vivo in a rat model of cholangiocarcinoma (CCA). We found that miR-195 is down-regulated in CCA cells, as well as in adjoining fibroblasts. Furthermore, we report that EVs shuttle miR-195 from fibroblasts to cancer cells. Last, we show that fibroblast-derived EVs, loaded with miR-195, can be administered in a rat model of CCA, concentrate within the tumor, decrease the size of cancers, and improve survival of treated rats. CONCLUSION EVs play a salient role in trafficking miR species between cancer cells and CAFs in human CCA. Understanding of these mechanisms may allow devising of novel therapeutics. (Hepatology 2017;65:501-514).
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Affiliation(s)
- Ling Li
- Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA
| | - Klaus Piontek
- Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA
| | - Masaharu Ishida
- Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA,Department of Surgery, Tohoku University, Sendai, Japan
| | - Michel Fausther
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Jonathan A. Dranoff
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Rongdang Fu
- Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA
| | - Esteban Mezey
- Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA
| | - Stephen J. Gould
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Francis K. Fordjour
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Stephen J. Meltzer
- Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA
| | - Alphonse E. Sirica
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Florin M. Selaru
- Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA,Sidney Kimmel Cancer Center, The Johns Hopkins University, Baltimore, Maryland, USA,The Institute for Nanobiotechnology, The Johns Hopkins University, Baltimore, Maryland, USA
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Wang H, Liu W, Tian M, Tang Z, Jiang X, Zhou P, Ding Z, Peng Y, Dai Z, Qiu S, Zhou J, Fan J, Shi Y. Coagulopathy associated with poor prognosis in intrahepatic cholangiocarcinoma patients after curative resection. Biosci Trends 2017; 11:469-474. [DOI: 10.5582/bst.2017.01080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Han Wang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
| | - Weiren Liu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
| | - Mengxin Tian
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
| | - Zheng Tang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
| | - Xifei Jiang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
| | - Peiyun Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
| | - Zhenbin Ding
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
| | - Yuanfei Peng
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
| | - Zhi Dai
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
| | - Shuangjian Qiu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
| | - Jian Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
- Institutes of Biomedical Sciences, Fudan University
| | - Jia Fan
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
- Institutes of Biomedical Sciences, Fudan University
| | - Yinghong Shi
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
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Laohaviroj M, Chamgramol Y, Pairojkul C, Mulvenna J, Sripa B. Clinicopathological Significance of Osteopontin in Cholangiocarcinoma Cases. Asian Pac J Cancer Prev 2016; 17:201-5. [PMID: 26838210 DOI: 10.7314/apjcp.2016.17.1.201] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Cholangiocarcinoma (CCA) is generally a rare primary liver tumor of the bile duct with extremely poor clinical outcomes due to late diagnosis. Osteopontin (OPN) is the most abundant expressed gene in intrahepatic CCA and its involvement in tumor aggressiveness suggests it could be a useful prognostic biomarker. However, the prognostic significance of OPN expression in CCA is still controversial. We therefore immunohistochemically studied OPN expression in 354 resected CCAs and correlated the results with patient clinicopathological parameters. OPN expression was separately scored according to the percentage of cancer cells or degree of stromal tissue staining and classified as low (score 0-1) and high (score 2-3). OPN expression in CCA cells was found in 177 out of 354 patients (56.5%), whereas stroma was positive in 185 out of 354 patients (52.3%). Univariate analysis with several of the aforementioned parameters revealed that stromal but not cancer cell OPN expression was significantly associated with tumor size, tumor direct invasion into normal liver parenchyma, regional lymph node metastasis and higher staging. The combination of cancer cell and stromal OPN expression demonstrated a positive trend for linkage with lymph node metastasis. Multivariate analysis identified gender, the presence of lymphatic permeation and lymph node metastasis, but not OPN expression, as independent prognostic factors. This study confirms the presence of stromal OPN expression in tumor aggressiveness but not survival in CCA patients.
