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Huang YP, Wang YX, Zhou H, Liu ZT, Zhang ZJ, Xiong L, Zou H, Wen Y. Surufatinib combined with photodynamic therapy induces ferroptosis to inhibit cholangiocarcinoma in vitro and in tumor models. Front Pharmacol 2024; 15:1288255. [PMID: 38645554 PMCID: PMC11027741 DOI: 10.3389/fphar.2024.1288255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 03/11/2024] [Indexed: 04/23/2024] Open
Abstract
The curative effect of single therapy for advanced cholangiocarcinoma (CCA) is poor, thus investigating combined treatment strategies holds promise for improving prognosis. Surufatinib (SUR) is a novel multikinase inhibitor that has been confirmed to prolong survival of patients with advanced CCA. Photodynamic therapy (PDT) can also ablate advanced CCA and relieve biliary obstruction. In this study, we explored the anti-CCA effect of SUR combined with PDT, and explored the underlying mechanism. We found that SUR could effectively inhibit the abilities of proliferation, migration and metastasis in CCA cells (HUCCT-1, RBE). The ability of SUR to inhibit CCA was also confirmed by the HUCCT-1 cell xenograft model in Balb/c nude mice and CCA patient-derived organoids. SUR combined with PDT can significantly enhance the inhibitory effect on CCA, and can be alleviated by two ferroptosis inhibitors (Ferrostatin-1, Deferoxamine). By detecting the level of reactive oxygen species, lipid peroxides, malondialdehyde and glutathione, we further confirmed that SUR combined with PDT can inhibit CCA cells by inducing ferroptosis. Glutathione peroxidase 4 (GPX4) belongs to the glutathione peroxidase family and is mainly responsible for the metabolism of intracellular hydrogen peroxide. GPX4 inhibits ferroptosis by reducing cytotoxic lipid peroxides (L-OOH) to the corresponding alcohols (L-OH). Acyl-CoA synthetase long-chain family member 4 (ACSL4) is a member of the long-chain fatty acid coenzyme a synthetase family and is mainly involved in the biosynthesis and catabolism of fatty acids. ACSL4 induces ferroptosis by promoting the accumulation of lipid peroxides. Both SUR and PDT can induce ferroptosis by promoting ACSL4 and inhibiting GPX4. The regulation effect is found to be more significant in combined treatment group. In conclusion, SUR combined with PDT exerted an anti-CCA effect by inducing ferroptosis. Combination therapy provides a new idea for the clinical treatment of CCA.
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Affiliation(s)
| | | | | | | | | | | | - Heng Zou
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yu Wen
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
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Isidan A, Yenigun A, Soma D, Aksu E, Lopez K, Park Y, Cross-Najafi A, Li P, Kundu D, House MG, Chakraborty S, Glaser S, Kennedy L, Francis H, Zhang W, Alpini G, Ekser B. Development and Characterization of Human Primary Cholangiocarcinoma Cell Lines. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:1200-1217. [PMID: 35640676 PMCID: PMC9472155 DOI: 10.1016/j.ajpath.2022.05.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 05/12/2022] [Accepted: 05/18/2022] [Indexed: 06/15/2023]
Abstract
Cholangiocarcinoma (CCA) is the second most common primary liver tumor and is associated with late diagnosis, limited treatment options, and a 5-year survival rate of around 30%. CCA cell lines were first established in 1971, and since then, only 70 to 80 CCA cell lines have been established. These cell lines have been essential in basic and translational research to understand and identify novel mechanistic pathways, biomarkers, and disease-specific genes. Each CCA cell line has unique characteristics, reflecting a specific genotype, sex-related properties, and patient-related signatures, making them scientifically and commercially valuable. CCA cell lines are crucial in the use of novel technologies, such as three-dimensional organoid models, which help to model the tumor microenvironment and cell-to-cell crosstalk between tumor-neighboring cells. This review highlights crucial information on CCA cell lines, including: i) type of CCA (eg, intra- or extrahepatic), ii) isolation source (eg, primary tumor or xenograft), iii) chemical digestion method (eg, trypsin or collagenase), iv) cell-sorting method (colony isolation or removal of fibroblasts), v) maintenance-medium choice (eg, RPMI or Dulbecco's modified Eagle's medium), vi) cell morphology (eg, spindle or polygonal shape), and vii) doubling time of cells.
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Affiliation(s)
- Abdulkadir Isidan
- Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ali Yenigun
- Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana; Department of General Surgery, Yeditepe University Faculty of Medicine, Istanbul, Turkey
| | - Daiki Soma
- Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana; Division of Transplantation & Hepatobiliary Surgery, Department of Surgery, University of Florida College of Medicine, Gainesville, Florida
| | - Eric Aksu
- Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Kevin Lopez
- Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Yujin Park
- Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Arthur Cross-Najafi
- Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ping Li
- Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Debjyoti Kundu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Division of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Michael G House
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Sanjukta Chakraborty
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, Texas
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, Texas
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Division of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Division of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Wenjun Zhang
- Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Division of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Burcin Ekser
- Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
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Cousin S, Cantarel C, Guegan JP, Mazard T, Gomez-Roca C, Metges JP, Bellera C, Adenis A, Korakis I, Poureau PG, Bourcier K, Toulmonde M, Kind M, Rey C, Auzanneau C, Bessede A, Soubeyran I, Italiano A. Regorafenib-avelumab combination in patients with biliary tract cancer (REGOMUNE): a single-arm, open-label, phase II trial. Eur J Cancer 2022; 162:161-169. [PMID: 34998048 DOI: 10.1016/j.ejca.2021.11.012] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 10/13/2021] [Accepted: 11/05/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND Regorafenib has shown substantial clinical activity in patients with advanced biliary tract cancers (BTCs). Preclinical data suggested that this drug modulates antitumour immunity and is synergistic with immune checkpoint inhibition. PATIENTS AND METHODS This is a single-arm, multicentric phase II trial. Regorafenib was given 3 weeks/4, 160 mg quaque die (once a day) (QD); avelumab 10 mg/kg IV was given every two weeks, beginning at C1D15 until progression or unacceptable toxicity. The primary end-point was the confirmed objective response rate under treatment, as per Response Evaluation Criteria in Solid Tumours 1.1. The secondary end-points included the following: 1-year non-progression rate; progression-free survival (PFS) and overall survival; safety and biomarkers studies performed on sequential tumour samples obtained at baseline and at cycle 2 day 1. RESULTS Thirty-four patients were enrolled in four centres. Twenty-nine patients were assessable for efficacy after central radiological review. The best response was partial response for four patients (13.8%), stable disease for 11 patients (37.9%) and progressive disease for 14 patients (48.3%). The median PFS and overall survival were 2.5 months (95% confidence interval [CI] [1.9-5.5]) and 11.9 months (95%CI [6.2-NA]) respectively. The most common grade 3 or 4 clinical adverse events related to treatment were hypertension (17.6%), fatigue (14.7%) and maculopapular rash (11.8%). High baseline levels of programmed cell death ligand 1 and of indoleamine 2, 3-dioxygénase expression were associated with improved outcomes. CONCLUSIONS Regorafenib combined with avelumab has antitumour activity in a subset of heavily pretreated biliary tract cancer population. Further investigations are needed in patients selected based on tumour microenvironment features. CLINICAL TRIAL REGISTRATION NCT03475953.