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Affiliation(s)
- Marut Laohaviroj
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand E-mail :
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Affo S, Yu LX, Schwabe RF. The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2016; 12:153-186. [PMID: 27959632 DOI: 10.1146/annurev-pathol-052016-100322] [Citation(s) in RCA: 482] [Impact Index Per Article: 53.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Liver cancer is the second leading cause of cancer mortality worldwide, causing more than 700,000 deaths annually. Because of the wide landscape of genomic alterations and limited therapeutic success of targeting tumor cells, a recent focus has been on better understanding and possibly targeting the microenvironment in which liver tumors develop. A unique feature of liver cancer is its close association with liver fibrosis. More than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers, suggesting an important role of liver fibrosis in the premalignant environment (PME) of the liver. Cholangiocarcinoma (CCA), in contrast, is characterized by a strong desmoplasia that typically occurs in response to the tumor, suggesting a key role of cancer-associated fibroblasts (CAFs) and fibrosis in its tumor microenvironment (TME). Here, we discuss the functional contributions of myofibroblasts, CAFs, and fibrosis to the development of HCC and CCA in the hepatic PME and TME, focusing on myofibroblast- and extracellular matrix-associated growth factors, fibrosis-associated immunosuppressive pathways, as well as mechanosensitive signaling cascades that are activated by increased tissue stiffness. Better understanding of the role of myofibroblasts in HCC and CCA development and progression may provide the basis to target these cells for tumor prevention or therapy.
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Affiliation(s)
- Silvia Affo
- Department of Medicine, Columbia University, New York, NY 10032;
| | - Le-Xing Yu
- Department of Medicine, Columbia University, New York, NY 10032;
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York, NY 10032;
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Expression of Molecular Differentiation Markers Does Not Correlate with Histological Differentiation Grade in Intrahepatic Cholangiocarcinoma. PLoS One 2016; 11:e0157140. [PMID: 27280413 PMCID: PMC4900546 DOI: 10.1371/journal.pone.0157140] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 05/25/2016] [Indexed: 12/12/2022] Open
Abstract
The differentiation status of tumor cells, defined by histomorphological criteria, is a prognostic factor for survival of patients affected with intrahepatic cholangiocarcinoma (ICC). To strengthen the value of morphological differentiation criteria, we wished to correlate histopathological differentiation grade with expression of molecular biliary differentiation markers and of microRNAs previously shown to be dysregulated in ICC. We analysed a series of tumors that were histologically classified as well, moderately or poorly differentiated, and investigated the expression of cytokeratin 7, 19 and 903 (CK7, CK19, CK903), SRY-related HMG box transcription factors 4 and 9 (SOX4, SOX9), osteopontin (OPN), Hepatocyte Nuclear Factor-1 beta (HNF1β), Yes-associated protein (YAP), Epithelial cell adhesion molecule (EPCAM), Mucin 1 (MUC1) and N-cadherin (NCAD) by qRT-PCR and immunostaining, and of miR-31, miR-135b, miR-132, miR-200c, miR-221 and miR-222. Unexpectedly, except for subcellular location of SOX9 and OPN, no correlation was found between the expression levels of these molecular markers and histopathological differentiation grade. Therefore, our data point toward necessary caution when investigating the evolution and prognosis of ICC on the basis of cell differentiation criteria.
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Zhu H, Han C, Lu D, Wu T. miR-17-92 cluster promotes cholangiocarcinoma growth: evidence for PTEN as downstream target and IL-6/Stat3 as upstream activator. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 184:2828-39. [PMID: 25239565 DOI: 10.1016/j.ajpath.2014.06.024] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Revised: 06/01/2014] [Accepted: 06/06/2014] [Indexed: 12/15/2022]
Abstract
miR-17-92 is an oncogenic miRNA cluster implicated in the development of several cancers; however, it remains unknown whether the miR-17-92 cluster is able to regulate cholangiocarcinogenesis. This study was designed to investigate the biological functions and molecular mechanisms of the miR-17-92 cluster in cholangiocarcinoma. In situ hybridization and quantitative RT-PCR analysis showed that the miR-17-92 cluster is highly expressed in human cholangiocarcinoma cells compared with the nonneoplastic biliary epithelial cells. Forced overexpression of the miR-17-92 cluster or its members, miR-92a and miR-19a, in cultured human cholangiocarcinoma cells enhanced tumor cell proliferation, colony formation, and invasiveness, in vitro. Overexpression of the miR-17-92 cluster or miR-92a also enhanced cholangiocarcinoma growth in vivo in hairless outbred mice with severe combined immunodeficiency (SHO-Prkdc(scid)Hr(hr)). The tumor-suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), was identified as a bona fide target of both miR-92a and miR-19a in cholangiocarcinoma cells via sequence prediction, 3' untranslated region luciferase activity assay, and Western blot analysis. Accordingly, overexpression of the PTEN open reading frame protein (devoid of 3' untranslated region) prevented miR-92a- or miR-19a-induced cholangiocarcinoma cell growth. Microarray analysis revealed additional targets of the miR-17-92 cluster in human cholangiocarcinoma cells, including APAF-1 and PRDM2. Moreover, we observed that the expression of the miR-17-92 cluster is regulated by IL-6/Stat3, a key oncogenic signaling pathway pivotal in cholangiocarcinogenesis. Taken together, our findings disclose a novel IL-6/Stat3-miR-17-92 cluster-PTEN signaling axis that is crucial for cholangiocarcinogenesis and tumor progression.
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Affiliation(s)
- Hanqing Zhu
- 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
| | - Dongdong Lu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
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Nanashima A, Hatachi G, Tominaga T, Murakami G, Takagi K, Arai J, Wada H, Nagayasu T, Sumida Y. Down-Regulation of Nogo-B Expression as a Newly Identified Feature of Intrahepatic Cholangiocarcinoma. TOHOKU J EXP MED 2015; 238:9-16. [PMID: 26656426 DOI: 10.1620/tjem.238.9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Nogo-B, located in the endoplasmic reticulum, is an isoform belonging to the reticulon protein family, which is expressed specifically in cholangiocytes and non-parenchymal cells in the liver. Nogo-B expression is down-regulated with the progression of liver fibrosis, but its distinct function in liver malignancies has not been fully clarified. We have hypothesized that Nogo-B expression may be altered in intrahepatic cholangiocarcinoma (ICC), a relatively rare type of primary liver cancer with highly malignant behavior. The present study aimed to investigate the relationship between Nogo-B expression, assessed by immunohistochemical staining, and clinicopathological factors and prognosis in 34 ICC patients. Positive expression was observed in 19 (56%) of 34 ICC specimens: 6 patients (18%) with positivity levels of 1+ (positive cells in 10-50% of cancer cells) and 13 patients (38%) with 2+ (positive cells over 50%). Importantly, the remaining 15 patients (44%) were categorized as negative expression (Nogo-B-positive cells, less than 10%). Conversely, the mass-forming type of ICC tended to express Nogo-B with the degree of 2+ positivity, compared to the periductal infiltration type (p = 0.064), and the mass-forming type showed a better 5-year survival rate (66% vs. 5%) after hepatectomy (p < 0.05). However, the degree of positivity was not associated with tumor relapse rate, disease-free and overall survival, although each of the periductal infiltration type, intrahepatic metastasis, larger tumor size, and lower microvessel counts was associated with lower survival rates. We propose that Nogo-B expression is down-regulated in ICC, the implication of which, however, remains to be investigated.
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Affiliation(s)
- Atsushi Nanashima
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences
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Intraarterial 5-fluorouracil and interferon therapy is safe and effective for nonresectable biliary tract adenocarcinoma. Hepatol Int 2015; 9:142-8. [PMID: 25788388 DOI: 10.1007/s12072-014-9583-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 09/09/2014] [Indexed: 10/24/2022]
Abstract
PURPOSE The prognosis in advanced biliary carcinoma has remained poor. The purpose of this study was to investigate the efficacy of intraarterial 5-fluorouracil and interferon therapy against unresectable biliary carcinoma. METHODS Patients with unresectable biliary carcinoma with performance status 0 or 1 were enrolled between January 2002 and September 2012. They received pegylated interferon-α 2a and intraarterial 5-FU every 4 weeks. The therapy was either terminated at the end of the first cycle for the patients with progressive disease or continued for at least three cycles. Patients' characteristics (physical, laboratory and radiographic) at the time of starting intraarterial 5-FU therapy were investigated. The relationship between the patients' characteristics and outcome, i.e., survival time and radiographic therapeutic evaluation of patients, was statistically analyzed. RESULTS Tumor sites were the intrahepatic bile ducts in 23 patients and gallbladder in 2 patients. Previous treatment had been administered in ten patients. The overall response rate was 24% (6 partial responses in 25 patients). Stable disease was observed in 13 patients. The median overall survival was 358 days. Among the six partial responses, three patients received surgery, and one patient received radiofrequency ablation because clinical downstaging was obtained. The treatment was well tolerated. The survival analyses revealed that two factors (serum albumin ≥ 3.5 and hypovascular tumor) were significantly associated with overall survival. CONCLUSIONS Combination therapy with 5-FU and interferon-α was safe and may improve the prognosis of advanced biliary carcinomas.