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Affiliation(s)
- Sophie Cousin
- Early Phase Trials Unit, Institut Bergonié, 229 Cours de L'Argonne, 33000, Bordeaux, France
| | - Coralie Cantarel
- Clinical and Epidemiological Research Unit, INSERM CIC1401, Institut Bergonié, Comprehensive Cancer Center, F-33000, Bordeaux, France
| | | | - Thibault Mazard
- Department of Medical Oncology, Institut Regional Du Cancer de Montpellier, 208 Avenue des Apothicaires, 34298, Montpellier, France
| | - Carlos Gomez-Roca
- Department of Medical Oncology, IUCT, 1 Avenue Irène Joliot-Curie, 31100, Toulouse, France
| | - Jean-Philippe Metges
- Department of Medical Oncology, CHRU de Brest - Hôpital Morvan, 2 Avenue Foch, 29609, Brest, France
| | - Carine Bellera
- Clinical and Epidemiological Research Unit, INSERM CIC1401, Institut Bergonié, Comprehensive Cancer Center, F-33000, Bordeaux, France; Bordeaux, Inserm, Bordeaux Population Health Research Center, Epicene Team, UMR 1219, F-33000, Bordeaux, France
| | - Antoine Adenis
- Department of Medical Oncology, Institut Regional Du Cancer de Montpellier, 208 Avenue des Apothicaires, 34298, Montpellier, France
| | - Iphigenie Korakis
- Department of Medical Oncology, IUCT, 1 Avenue Irène Joliot-Curie, 31100, Toulouse, France
| | - Pierre-Guillaume Poureau
- Department of Medical Oncology, CHRU de Brest - Hôpital Morvan, 2 Avenue Foch, 29609, Brest, France
| | - Kevin Bourcier
- Early Phase Trials Unit, Institut Bergonié, 229 Cours de L'Argonne, 33000, Bordeaux, France
| | - Maud Toulmonde
- Early Phase Trials Unit, Institut Bergonié, 229 Cours de L'Argonne, 33000, Bordeaux, France
| | - Michèle Kind
- Department of Radiology, Institut Bergonié, 229 Cours de L'Argonne, 33000, Bordeaux, France
| | | | - Céline Auzanneau
- Department of Biopathology, Institut Bergonié, 229 Cours de L'Argonne, 33000, Bordeaux, France
| | | | - Isabelle Soubeyran
- Department of Biopathology, Institut Bergonié, 229 Cours de L'Argonne, 33000, Bordeaux, France
| | - Antoine Italiano
- Early Phase Trials Unit, Institut Bergonié, 229 Cours de L'Argonne, 33000, Bordeaux, France; University of Bordeaux, Bordeaux, France; Gustave Roussy, Villejuif, France.
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Rimini M, Puzzoni M, Pedica F, Silvestris N, Fornaro L, Aprile G, Loi E, Brunetti O, Vivaldi C, Simionato F, Zavattari P, Scartozzi M, Burgio V, Ratti F, Aldrighetti L, Cascinu S, Casadei-Gardini A. Cholangiocarcinoma: new perspectives for new horizons. Expert Rev Gastroenterol Hepatol 2021; 15:1367-1383. [PMID: 34669536 DOI: 10.1080/17474124.2021.1991313] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Biliary tract cancer represents a heterogeneous group of malignancies characterized by dismal prognosis and scarce therapeutic options. AREA COVERED In the last years, a growing interest in BTC pathology has emerged, thus highlighting a significant heterogeneity of the pathways underlying the carcinogenesis process, from both a molecular and genomic point of view. A better understanding of these differences is mandatory to deepen the behavior of this complex disease, as well as to identify new targetable target mutations, with the aim to improve the survival outcomes. The authors decided to provide a comprehensive overview of the recent highlights on BTCs, with a special focus on the genetic, epigenetic and molecular alterations, which may have an interesting clinical application in the next future. EXPERT OPINION In the last years, the efforts resulted from international collaborations have led to the identification of new promising targets for precision medicine approaches in the BTC setting. Further investigations and prospective trials are needed, but the hope is that these new knowledge in cooperation with the new technologies and procedures, including bio-molecular and genomic analysis as well radiomic studies, will enrich the therapeutic armamentarium thus improving the survival outcomes in a such lethal and complex disease.
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Affiliation(s)
- Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Puzzoni
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Federica Pedica
- Department of Pathology, San Raffaele Scientific Institute, Milan, Italy
| | - Nicola Silvestris
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy.,Department of Biomedical Sciences and Human Oncology, Aldo Moro University of Bari, Bari, Italy
| | - Lorenzo Fornaro
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Eleonora Loi
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Oronzo Brunetti
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy
| | - Caterina Vivaldi
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Francesca Simionato
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Patrizia Zavattari
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Valentina Burgio
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Francesca Ratti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Stefano Cascinu
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
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Maier CF, Zhu L, Nanduri LK, Kühn D, Kochall S, Thepkaysone ML, William D, Grützmann K, Klink B, Betge J, Weitz J, Rahbari NN, Reißfelder C, Schölch S. Patient-Derived Organoids of Cholangiocarcinoma. Int J Mol Sci 2021; 22:ijms22168675. [PMID: 34445380 PMCID: PMC8395494 DOI: 10.3390/ijms22168675] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/03/2021] [Accepted: 08/07/2021] [Indexed: 12/16/2022] Open
Abstract
Cholangiocarcinoma (CC) is an aggressive malignancy with an inferior prognosis due to limited systemic treatment options. As preclinical models such as CC cell lines are extremely rare, this manuscript reports a protocol of cholangiocarcinoma patient-derived organoid culture as well as a protocol for the transition of 3D organoid lines to 2D cell lines. Tissue samples of non-cancer bile duct and cholangiocarcinoma were obtained during surgical resection. Organoid lines were generated following a standardized protocol. 2D cell lines were generated from established organoid lines following a novel protocol. Subcutaneous and orthotopic patient-derived xenografts were generated from CC organoid lines, histologically examined, and treated using standard CC protocols. Therapeutic responses of organoids and 2D cell lines were examined using standard CC agents. Next-generation exome and RNA sequencing was performed on primary tumors and CC organoid lines. Patient-derived organoids closely recapitulated the original features of the primary tumors on multiple levels. Treatment experiments demonstrated that patient-derived organoids of cholangiocarcinoma and organoid-derived xenografts can be used for the evaluation of novel treatments and may therefore be used in personalized oncology approaches. In summary, this study establishes cholangiocarcinoma organoids and organoid-derived cell lines, thus expanding translational research resources of cholangiocarcinoma.
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Affiliation(s)
- Christopher Fabian Maier
- Junior Clinical Cooperation Unit Translational Surgical Oncology (A430), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (C.F.M.); (L.Z.)
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, 68167 Mannheim, Germany; (N.N.R.); (C.R.)
| | - Lei Zhu
- Junior Clinical Cooperation Unit Translational Surgical Oncology (A430), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (C.F.M.); (L.Z.)
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, 68167 Mannheim, Germany; (N.N.R.); (C.R.)
| | - Lahiri Kanth Nanduri
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (L.K.N.); (D.K.); (S.K.); (M.-L.T.); (J.W.)
| | - Daniel Kühn
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (L.K.N.); (D.K.); (S.K.); (M.-L.T.); (J.W.)
| | - Susan Kochall
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (L.K.N.); (D.K.); (S.K.); (M.-L.T.); (J.W.)
| | - May-Linn Thepkaysone
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (L.K.N.); (D.K.); (S.K.); (M.-L.T.); (J.W.)
| | - Doreen William
- Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT) Partner Site Dresden, 01307 Dresden, Germany; (D.W.); (K.G.); (B.K.)
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Konrad Grützmann
- Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT) Partner Site Dresden, 01307 Dresden, Germany; (D.W.); (K.G.); (B.K.)
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Barbara Klink
- Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT) Partner Site Dresden, 01307 Dresden, Germany; (D.W.); (K.G.); (B.K.)
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- National Center of Genetics, Laboratoire National de Santé (LNS), 3555 Dudelange, Luxembourg
| | - Johannes Betge
- Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models (B440), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;
- Department of Medicine II, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Jürgen Weitz
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (L.K.N.); (D.K.); (S.K.); (M.-L.T.); (J.W.)
| | - Nuh N. Rahbari
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, 68167 Mannheim, Germany; (N.N.R.); (C.R.)
| | - Christoph Reißfelder
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, 68167 Mannheim, Germany; (N.N.R.); (C.R.)
| | - Sebastian Schölch
- Junior Clinical Cooperation Unit Translational Surgical Oncology (A430), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (C.F.M.); (L.Z.)
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, 68167 Mannheim, Germany; (N.N.R.); (C.R.)
- Correspondence:
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Rimini M, Casadei-Gardini A. Angiogenesis in biliary tract cancer: targeting and therapeutic potential. Expert Opin Investig Drugs 2021; 30:411-418. [PMID: 33491502 DOI: 10.1080/13543784.2021.1881479] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Introduction: Biliary Tract Cancer (BTC) is a heterogeneous group of malignant neoplasms with a complex molecular pathogenesis. The prognosis of metastatic disease is dramatically dismal and therapeutic options are scarce. Systemic chemotherapy is the gold standard for the metastatic disease. However, because of the disappointing results with conventional chemotherapy, investigators have turned to new biological therapeutic options targeting the main molecular pathways, neo-angiogenesis, involved in the disease pathogenesis.Areas covered: This paper examines the rationale of using antiangiogenic therapies in this setting, evaluates the therapeutic implications, and highlights ongoing studies and future perspectives. A Pubmed systematic review of preclinical and clinical data was performed which enabled the composition of this paper.Expert opinion: Amore in-depth understanding of the interplay between the neo-angiogenesis pathways, and the microenvironment will could propel the design new therapeutic strategies. Nowadays, the combination of antiangiogenic drugs and immune check-point inhibitors looks promising, but further, more comprehensive data are necessary to gain afuller picture. In an era of novel technologies and techniques, which includes radiomics, the challenge is to identify the biomarkers of response to antiangiogenic drugs which will permit the selection of patients that are more likely to respond to antiangiogenic therapies.