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Haga H, Yan IK, Takahashi K, Wood J, Zubair A, Patel T. Tumour cell-derived extracellular vesicles interact with mesenchymal stem cells to modulate the microenvironment and enhance cholangiocarcinoma growth. J Extracell Vesicles 2015; 4:24900. [PMID: 25557794 PMCID: PMC4283029 DOI: 10.3402/jev.v4.24900] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2014] [Revised: 10/31/2014] [Accepted: 11/28/2014] [Indexed: 12/15/2022] Open
Abstract
The contributions of mesenchymal stem cells (MSCs) to tumour growth and stroma formation are poorly understood. Tumour cells can transfer genetic information and modulate cell signalling in other cells through the release of extracellular vesicles (EVs). We examined the contribution of EV-mediated inter-cellular signalling between bone marrow MSCs and tumour cells in human cholangiocarcinoma, highly desmoplastic cancers that are characterized by tumour cells closely intertwined within a dense fibrous stroma. Exposure of MSCs to tumour cell–derived EVs enhanced MSC migratory capability and expression of alpha-smooth muscle actin mRNA, in addition to mRNA expression and release of CXCL-1, CCL2 and IL-6. Conditioned media from MSCs exposed to tumour cell–derived EVs increased STAT-3 phosphorylation and proliferation in tumour cells. These effects were completely blocked by anti-IL-6R antibody. In conclusion, tumour cell–derived EVs can contribute to the generation of tumour stroma through fibroblastic differentiation of MSCs, and can also selectively modulate the cellular release of soluble factors such as IL-6 by MSCs that can, in turn, alter tumour cell proliferation. Thus, malignant cells can “educate” MSCs to induce local microenvironmental changes that enhance tumour cell growth.
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Affiliation(s)
- Hiroaki Haga
- Department of Cancer Biology, Mayo Clinic Jacksonville, FL, USA
| | - Irene K Yan
- Department of Cancer Biology, Mayo Clinic Jacksonville, FL, USA
| | - Kenji Takahashi
- Department of Cancer Biology, Mayo Clinic Jacksonville, FL, USA
| | - Joseph Wood
- Department of Cancer Biology, Mayo Clinic Jacksonville, FL, USA
| | - Abba Zubair
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, USA
| | - Tushar Patel
- Department of Cancer Biology, Mayo Clinic Jacksonville, FL, USA; Department of Transplantation, Mayo Clinic Jacksonville, FL, USA;
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Periostin in intrahepatic cholangiocarcinoma: pathobiological insights and clinical implications. Exp Mol Pathol 2014; 97:515-24. [PMID: 25446840 DOI: 10.1016/j.yexmp.2014.10.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 10/24/2014] [Indexed: 12/31/2022]
Abstract
Periostin is a modular glycoprotein frequently observed to be a major constituent of the extracellular milieu of mass-forming intrahepatic cholangiocarcinoma and other desmoplastic malignant tumors. In intrahepatic cholangiocarcinoma, as well as in desmoplastic pancreatic ductal adenocarcinoma, periostin is overexpressed and hypersecreted in large part, if not exclusively, by cancer-associated fibroblasts within the tumor stroma. Through its interaction with specific components of the extracellular tumor matrix, particularly collagen type I and tenascin-C, and with cell surface receptors, notably integrins leading to activation of the Akt and FAK signaling pathways, this TGF-β family-inducible matricellular protein appears to be functioning as a key extracellular matrix molecule regulating such critically important and diverse malignant tumor behaviors as tumor fibrogenesis and desmoplasia, invasive malignant cell growth, chemoresistance, and metastatic colonization. This review will discuss current evidence and basic molecular mechanisms implicating periostin as a mediator of intrahepatic cholangiocarcinoma invasive growth. In addition, its significance as a potential prognostic biomarker for intrahepatic cholangiocarcinoma patients, as well as future possibilities and challenges as a molecular target for cholangiocarcinoma therapy and/or prevention, will be critically evaluated.
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Bae BC, Yang SG, Jeong S, Lee DH, Na K, Kim JM, Costamagna G, Kozarek RA, Isayama H, Deviere J, Seo DW, Nageshwar Reddy D. Polymeric photosensitizer-embedded self-expanding metal stent for repeatable endoscopic photodynamic therapy of cholangiocarcinoma. Biomaterials 2014; 35:8487-95. [PMID: 25043500 DOI: 10.1016/j.biomaterials.2014.07.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 07/01/2014] [Indexed: 02/07/2023]
Abstract
Photodynamic therapy (PDT) is a new therapeutic approach for the palliative treatment of malignant bile duct obstruction. In this study, we designed photosensitizer-embedded self-expanding nonvascular metal stent (PDT-stent) which allows repeatable photodynamic treatment of cholangiocarcinoma without systemic injection of photosensitizer. Polymeric photosensitizer (pullulan acetate-conjugated pheophorbide A; PPA) was incorporated in self-expanding nonvascular metal stent. Residence of PPA in the stent was estimated in buffer solution and subcutaneous implantation on mouse. Photodynamic activity of PDT-stent was evaluated through laserexposure on stent-layered tumor cell lines, HCT-116 tumor-xenograft mouse models and endoscopic intervention of PDT-stent on bile duct of mini pigs. Photo-fluorescence imaging of the PDT-stent demonstrated homogeneous embedding of polymeric Pheo-A (PPA) on stent membrane. PDT-stent sustained its photodynamic activities at least for 2 month. And which implies repeatable endoscopic PDT is possible after stent emplacement. The PDT-stent after light exposure successfully generated cytotoxic singlet oxygen in the surrounding tissues, inducing apoptotic degradation of tumor cells and regression of xenograft tumors on mouse models. Endoscopic biliary in-stent photodynamic treatments on minipigs also suggested the potential efficacy of PDT-stent on cholangiocarcinoma. In vivo and in vitro studies revealed our PDT-stent, allows repeatable endoscopic biliary PDT, has the potential for the combination therapy (stent plus PDT) of cholangiocarcinoma.
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Affiliation(s)
- Byoung-chan Bae
- Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea
| | - Su-Geun Yang
- Department of New Drug Development and NCEED, School of Medicine, Inha University, Incheon, Republic of Korea
| | - Seok Jeong
- Division of Gastroenterology, Department of Internal Medicine, Inha University Hospital, Incheon, Republic of Korea
| | - Don Haeng Lee
- Utah-Inha DDS and Advanced Therapeutics, B-404, Meet-You-All Tower, Songdo-dong, Yeonsu-gu, Incheon, Republic of Korea; Division of Gastroenterology, Department of Internal Medicine, Inha University Hospital, Incheon, Republic of Korea; Department of New Drug Development and NCEED, School of Medicine, Inha University, Incheon, Republic of Korea
| | - Kun Na
- Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea.
| | - Joon Mee Kim
- Department of Pathology, Inha University Hospital, Incheon, Republic of Korea
| | - Guido Costamagna
- Digestive Endoscopy Unit, Department of Surgery, Catholic University, Rome, Italy; Department of Radiology, Catholic University, Rome, Italy
| | - Richard A Kozarek
- Digestive Disease Institute, Virginia Mason Medical Center, Seattle, USA
| | - Hiroyuki Isayama
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Jacques Deviere
- Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium
| | - Dong Wan Seo
- Division of Gastroenterology, Asan Medical Center, Seoul, Republic of Korea
| | - D Nageshwar Reddy
- Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
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High-mobility group AT-hook 2: an independent marker of poor prognosis in intrahepatic cholangiocarcinoma. Hum Pathol 2014; 45:2334-40. [PMID: 25245603 DOI: 10.1016/j.humpath.2014.04.026] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 03/25/2014] [Accepted: 04/02/2014] [Indexed: 12/24/2022]
Abstract
High-mobility group AT-hook 2 (HMGA2) regulates cell growth, differentiation, apoptosis, and neoplastic transformation. Previous studies have shown that malignant tumors expressing HMGA2, such as gastric, lung, and colorectal carcinomas, usually have a poor prognosis. HMGA2 expression and its clinical significance in intrahepatic cholangiocarcinomas have not been studied. We identified 55 intrahepatic cholangiocarcinomas resected at our institution from 1994 to 2003. Hematoxylin-eosin-stained slides were reviewed, and histopathologic characteristics were recorded, including mitotic count, tumor grade, vascular and perineural invasion, lymph node metastasis, and margin status. Using immunohistochemical stains, we examined expression of HMGA2, p53, p16, Kit, α-fetoprotein, and Ki-67, and we analyzed the correlation of survival with clinicopathological characteristics and immunohistochemical findings. Positive staining for HMGA2, p53, p16, Kit, α-fetoprotein, and Ki-67 was seen in 18 (33%), 37 (69%), 26 (47%), 21 (38%), 2 (4%), and 34 (63%) tumors, respectively. HMGA2 expression correlated positively with p53 expression (P = .02; ρ = 0.32) and negatively with p16 expression (P = .04; ρ = -0.28). Univariate analysis showed that HMGA2 expression and lymph node metastasis were associated with shorter patient survival and were independent indicators of poor survival (P = .02 and P = .03, respectively). Tumorigenic effects of HMGA2 in intrahepatic cholangiocarcinoma may partly reflect its ability to negatively regulate expression of p16 tumor suppressors and to be associated with p53 abnormalities.