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Affiliation(s)
- Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University Hospital Modena, Modena, Italy
| | - Andrea Casadei-Gardini
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.,Unit of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Rahnemai-Azar AA, Pawlik TM. Cholangiocarcinoma: shedding light on the most promising drugs in clinical development. Expert Opin Investig Drugs 2021; 30:419-427. [PMID: 33645382 DOI: 10.1080/13543784.2021.1897103] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Cholangiocarcinoma (CCA) is a diverse group of fatal malignancies arising from the biliary tract. Surgical resection with negative margin offers the only potentially curative option. The majority of patients present at locally advanced or metastatic stages, when surgical resection is not feasible, highlighting the significance of systemic therapy. Given the limited effectiveness of traditional chemotherapy regimens in CCA, many investigators have focused on developing novel molecular therapies targeting key aberrant signaling pathways.Areas covered: We present the main genomic aberrations known to play a key role in cholangiocarcinogenesis and discuss promising targeted therapies in clinical development.In October of 2020, a review of the English literature was performed utilizing PubMed and Web of Science databases for the keywords of 'cholangiocarcinoma', 'biliary tract cancer', and 'targeted therapy'.Expert opinion: Unfortunately, despite encouraging results in preclinical studies, the outcome of clinical trials with established targeted therapies like anti-EGFR medications have been discouraging. Currently, agents targeting FGFR2 fusion and IDH1/2 mutations hold great promise for improving the management of CCA. Future studies focused on enhancing our understanding of key aberrant signaling pathways of cholangiocarcinogenesis and the design of homogeneous and biomarker-driven cohorts are key elements of establishing precision medicine in CCA.
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Affiliation(s)
- Amir A Rahnemai-Azar
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, The James Comprehensive Cancer Center, Columbus, OH, USA
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Rodrigues PM, Olaizola P, Paiva NA, Olaizola I, Agirre-Lizaso A, Landa A, Bujanda L, Perugorria MJ, Banales JM. Pathogenesis of Cholangiocarcinoma. ANNUAL REVIEW OF PATHOLOGY 2021; 16:433-463. [PMID: 33264573 DOI: 10.1146/annurev-pathol-030220-020455] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cholangiocarcinoma (CCA) encompasses a group of malignancies that can arise at any point in the biliary tree. Although considered a rare cancer, the incidence of CCA is increasing globally. The silent and asymptomatic nature of these tumors, particularly in their early stages, in combination with their high aggressiveness, intra- and intertumor heterogeneity, and chemoresistance, significantly compromises the efficacy of current therapeutic options, contributing to a dismal prognosis. During the last few years, increasing efforts have been made to unveil the etiologies and pathogenesis of these tumors and to develop more effective therapies. In this review, we summarize current findings in the field of CCA, mainly focusing on the mechanisms of pathogenesis, cells of origin, genomic and epigenetic abnormalities, molecular alterations, chemoresistance, and therapies.
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Affiliation(s)
- Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Paula Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Nuno A Paiva
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Irene Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Alona Agirre-Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Ana Landa
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
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9
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He J, Li G, Liu X, Ma L, Zhang J, Zheng S, Wang J, Liu J. Mesencephalic Astrocyte-Derived Neurotrophic Factor, a Prognostic Factor of Cholangiocarcinoma, Affects Sorafenib Sensitivity of Cholangiocarcinoma Cells by Deteriorating ER Stress. Onco Targets Ther 2020; 13:9169-9184. [PMID: 32982305 PMCID: PMC7502388 DOI: 10.2147/ott.s245575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 08/11/2020] [Indexed: 01/06/2023] Open
Abstract
Purpose Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignant tumor characterized by high malignancy and poor prognosis. Although the efficacy of sorafenib against cholangiocarcinoma cell lines has been demonstrated in vivo and in vitro, limited clinical data are available on the efficacy of sorafenib in patients with cholangiocarcinoma. Sorafenib can enhance endoplasmic reticulum (ER) stress-mediated apoptosis, and ER stress and unfolded protein response are also the mechanisms by which cancer cells resist drug therapy. Mesencephalic astrocyte-derived neurotrophic factor (MANF), initially identified as a neurotrophic factor, can be regulated by ER stress activation. There are no available studies on the diagnostic value and therapeutic significance of MANF in ICC. Hence, the purpose of this study was to evaluate the role of MANF in cholangiocarcinoma, investigating the possibility of whether sorafenib could become a reliable strategy for cholangiocarcinoma therapy. Methods In this study, the expression level of MANF in ICC patients was investigated by bioinformatic analysis and the results were verified by tissue microarray assay. Cholangiocarcinoma cell lines were also used to determine how MANF regulates the therapeutic effect of sorafenib and to identify the underlying mechanisms. Results The results showed that MANF was correlated with poor prognosis and MANF knockdown could facilitate sorafenib-mediated apoptosis and increase the sensitivity of sorafenib treatment by activating excessive ER stress. Conclusion MANF is a prognostic marker of cholangiocarcinoma. MANF knockdown increases sorafenib-mediated ER stress and apoptosis in the cholangiocarcinoma cell lines. This mechanism may lead to a new therapeutic strategy in cholangiocarcinoma.
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Affiliation(s)
- Jingyi He
- Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.,Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Guangbing Li
- Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.,Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Xihan Liu
- Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Liye Ma
- Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.,Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Jiayao Zhang
- Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.,Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Shunzhen Zheng
- Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.,Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Jianping Wang
- Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.,Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Jun Liu
- Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.,Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
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10
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Emerging pathways for precision medicine in management of cholangiocarcinoma. Surg Oncol 2020; 35:47-55. [PMID: 32827952 DOI: 10.1016/j.suronc.2020.08.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 08/06/2020] [Indexed: 12/27/2022]
Abstract
Cholangiocarcinoma (CCA) is the second most common biliary tract malignancy with a dismal prognosis. Surgical resection with a negative microscopic margin offers the only hope for long-term survival. However, the majority of patients present with advanced disease not amenable to curative resection, mainly due to late presentation and aggressive nature of the disease. Unfortunately, due to the heterogeneous nature of CCA as well as limitations of available chemotherapy medications, traditional chemotherapy regimens offer limited survival benefit. Recent advances in genomic studies and next-generation sequencing techniques have assisted in better understanding of cholangiocarcinogenesis and identification of potential aberrant signaling pathways. Targeting the specific genomic abnormalities via novel molecular therapies has opened a new avenue in management of CCA with encouraging results in preclinical studies and early clinical trials. In this review, we present emerging therapies for precision medicine in CCA.
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11
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Zheng Y, Zhang J, Ye B. miR-138 mediates sorafenib-induced cell survival and is associated with poor prognosis in cholangiocarcinoma cells. Clin Exp Pharmacol Physiol 2019; 47:459-465. [PMID: 31663629 DOI: 10.1111/1440-1681.13205] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 10/22/2019] [Accepted: 10/28/2019] [Indexed: 12/22/2022]
Abstract
Cholangiocarcinoma is an aggressive malignancy with rapid invasion, metastasis and poor prognosis, however, the mechanism mediating its cholangiocarcinoma development needs further investigation. Here, we demonstrate that decreased miR-138 in tumor tissues is related to the poor prognosis in patients, and that miR-138 mediates sorafenib-induced cell survival in cholangiocarcinoma cells. Moreover, miR-138 negatively regulates SOX4 expression by specifically targeting its 3' untranslated region (3' UTR). As per our results, overexpression of SOX4 reversed sorafenib-induced changes in cell viability and apoptosis. Furthermore, the elevated levels of SOX4 in the tumor tissues that correlated with poor prognosis. Overall, the present study reveals that miR-138/SOX4 is involved in sorafinib-mediated cell survival in cholangiocarcinoma cells, and is associated with poor prognosis.
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Affiliation(s)
- Yingjie Zheng
- Department of Gastroenterology, Lianshui County People's Hospital, Huai'an, China
| | - Jingyu Zhang
- Department of Gastroenterology, Lianshui County People's Hospital, Huai'an, China
| | - Bin Ye
- Department of Gastroenterology, Huai'an Second People's Hospital, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China
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12
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Lozano E, Macias RIR, Monte MJ, Asensio M, Del Carmen S, Sanchez-Vicente L, Alonso-Peña M, Al-Abdulla R, Munoz-Garrido P, Satriano L, O'Rourke CJ, Banales JM, Avila MA, Martinez-Chantar ML, Andersen JB, Briz O, Marin JJG. Causes of hOCT1-Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor-Selective Gene Therapy. Hepatology 2019; 70:1246-1261. [PMID: 30972782 DOI: 10.1002/hep.30656] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 04/04/2019] [Indexed: 12/19/2022]
Abstract
Although the multi-tyrosine kinase inhibitor sorafenib is useful in the treatment of several cancers, cholangiocarcinoma (CCA) is refractory to this drug. Among other mechanisms of chemoresistance, impaired uptake through human organic cation transporter type 1 (hOCT1) (gene SLC22A1) has been suggested. Here we have investigated the events accounting for this phenotypic characteristic and have evaluated the interest of selective gene therapy strategies to overcome this limitation. Gene expression and DNA methylation of SLC22A1 were analyzed using intrahepatic (iCCA) and extrahepatic (eCCA) biopsies (Copenhagen and Salamanca cohorts; n = 132) and The Cancer Genome Atlas (TCGA)-CHOL (n = 36). Decreased hOCT1 mRNA correlated with hypermethylation status of the SLC22A1 promoter. Treatment of CCA cells with decitabine (demethylating agent) or butyrate (histone deacetylase inhibitor) restored hOCT1 expression and increased sorafenib uptake. MicroRNAs able to induce hOCT1 mRNA decay were analyzed in paired samples of TCGA-CHOL (n = 9) and Copenhagen (n = 57) cohorts. Consistent up-regulation in tumor tissue was found for miR-141 and miR-330. High proportion of aberrant hOCT1 mRNA splicing in CCA was also seen. Lentiviral-mediated transduction of eCCA (EGI-1 and TFK-1) and iCCA (HuCCT1) cells with hOCT1 enhanced sorafenib uptake and cytotoxic effects. In chemically induced CCA in rats, reduced rOct1 expression was accompanied by impaired sorafenib uptake. In xenograft models of eCCA cells implanted in mouse liver, poor response to sorafenib was observed. However, tumor growth was markedly reduced by cotreatment with sorafenib and adenoviral vectors encoding hOCT1 under the control of the BIRC5 promoter, a gene highly up-regulated in CCA. Conclusion: The reason for impaired hOCT1-mediated sorafenib uptake by CCA is multifactorial. Gene therapy capable of selectively inducing hOCT1 in tumor cells can be considered a potentially useful chemosensitization strategy to improve the response of CCA to sorafenib.
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Affiliation(s)
- Elisa Lozano
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain
| | - Rocio I R Macias
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain
| | - Maria J Monte
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Sofia Del Carmen
- Salamanca University Hospital, IBSAL, University of Salamanca, Salamanca, Spain
| | - Laura Sanchez-Vicente
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Marta Alonso-Peña
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Ruba Al-Abdulla
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Patricia Munoz-Garrido
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Letizia Satriano
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Colm J O'Rourke
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jesus M Banales
- Department of Hepatology and Gastroenterology, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, San Sebastian, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain
| | - Matias A Avila
- Hepatology Programme, Center for Applied Medical Research (CIMA), IDISNA, University of Navarra, Pamplona, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain
| | - Maria L Martinez-Chantar
- Liver Disease Laboratory, CIC bioGUNE, Technology Park of Vizcaya, Vizcaya, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain
| | - Jesper B Andersen
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain
| | - Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain
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13
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Fabris L, Perugorria MJ, Mertens J, Björkström NK, Cramer T, Lleo A, Solinas A, Sänger H, Lukacs-Kornek V, Moncsek A, Siebenhüner A, Strazzabosco M. The tumour microenvironment and immune milieu of cholangiocarcinoma. Liver Int 2019; 39 Suppl 1:63-78. [PMID: 30907492 PMCID: PMC10878127 DOI: 10.1111/liv.14098] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 02/25/2019] [Accepted: 02/27/2019] [Indexed: 12/11/2022]
Abstract
Tumour microenvironment is a complex, multicellular functional compartment that, particularly when assembled as an abundant desmoplastic reaction, may profoundly affect the proliferative and invasive abilities of epithelial cancer cells. Tumour microenvironment comprises not only stromal cells, mainly cancer-associated fibroblasts, but also immune cells of both the innate and adaptive system (tumour-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes), and endothelial cells. This results in an intricate web of mutual communications regulated by an extensively remodelled extracellular matrix, where the tumour cells are centrally engaged. In this regard, cholangiocarcinoma, in particular the intrahepatic variant, has become the focus of mounting interest in the last years, largely because of the lack of effective therapies despite its rising incidence and high mortality rates worldwide. On the other hand, recent studies in pancreatic cancer, which similarly to cholangiocarcinoma, is highly desmoplastic, have argued against a tumour-promoting function of the tumour microenvironment. In this review, we will discuss recent developments concerning the role of each cellular population and their multifaceted interplay with the malignant biliary epithelial counterpart. We ultimately hope to provide the working knowledge on how their manipulation may lead to a therapeutic gain in cholangiocarcinoma.
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Affiliation(s)
- Luca Fabris
- Department of Molecular Medicine, University of Padua, Padova, Italy
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - María Jesús Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Joachim Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Niklas K. Björkström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Thorsten Cramer
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
- ESCAM – European Surgery Center Aachen Maastricht, Germany and The Netherlands
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Ana Lleo
- Division of Internal Medicine and Hepatology, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy
| | - Antonio Solinas
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Hanna Sänger
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital, Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Veronika Lukacs-Kornek
- Institute of Experimental Immunology, University Hospital, Friedrich-Wilhelms-Universität Bonn, Germany
| | - Anja Moncsek
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Alexander Siebenhüner
- Department of Hematology and Medical Oncology, University Hospital Zürich, Zürich, Switzerland
| | - Mario Strazzabosco
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA
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14
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Zhao Q, Zheng B, Meng S, Xu Y, Guo J, Chen LJ, Xiao J, Zhang W, Tan ZR, Tang J, Chen L, Chen Y. Increased expression of SLC46A3 to oppose the progression of hepatocellular carcinoma and its effect on sorafenib therapy. Biomed Pharmacother 2019; 114:108864. [PMID: 30981107 DOI: 10.1016/j.biopha.2019.108864] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 03/21/2019] [Accepted: 04/04/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) prognosis remains dismal due to postsurgical recurrence and distant metastasis. Therefore, novel prognostic biomarkers and therapeutic targets for HCC therapy are urgently needed to improve the survival of liver cancer patients. Our evidence suggests that SLC46A3 (the gene solute carrier family 46 (sodium phosphate), member 3) is a member of the SLC46 family and has a potential role in the progression and treatment of HCC. The objective of the present study was to estimate the expression pattern and biological function of SLC46A3 in the progression of HCC, which may serve as a promising biomarker for diagnosis and therapy. In order to determine the expression pattern of SLC46A3 in HCC, several public HCC databases and tissue chips were used to examine 129 sets of primary HCC and non-tumor adjacent tissues from patients who had undergone surgery. The expression of SLC46A3 in 80 sets of HCC and non-tumor adjacent tissues were then compared by RT-PCR and Western Blot. The proliferation, invasion, migration and sphere-forming abilities of SLC46A3 knock-down and overexpressing cell lines were evaluated and the expression of related molecules in the epithelial mesenchymal transition (EMT) were detected by RT-PCR, western blot and immunofluorescence assay. The IC50 value was used to evaluate the effect of SLC46A3 on sorafenib resistance. A lung metastasis model of mice HCC was constructed to test the potential effect of SLC46A3 on cancer metastasis and a subcutaneous xenografted tumor mice model was designed to verify the effect of SLC46A3 on the resistance of HCC cell lines to sorafenib. The expression of SLC46A3 was down-regulated in 83.2% of human HCC tissues compared to non-tumor adjacent tissues. Tumors that expressed low levels of SLC46A3 had more aggressive phenotypes, and patients with these tumors had shorter survival times after surgery compared to patients whose tumors expressed high levels of SLC46A3. Hepatocellular carcinoma cell lines that stably overexpressed SLC46A3 inhibited the levels of migration and invasion compared with control HCC cells, and formed smaller xenograft tumors with more metastases in mice compared with HCC cells that did not overexpress SLC46A3. In addition, overexpression of SLC46A3 obviously inhibited epithelial-to-mesenchymal transition-activating transcription factors such as N-cadherin and Vimentin. Furthermore, descended of IC50 showed that overexpressed SLC46A3 could reduce sorafenib resistance and improve drug response in vivo and in vitro. In conclusion, increased expression of SLC46A3 could favor a better clinical prognosis for patients with HCC, ameliorate sorafenib resistance, and improve drug response. SLC46A3 might serve as a potential prognostic biomarker and therapeutic target in HCC.