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Tian X, Wang Q, Li Y, Hu J, Wu L, Ding Q, Zhang C. The expression of S100A4 protein in human intrahepatic cholangiocarcinoma: clinicopathologic significance and prognostic value. Pathol Oncol Res 2014; 21:195-201. [PMID: 24985031 DOI: 10.1007/s12253-014-9806-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Accepted: 05/28/2014] [Indexed: 12/12/2022]
Abstract
Intrahepatic cholangiocarcinoma(ICC) is a highly malignant adenocarcinoma arising from bile duct epithelial cells of the intrahepatic biliary system with early hematogenous and lymphatic extrahepatic spread. The current treatment methods for ICC are far from ideal. Identifying novel effective prognostic biomarkers which might be related to the development and progression of ICC may help provide new therapeutic strategies. Both calcium-binding protein S100A4 and Matrix metalloproteinase-9(MMP-9) are correlated with development and progression of many carcinomas. In the present study, we investigated expression of S100A4 as well as MMP-9 in ICC tissues from 65 patients using immunohistochemistry. The correlation of S100A4 and MMP-9 expression with clinicopathological features and prognosis of patients were analyzed. S100A4 and MMP-9 were positively expressed in 32(49.2 %) and 35(53.8%) patients, respectively. The positive correlation between S100A4 and MMP-9 expression was statistically significant (P = 0.018). S100A4 positive expression was significantly correlated with vascular invasion (P = 0.008), lymph node metastasis (P = 0.029) and the TNM stage (P = 0.008). MMP-9 expression was not found to be correlated with any clinicopathological parameter. Patients with S100A4 positive expression had a significantly poorer overall survival rate than those with S100A4 negative expression (P = 0.000). MMP-9 positive expression was also correlated with poor survival (P = 0.044). However, only S100A4 expression (P = 0.004) and the surgical margin (P = 0.024) were significantly independent prognostic predictors by multivariate analysis. In conclusion, expression of S100A4 is correlated with MMP-9 expression and it could be a useful marker for predicting the progression, metastasis and prognosis of ICC.
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Affiliation(s)
- Xiangguo Tian
- Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University, 324 Jingwu Weiqi Road, Jinan, 250021, People's Republic of China
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Li T, Qin LX, Zhou J, Sun HC, Qiu SJ, Ye QH, Wang L, Tang ZY, Fan J. Staging, prognostic factors and adjuvant therapy of intrahepatic cholangiocarcinoma after curative resection. Liver Int 2014; 34:953-60. [PMID: 24134199 DOI: 10.1111/liv.12364] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2013] [Accepted: 10/13/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Prognostic factors and adjuvant therapy of intrahepatic cholangiocarcinoma (ICC) after curative resection were not clear. We aim to analyse prognostic factors after curative resection and evaluate adjuvant therapy and survival based on the new staging system. METHODS A retrospective analysis of 283 patients who underwent surgical exploration for ICC was performed. Staging was performed according to the 7th edition AJCC staging manual. Univariate and multivariate analyses were used to evaluate independent prognostic factors. RESULTS The difference for OS at different TNM stages after R0 resection was significant (P < 0.001). Despite regional lymph node metastasis, tumour number and vascular invasion, serum GGT level was also an independent prognostic factor for OS of patients after R0 resection. The incidence of biliary and vascular invasion was significantly higher in high GGT group than in normal GGT group. Factors predictive of recurrence were multiple tumours and regional lymph node metastasis. After R0 resection, adjuvant TACE not only did not improve the OS of patients at TNM stage I (P = 0.508), but significantly promoted recurrence of these patients (P = 0.006). Only patients at TNM stage II, III and IV benefited from adjuvant TACE for longer survival, while the recurrence rates were not affected. CONCLUSIONS The new staging system can predict the survival of ICC patients after R0 resection. High GGT level may be suggestive of biliary and vascular invasion and was an independent risk factor for OS after R0 resection. Adjuvant TACE may be indicated only for patients at advanced stages for better survival.