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Affiliation(s)
- Qing Zhao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
| | - Bo Zheng
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai 200438, PR China.
| | - Shiquan Meng
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai 200438, PR China.
| | - Ying Xu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
| | - Jing Guo
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
| | - Li-Jie Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
| | - Jian Xiao
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
| | - Zhi-Rong Tan
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
| | - Jie Tang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
| | - Lei Chen
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai 200438, PR China.
| | - Yao Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
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15
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Futsukaichi Y, Tajiri K, Kobayashi S, Nagata K, Yasumura S, Takahara T, Minemura M, Yasuda I. Combined hepatocellular-cholangiocarcinoma successfully treated with sorafenib: case report and review of the literature. Clin J Gastroenterol 2019; 12:128-134. [PMID: 30374884 DOI: 10.1007/s12328-018-0918-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 10/20/2018] [Indexed: 02/05/2023]
Abstract
Sorafenib, a multiple kinase inhibitor, has been established as first-line standard systemic chemotherapy for patients with advanced hepatocellular carcinoma (HCC). We encountered a patient with combined hepatocellular and cholangiocarcinoma (CHC) who achieved complete remission in response to sorafenib treatment. A 58-year old man with hepatitis C virus (HCV)-induced liver cirrhosis was diagnosed with CHC in segments 6th and 7th of the liver and underwent partial surgical resection. Three months later, CHC recurred as metastases at multiple intrahepatic sites, lymph nodes, and bones, making surgery impossible. Treatment with sorafenib was initiated at 400 mg b.i.d., later reduced to 400 mg/day. After 6 months of sorafenib administration, he no longer showed abnormal uptake on fluorodeoxyglucose positron emission tomography. He was continued on sorafenib for 2.5 years, but later discontinued due to adverse events. He has shown no evidence of tumor recurrence more than 1 year after sorafenib discontinuation. His HCV was eradicated by direct-acting antivirals, and he remains in good health.
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Affiliation(s)
- Yuka Futsukaichi
- Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Kazuto Tajiri
- Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan.
| | - Saito Kobayashi
- Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Kohei Nagata
- Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Satoshi Yasumura
- Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Terumi Takahara
- Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Masami Minemura
- Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Ichiro Yasuda
- Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan
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16
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Cheng R, Chen Y, Zhou H, Wang B, Du Q, Chen Y. B7-H3 expression and its correlation with clinicopathologic features, angiogenesis, and prognosis in intrahepatic cholangiocarcinoma. APMIS 2018; 126:396-402. [PMID: 29696716 DOI: 10.1111/apm.12837] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Accepted: 03/13/2018] [Indexed: 01/10/2023]
Abstract
This study was designed to explore the expression of B7-H3 in human intrahepatic cholangiocarcinoma (ICC) and its association with the clinicopathologic factors. In the current study, the expression of B7-H3 in 45 patients with intrahepatic cholangiocarcinoma and 8 patients with hepatolithiasis was analyzed by immunohistochemistry, which revealed that B7-H3 was not expressed in hepatolithiatic tissues, but positively expressed in 57.8% (26/45) of the ICC cases. The expression of B7-H3 was significantly associated with lymph node metastases and venous invasion. A positive correlation was also observed between the expression of B7-H3 and MVD, an index for tumor angiogenesis. Further survival analysis indicated that patients with B7-H3 negative expression had higher overall survival (OS) and cancer-specific survival (CSS) rates than those with B7-H3 positive expression. Multivariate analysis revealed that B7-H3 expression was an independent prognostic indicator for poor OS and CSS of ICC patients. Our results suggest that B7-H3 may be a valuable biomarker in determining tumor progression and prognosis of intrahepatic cholangiocarcinoma. It is also a potential target for antivascular therapy of ICC.
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Affiliation(s)
- Rui Cheng
- Department of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Yongqin Chen
- Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Haohui Zhou
- Department of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Bi Wang
- Department of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Qiang Du
- Department of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Yanling Chen
- Department of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
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17
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Heldin CH, Lennartsson J, Westermark B. Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis. J Intern Med 2018; 283:16-44. [PMID: 28940884 DOI: 10.1111/joim.12690] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Platelet-derived growth factor (PDGF) isoforms and their receptors have important roles during embryogenesis, particularly in the development of various mesenchymal cell types in different organs. In the adult, PDGF stimulates wound healing and regulates tissue homeostasis. However, overactivity of PDGF signalling is associated with malignancies and other diseases characterized by excessive cell proliferation, such as fibrotic conditions and atherosclerosis. In certain tumours, genetic or epigenetic alterations of the genes for PDGF ligands and receptors drive tumour cell proliferation and survival. Examples include the rare skin tumour dermatofibrosarcoma protuberance, which is driven by autocrine PDGF stimulation due to translocation of a PDGF gene, and certain gastrointestinal stromal tumours and leukaemias, which are driven by constitute activation of PDGF receptors due to point mutations and formation of fusion proteins of the receptors, respectively. Moreover, PDGF stimulates cells in tumour stroma and promotes angiogenesis as well as the development of cancer-associated fibroblasts, both of which promote tumour progression. Inhibitors of PDGF signalling may thus be of clinical usefulness in the treatment of certain tumours.
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Affiliation(s)
- C-H Heldin
- Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.,Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - J Lennartsson
- Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.,Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
| | - B Westermark
- Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden
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18
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Chemoresistance and chemosensitization in cholangiocarcinoma. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1444-1453. [PMID: 28600147 DOI: 10.1016/j.bbadis.2017.06.005] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Accepted: 06/05/2017] [Indexed: 02/07/2023]
Abstract
One of the main difficulties in the management of patients with advanced cholangiocarcinoma (CCA) is their poor response to available chemotherapy. This is the result of powerful mechanisms of chemoresistance (MOC) of quite diverse nature that usually act synergistically. The problem is often worsened by altered MOC gene expression in response to pharmacological treatment. Since CCA includes a heterogeneous group of cancers their genetic signature coding for MOC genes is also diverse; however, several shared traits have been defined. Some of these characteristics are shared with other types of liver cancer, namely hepatocellular carcinoma and hepatoblastoma. An important goal in modern oncologic pharmacology is to develop novel strategies to overcome CCA chemoresistance either by increasing drug specificity, such as in targeted therapies aimed to inhibit receptors with tyrosine kinase activity, or to increase the amounts of active agents inside CCA cells by enhancing drug uptake or reducing efflux through export pumps. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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19
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Rahnemai-Azar AA, Weisbrod AB, Dillhoff M, Schmidt C, Pawlik TM. Intrahepatic cholangiocarcinoma: current management and emerging therapies. Expert Rev Gastroenterol Hepatol 2017; 11:439-449. [PMID: 28317403 DOI: 10.1080/17474124.2017.1309290] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a malignancy with an increasing incidence and a high-case fatality. While surgery offers the best hope at long-term survival, only one-third of tumors are amenable to surgical resection at the time of the diagnosis. Unfortunately, conventional chemotherapy offers limited survival benefit in the management of unresectable or metastatic disease. Recent advances in understanding the molecular pathogenesis of iCCA and the use of next-generation sequencing techniques have provided a chance to identify 'target-able' molecular aberrations. These novel molecular therapies offer the promise to personalize therapy for patients with iCCA and, in turn, improve the outcomes of patients. Area covered: We herein review the current management options for iCCA with a focus on defining both established and emerging therapies. Expert commentary: Surgical resection remains as an only hope for cure in iCCA patients. However, frequently the diagnosis is delayed till advanced stages when surgery cannot be offered; signifying the urge for specific diagnostic tumor biomarkers and targeted therapies. New advances in genomic profiling have contributed to a better understanding of the landscape of molecular alterations in iCCA and offer hope for the development of novel diagnostic biomarkers and targeted therapies.