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Affiliation(s)
- Tao Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
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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: 172] [Impact Index Per Article: 14.3] [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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Zabron A, Edwards RJ, Khan SA. The challenge of cholangiocarcinoma: dissecting the molecular mechanisms of an insidious cancer. Dis Model Mech 2013; 6:281-92. [PMID: 23520144 PMCID: PMC3597011 DOI: 10.1242/dmm.010561] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinoma is a fatal cancer of the biliary epithelium and has an incidence that is increasing worldwide. Survival beyond a year of diagnosis is less than 5%, and therapeutic options are few. Known risk factors include biliary diseases such as primary sclerosing cholangitis and parasitic infestation of the biliary tree, but most cases are not associated with any of these underlying diseases. Numerous in vitro and in vivo models, as well as novel analytical techniques for human samples, are helping to delineate the many pathways implicated in this disease, albeit at a frustratingly slow pace. As yet, however, none of these studies has been translated into improved patient outcome and, overall, the pathophysiology of cholangiocarcinoma is still poorly understood. There remains an urgent need for new approaches and models to improve management of this insidious and devastating disease. In this review, we take a bedside-to-bench approach to discussing cholangiocarcinoma and outline research opportunities for the future in this field.
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Affiliation(s)
- Abigail Zabron
- Hepatology and Gastroenterology Section, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, St Mary's Hospital Campus, South Wharf Road, London, W2 1NY, UK.
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Mertens JC, Fingas CD, Christensen JD, Smoot RL, Bronk SF, Werneburg NW, Gustafson MP, Dietz AB, Roberts LR, Sirica AE, Gores GJ. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res 2012; 73:897-907. [PMID: 23221385 DOI: 10.1158/0008-5472.can-12-2130] [Citation(s) in RCA: 153] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Cancer-associated fibroblasts (CAF) are abundant in the stroma of desmoplastic cancers where they promote tumor progression. CAFs are "activated" and as such may be uniquely susceptible to apoptosis. Using cholangiocarcinoma as a desmoplastic tumor model, we investigated the sensitivity of liver CAFs to the cytotoxic drug navitoclax, a BH3 mimetic. Navitoclax induced apoptosis in CAF and in myofibroblastic human hepatic stellate cells but lacked similar effects in quiescent fibroblasts or cholangiocarcinoma cells. Unlike cholangiocarcinoma cells, neither CAF nor quiescent fibroblasts expressed Mcl-1, a known resistance factor for navitoclax cytotoxicity. Explaining this paradox, we found that mitochondria isolated from CAFs or cells treated with navitoclax both released the apoptogenic factors Smac and cytochrome c, suggesting that they are primed for cell death. Such death priming in CAFs appeared to be due, in part, to upregulation of the proapoptotic protein Bax. Short hairpin RNA-mediated attenuation of Bax repressed navitoclax-mediated mitochondrial dysfunction, release of apoptogenic factors, and apoptotic cell death. In a syngeneic rat model of cholangiocarcinoma, navitoclax treatment triggered CAF apoptosis, diminishing expression of the desmoplastic extracellular matrix protein tenascin C, suppressing tumor outgrowth, and improving host survival. Together, our findings argue that navitoclax may be useful for destroying CAFs in the tumor microenvironment as a general strategy to attack solid tumors.
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Affiliation(s)
- Joachim C Mertens
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA
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