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Affiliation(s)
- Amir A Rahnemai-Azar
- a Department of Surgery , University of Washington Medical Center , Seattle , WA , USA
| | - Allison B Weisbrod
- b Department of Surgery , The Ohio State University Wexner Medical Center , Columbus , OH , USA
| | - Mary Dillhoff
- b Department of Surgery , The Ohio State University Wexner Medical Center , Columbus , OH , USA
| | - Carl Schmidt
- b Department of Surgery , The Ohio State University Wexner Medical Center , Columbus , OH , USA
| | - Timothy M Pawlik
- b Department of Surgery , The Ohio State University Wexner Medical Center , Columbus , OH , USA
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20
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Pan TT, Wang W, Jia WD, Xu GL. A single-center experience of sorafenib monotherapy in patients with advanced intrahepatic cholangiocarcinoma. Oncol Lett 2017; 13:2957-2964. [PMID: 28529557 PMCID: PMC5431743 DOI: 10.3892/ol.2017.5847] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Accepted: 01/26/2017] [Indexed: 12/14/2022] Open
Abstract
Patients with advanced intrahepatic cholangiocarcinoma (ICC) have a poor prognosis and the therapeutic options available for treating ICC are limited. Sorafenib, a multikinase inhibitor of vascular endothelial growth factor receptor 2 and 3, platelet derived growth factor receptor-β, B-Raf proto-oncogene, serine/threonine kinase and C-Raf proto-oncogene, serine/threonine kinase, is a novel reference standard for the treatment of advanced hepatocellular carcinoma. Sorafenib has previously been demonstrated to exhibit significant antitumor activity in various cholangiocarcinoma cell lines and in xenograft ICC models. The present study aimed to assess the efficacy and safety of sorafenib as a single-agent treatment in patients with advanced ICC. Eligible patients were administere no prior therapy for metastatic or unresectable disease. Sorafenib was administered orally at a dose of 400 mg twice daily continuously. The primary endpoint was considered as the disease control rate (DCR) at 12 weeks. Secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), duration of treatment (DOT) and the adverse event profile. A total of 15 patients were enrolled in the present study, with a median DOT of 3.2 months (range, 1.5-30 months). A total of 4 patients achieved a partial response and 7 patients achieved stable disease, with a DCR of 73.3%. The median OS time was 5.7 months [95% confidence interval (CI), 5.0-6.4], the PFS time was 5.5 months (95% CI, 3.9-7.1) and the median TTP was 3.2 months (range, 1.5-29 months). The most common toxicity was a skin rash, which w1as observed in 5 patients (33.3%). Grade 3 hand-foot syndrome was observed in 1 patient (6.7%), which required treatment termination. The results of the present study suggest that sorafenib monotherapy may exhibit promising anticancer activity in patients with advanced ICC and that it has a manageable toxicity profile.
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Affiliation(s)
- Ting-Ting Pan
- Department of Hepatic Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui 230001, P.R. China.,Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui 230001, P.R. China
| | - Wei Wang
- Department of Medical Oncology, Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui 230001, P.R. China
| | - Wei-Dong Jia
- Department of Hepatic Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui 230001, P.R. China.,Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui 230001, P.R. China
| | - Ge-Liang Xu
- Department of Hepatic Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui 230001, P.R. China.,Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui 230001, P.R. China
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21
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Luo X, Jia W, Huang Z, Li X, Xing B, Jiang X, Li J, Si A, Yang T, Gao C, Lau WY, Shen F. Effectiveness and safety of sorafenib in the treatment of unresectable and advanced intrahepatic cholangiocarcinoma: a pilot study. Oncotarget 2017; 8:17246-17257. [PMID: 27783997 PMCID: PMC5370037 DOI: 10.18632/oncotarget.12825] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 10/14/2016] [Indexed: 02/06/2023] Open
Abstract
Patients with unresectable and advanced intrahepatic cholangiocarcinoma (ICC) usually have short survival due to a lack of effective treatment. This multicenter, single arm, open labeled, prospective study was conducted to evaluate the effectiveness and safety of sorafenib combined with best supportive care (BSC) in these patients. We enrolled 44 patients with unresectable and advanced ICC who were treated with sorafenib (400 mg, twice daily) and BSC. The primary endpoint was disease control rate (DCR) at week 12, and the secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), duration of therapy (DOT), and adverse events (AEs). Our results showed that the DCR was 15.9%, the median TTP was 5.6 months, and the median PFS and OS were 3.2 and 5.7 months (95% confidence interval [CI]: 2.4-4.1 months; 3.7-8.5 months), respectively. The median DOT was 1.8 months (95% CI: 1.9-3.9 months). AEs of grades 1 and 2 events occurred in 75% of patients, and AE of grade 4 (severe) was observed in 1 patient. Therefore, sorafenib in combination with BSC had an acceptable DCR and safety profile in patients with unresectable and advanced ICC.
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Affiliation(s)
- Xiangji Luo
- Department of Biliary Surgery, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Weidong Jia
- Department of Hepatobiliary Surgery, The Anhui Provincial Hospital, Hefei, China
| | - Zhiyong Huang
- Department of Hepatobiliary Surgery, The Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangcheng Li
- Department of Hepatobiliary Surgery, The Jiangsu Provincial Peoples Hospital, Nanjing, China
| | - Baocai Xing
- Department of Hepatobiliary Surgery, The Beijing Cancer Hospital, Beijing, China
| | - Xiaoqing Jiang
- Department of Biliary Surgery, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jun Li
- Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Anfeng Si
- Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Tian Yang
- Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Chunfang Gao
- Department of Laboratory Diagnosis, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wan Yee Lau
- Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, China
| | - Feng Shen
- Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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22
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Simone V, Brunetti O, Lupo L, Testini M, Maiorano E, Simone M, Longo V, Rolfo C, Peeters M, Scarpa A, Azzariti A, Russo A, Ribatti D, Silvestris N. Targeting Angiogenesis in Biliary Tract Cancers: An Open Option. Int J Mol Sci 2017; 18:418. [PMID: 28212293 PMCID: PMC5343952 DOI: 10.3390/ijms18020418] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2016] [Revised: 02/08/2017] [Accepted: 02/10/2017] [Indexed: 12/17/2022] Open
Abstract
Biliary tract cancers (BTCs) are characterized by a bad prognosis and the armamentarium of drugs for their treatment is very poor. Although the inflammatory status of biliary tract represents the first step in the cancerogenesis, the microenvironment also plays a key role in the pathogenesis of BTCs, promoting tumor angiogenesis, invasion and metastasis. Several molecules, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), are involved in the angiogenesis process and their expression on tumor samples has been explored as prognostic marker in both cholangiocarcinoma and gallbladder cancer. Recent studies evaluated the genomic landscape of BTCs and evidenced that aberrations in several genes enrolled in the pro-angiogenic signaling, such as FGF receptor-2 (FGFR-2), are characteristic of BTCs. New drugs targeting the signaling pathways involved in angiogenesis have been tested in preclinical studies both in vitro and in vivo with promising results. Moreover, several clinical studies tested monoclonal antibodies against VEGF and tyrosine kinase inhibitors targeting the VEGF and the MEK/ERK pathways. Herein, we evaluate both the pathogenic mechanisms of BTCs focused on angiogenesis and the preclinical and clinical data available regarding the use of new anti-angiogenic drugs in these malignancies.
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Affiliation(s)
- Valeria Simone
- Operative Unit of Internal Medicine, Hospital "F.Ferrari", 73042 Casarano (Le), Italy.
| | - Oronzo Brunetti
- Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
| | - Luigi Lupo
- Department of Emergency and Organ Transplantation, Institute of General Surgery and Liver Transplantation, University of Bari, 70124 Bari, Italy.
| | - Mario Testini
- Department of Biomedical Sciences and Human Oncology, Unit of Endocrine, Digestive and Emergency Surgery, 70124 Bari, Italy.
| | - Eugenio Maiorano
- Department of Emergency and Organ Transplantation, Operating Unit of Pathological Anatomy, "Aldo Moro" University, 70124 Bari, Italy.
| | - Michele Simone
- Surgical Oncology Unit, Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
| | - Vito Longo
- Medical Oncology Unit, Hospital of Taranto, 74010 Taranto, Italy.
| | - Christian Rolfo
- Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital & Center for Oncological Research, 2650 Edegem, Belgium.
| | - Marc Peeters
- Oncology Department, Antwerp University Hospital, 2650 Edegem, Belgium.
| | - Aldo Scarpa
- ARC-NET (Applied Research on Cancer-Network) Research Centre, University of Verona, 37134 Verona, Italy.
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy.
| | - Amalia Azzariti
- Preclinical and Clinical Pharmacology Unit, Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
| | - Antonio Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90144 Palermo, Italy.
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy.
- Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
| | - Nicola Silvestris
- Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
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23
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Squadroni M, Tondulli L, Gatta G, Mosconi S, Beretta G, Labianca R. Cholangiocarcinoma. Crit Rev Oncol Hematol 2016; 116:11-31. [PMID: 28693792 DOI: 10.1016/j.critrevonc.2016.11.012] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 11/07/2016] [Accepted: 11/22/2016] [Indexed: 12/15/2022] Open
Abstract
Biliary tract cancer accounts for <1% of all cancers and affects chiefly an elderly population, with predominance in men. We distinguish cholangiocarcinoma (intrahepatic, hilar and distal) and gallbladder cancer, with different pathogenesis and prognosis. The treatment is based on surgery (whenever possible), radiotherapy in selected cases, and chemotherapy. The standard cytotoxic treatment for advanced/metastatic disease is represented by the combination of gemcitabine and cisplatin, whereas fluoropyrimidines are generally administered in second line setting. At the present time, no biologic drug demonstrated a clear efficacy in this cancer, although the molecular characterisation could provide a promising basis for experimental treatments. A good supportive care and an early palliative care are warranted in most patients and should be delivered as a part of a global approach.
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Affiliation(s)
| | - Luca Tondulli
- Medical Oncology Unit, Borgo Roma Hospital, Verona, Italy
| | - Gemma Gatta
- Italian National Cancer Institute, Milan, Italy
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24
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Optimal combination of gemcitabine, sorafenib, and S-1 shows increased efficacy in treating cholangiocarcinoma in vitro and in vivo. Anticancer Drugs 2016; 27:600-8. [DOI: 10.1097/cad.0000000000000365] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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25
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Ding X, Chaiteerakij R, Moser CD, Shaleh H, Boakye J, Chen G, Ndzengue A, Li Y, Zhou Y, Huang S, Sinicrope FA, Zou X, Thomas MB, Smith CD, Roberts LR. Antitumor effect of the novel sphingosine kinase 2 inhibitor ABC294640 is enhanced by inhibition of autophagy and by sorafenib in human cholangiocarcinoma cells. Oncotarget 2016; 7:20080-92. [PMID: 26956050 PMCID: PMC4991440 DOI: 10.18632/oncotarget.7914] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 02/13/2016] [Indexed: 12/12/2022] Open
Abstract
Sphingosine kinase 2 (Sphk2) has an oncogenic role in cancer. A recently developed first-in-class Sphk2 specific inhibitor ABC294640 displays antitumor activity in many cancer models. However, the role of Sphk2 and the antitumor activity of its inhibitor ABC294640 are not known in cholangiocarcinoma. We investigated the potential of targeting Sphk2 for the treatment of cholangiocarcinoma. We found that Sphk2 is overexpressed in five established human cholangiocarcinoma cell lines (WITT, HuCCT1, EGI-1, OZ and HuH28) and a new patient-derived cholangiocarcinoma cell line (LIV27) compared to H69 normal cholangiocytes. Inhibition of Sphk2 by ABC294640 inhibited proliferation and induced caspase-dependent apoptosis. Furthermore, we found that ABC294640 inhibited STAT3 phosphorylation, one of the key signaling pathways regulating cholangiocarcinoma cell proliferation and survival. ABC294640 also induced autophagy. Inhibition of autophagy by bafilomycin A1 or chloroquine potentiated ABC294640-induced cytotoxicity and apoptosis. In addition, ABC294640 in combination with sorafenib synergistically inhibited cell proliferation of cholangiocarcinoma cells. Strong decreases in STAT3 phosphorylation were observed in WITT and HuCCT1 cells exposed to the ABC294640 and sorafenib combination. These findings provide novel evidence that Sphk2 may be a rational therapeutic target in cholangiocarcinoma. Combinations of ABC294640 with sorafenib and/or autophagy inhibitors may provide novel strategies for the treatment of cholangiocarcinoma.
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Affiliation(s)
- Xiwei Ding
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA
| | - Roongruedee Chaiteerakij
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA
- Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Catherine D. Moser
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA
| | - Hassan Shaleh
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA
| | - Jeffrey Boakye
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA
| | - Gang Chen
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA
| | - Albert Ndzengue
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA
| | - Ying Li
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA
| | - Yanling Zhou
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA
| | - Shengbing Huang
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA
| | - Frank A. Sinicrope
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA
| | - Xiaoping Zou
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Melanie B. Thomas
- Hollings Cancer Center, Division of Hematology-Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | | | - Lewis R. Roberts
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA
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26
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Marks EI, Yee NS. Molecular genetics and targeted therapeutics in biliary tract carcinoma. World J Gastroenterol 2016; 22:1335-1347. [PMID: 26819503 PMCID: PMC4721969 DOI: 10.3748/wjg.v22.i4.1335] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 10/29/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.
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27
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Cholangiocarcinoma: from molecular biology to treatment. Med Oncol 2015; 32:245. [PMID: 26427701 DOI: 10.1007/s12032-015-0692-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 09/25/2015] [Indexed: 12/23/2022]
Abstract
Cholangiocarcinoma is a rare tumor originating in the bile ducts, which, according to their anatomical location, is classified as intrahepatic, extrahepatic and hilar. Nevertheless, incidence rates have increased markedly in recent decades. With respect to tumor biology, several genetic alterations correlated with resistance to chemotherapy and radiotherapy have been identified. Here, we highlight changes in KRAS and TP53 genes that are normally associated with a more aggressive phenotype. Also IL-6 and some proteins of the BCL-2 family appear to be involved in the resistance that the cholangiocarcinoma presents toward conventional therapies. With regard to diagnosis, tumor markers most commonly used are CEA and CA 19-9, and although its use isolated appears controversial, their combined value has been increasingly advocated. In imaging terms, various methods are needed, such as abdominal ultrasound, computed tomography and cholangiopancreatography. Regarding therapy, surgical modalities are the only ones that offer chance of cure; however, due to late diagnosis, most patients cannot take advantage of them. Thus, the majority of patients are directed to other therapeutic modalities like chemotherapy, which, in this context, assumes a purely palliative role. Thus, it becomes urgent to investigate new therapeutic options for this highly aggressive type of tumor.
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28
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Yamada T, Abei M, Danjoh I, Shirota R, Yamashita T, Hyodo I, Nakamura Y. Identification of a unique hepatocellular carcinoma line, Li-7, with CD13(+) cancer stem cells hierarchy and population change upon its differentiation during culture and effects of sorafenib. BMC Cancer 2015; 15:260. [PMID: 25885470 PMCID: PMC4396571 DOI: 10.1186/s12885-015-1297-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2014] [Accepted: 03/31/2015] [Indexed: 12/26/2022] Open
Abstract
Backgrounds Cancer stem cell (CSC) research has highlighted the necessity of developing drugs targeting CSCs. We investigated a hepatocellular carcinoma (HCC) cell line that not only has CSC hierarchy but also shows phenotypic changes (population changes) upon differentiation of CSC during culture and can be used for screening drugs targeting CSC. Methods Based on a hypothesis that the CSC proportion should decrease upon its differentiation into progenitors (population change), we tested HCC cell lines (HuH-7, Li-7, PLC/PRF/5, HLF, HLE) before and after 2 months culture for several markers (CD13, EpCAM, CD133, CD44, CD90, CD24, CD166). Tumorigenicity was tested using nude mice. To evaluate the CSC hierarchy, we investigated reconstructivity, proliferation, ALDH activity, spheroid formation, chemosensitivity and microarray analysis of the cell populations sorted by FACS. Results Only Li-7 cells showed a population change during culture: the proportion of CD13 positive cells decreased, while that of CD166 positive cells increased. The high tumorigenicity of the Li-7 was lost after the population change. CD13(+)/CD166(−) cells showed slow growth and reconstructed the bulk Li-7 populations composed of CD13(+)/CD166(−), CD13(−)/CD166(−) and CD13(−)/CD166(+) fractions, whereas CD13(−)/CD166(+) cells showed rapid growth but could not reproduce any other population. CD13(+)/CD166(−) cells showed high ALDH activity, spheroid forming ability and resistance to 5-fluorouracil. Microarray analysis demonstrated higher expression of stemness-related genes in CD166(−) than CD166(+) fraction. These results indicated a hierarchy in Li-7 cells, in which CD13(+)/CD166(−) and CD13(−)/CD166(+) cells serve as slow growing CSCs and rapid growing progenitors, respectively. Sorafenib selectively targeted the CD166(−) fraction, including CD13(+) CSCs, which exhibited higher mRNA expression for FGF3 and FGF4, candidate biomarkers for sorafenib. 5-fluorouracil followed by sorafenib inhibited the growth of bulk Li-7 cells more effectively than the reverse sequence or either alone. Conclusions We identified a unique HCC line, Li-7, which not only shows heterogeneity for a CD13(+) CSC hierarchy, but also undergoes a “population change” upon CSC differentiation. Sorafenib targeted the CSC in vitro, supporting the use of this model for screening drugs targeting the CSC. This type of “heterogeneous, unstable” cell line may prove more useful in the CSC era than conventional “homogeneous, stable” cell lines. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1297-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Takeshi Yamada
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8575, Japan. .,Cell Engineering Division, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki, 305-0074, Japan.
| | - Masato Abei
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8575, Japan.
| | - Inaho Danjoh
- Functional Evaluation of Genomic Polymorphisms, Tohoku Medical Megabank Organization, Sendai, Japan.
| | - Ryoko Shirota
- Cell Engineering Division, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki, 305-0074, Japan.
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, 13-1, Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
| | - Ichinosuke Hyodo
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8575, Japan.
| | - Yukio Nakamura
- Cell Engineering Division, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki, 305-0074, Japan.
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Sie M, den Dunnen WFA, Lourens HJ, Meeuwsen-de Boer TGJ, Scherpen FJG, Zomerman WW, Kampen KR, Hoving EW, de Bont ESJM. Growth-factor-driven rescue to receptor tyrosine kinase (RTK) inhibitors through Akt and Erk phosphorylation in pediatric low grade astrocytoma and ependymoma. PLoS One 2015; 10:e0122555. [PMID: 25799134 PMCID: PMC4370756 DOI: 10.1371/journal.pone.0122555] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 02/23/2015] [Indexed: 01/20/2023] Open
Abstract
Up to now, several clinical studies have been started investigating the relevance of receptor tyrosine kinase (RTK) inhibitors upon progression free survival in various pediatric brain tumors. However, single targeted kinase inhibition failed, possibly due to tumor resistance mechanisms. The present study will extend our previous observations that vascular endothelial growth factor receptor (VEGFR)-2, platelet derived growth factor receptor (PDGFR)β, Src, the epidermal growth factor receptor (ErbB) family, and hepatocyte growth factor receptor (HGFR/cMet) are potentially drugable targets in pediatric low grade astrocytoma and ependymoma with investigations concerning growth-factor-driven rescue. This was investigated in pediatric low grade astrocytoma and ependymoma cell lines treated with receptor tyrosine kinase (RTK) inhibitors e.g. sorafenib, dasatinib, canertinib and crizotinib. Flow cytometry analyses showed high percentage of cells expressing VEGFR-1, fibroblast growth factor receptor (FGFR)-1, ErbB1/EGFR, HGFR and recepteur d’origine nantais (RON) (respectively 52-77%, 34-51%, 63-90%, 83-98%, 65-95%). Their respective inhibitors induced decrease of cell viability, measured with WST-1 cell viability assays. At least this was partially due to increased apoptotic levels measured by Annexin V/Propidium Iodide apoptosis assays. EGF, HGF and FGF, which are normally expressed in brain (tumor) tissue, showed to be effective rescue inducing growth factors resulting in increased cell survival especially during treatment with dasatinib (complete rescue) or sorafenib (partial rescue). Growth-factor-driven rescue was less prominent when canertinib or crizotinib were used. Rescue was underscored by significantly activating downstream Akt and/or Erk phosphorylation and increased tumor cell migration. Combination treatment showed to be able to overcome the growth-factor-driven rescue. In conclusion, our study highlights the extensive importance of environmentally present growth factors in developing tumor escape towards RTK inhibitors in pediatric low grade astrocytoma and ependymoma. It is of great interest to anticipate upon these results for the design of new therapeutic trials with RTK inhibitors in these pediatric brain tumors.
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Affiliation(s)
- Mariska Sie
- Department of Pediatrics, Beatrix Children’s Hospital, Pediatric Oncology/Hematology division, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Wilfred F. A. den Dunnen
- Department of Pathology and Medical Biology, Pathology division, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Harm Jan Lourens
- Department of Pediatrics, Beatrix Children’s Hospital, Pediatric Oncology/Hematology division, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Tiny G. J. Meeuwsen-de Boer
- Department of Pediatrics, Beatrix Children’s Hospital, Pediatric Oncology/Hematology division, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Frank J. G. Scherpen
- Department of Pediatrics, Beatrix Children’s Hospital, Pediatric Oncology/Hematology division, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Walderik W. Zomerman
- Department of Pediatrics, Beatrix Children’s Hospital, Pediatric Oncology/Hematology division, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Kim R. Kampen
- Department of Pediatrics, Beatrix Children’s Hospital, Pediatric Oncology/Hematology division, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Eelco W. Hoving
- Department of Neurosurgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Eveline S. J. M. de Bont
- Department of Pediatrics, Beatrix Children’s Hospital, Pediatric Oncology/Hematology division, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- * E-mail:
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New insights into the molecular pathogenesis of intrahepatic cholangiocarcinoma. J Gastroenterol 2014; 49:165-72. [PMID: 24145988 PMCID: PMC3944910 DOI: 10.1007/s00535-013-0894-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Accepted: 09/24/2013] [Indexed: 02/04/2023]
Abstract
Intrahepatic cholangiocarcinoma is an aggressive malignancy and is one of the most devastating cancers of the gastrointestinal tract. The molecular mechanisms contributing to the pathogenesis of these cancers are not well understood. The recognition and distinction of these cancers from other tumors such as perihilar or extrahepatic distal cholangiocarcinoma and hepatocellular carcinoma are important in defining the pathogenesis. New insights into molecular mechanisms contributing to disease pathogenesis are emerging from recent epidemiological, genome-wide profiling and laboratory based studies. These have contributed to an improved understanding of risk factors, genetic mutations and pathophysiological mechanisms that are associated with these tumors. The contribution of well-established risk factors such as biliary tract inflammation and key signaling pathways involved in intrahepatic cholangiocarcinoma are being further defined. These new insights have several important implications for both molecular diagnosis and therapy of these cancers.
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Andersen JB, Thorgeirsson SS. A perspective on molecular therapy in cholangiocarcinoma: present status and future directions. Hepat Oncol 2014; 1:143-157. [PMID: 24772266 PMCID: PMC3997260 DOI: 10.2217/hep.13.4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Cholangiocarcinoma (CCA) is an orphan cancer with limited understanding of its genetic and genomic pathogenesis. Typically, it is highly treatment-refractory and patient outcome is dismal. Currently, there are no approved therapeutics for CCA and surgical resection remains the only option with curative intent. Clinical trials are currently being performed in a mixed cohort of biliary tract cancers that includes intrahepatic CCA, extrahepatic/perihilar CCA, distal extrahepatic CCA, gallbladder carcinoma and, in rare cases, even pancreatic cancers. Today, clinical trials fail primarily because they are underpowered mixed cohorts and designed without intent to enrich for markers to optimize success for targeted therapy. This review aims to emphasize current clinical attempts for targeted therapy of CCA, as well as highlight promising new candidate pathways revealed by translational genomics.
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Affiliation(s)
- Jesper B Andersen
- National Cancer Institute, Laboratory of Experimental Carcinogenesis, NIH, Building 37, Room 4146A, 37 Convent Drive, Bethesda, MD 20892-4262, USA
- Biotech Research & Innovation Centre, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Snorri S Thorgeirsson
- National Cancer Institute, Laboratory of Experimental Carcinogenesis, NIH, Building 37, Room 4146A, 37 Convent Drive, Bethesda, MD 20892-4262, USA
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Abstract
Sorafenib (BAY 43-9006, Nexavar®) is an oral multiple tyrosine kinase inhibitor. Main targets are receptor tyrosine kinase pathways frequently deregulated in cancer such as the Raf-Ras pathway, vascular endothelial growth factor (VEGF) pathway, and FMS-like tyrosine kinase 3 (FLT3). Sorafenib was approved by the FDA in fast track for advanced renal cell cancer and hepatocellular cancer and shows good clinical activity in thyroid cancer. Multiple clinical trials are undertaken to further investigate the role of sorafenib alone or in combination for the treatment of various tumor entities.
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Affiliation(s)
- Jens Hasskarl
- Department Innere Medizin, Klinik für Innere Medizin I, Schwerpunkt Hämatologie, Onkologie und Stammzelltransplantation, Hugstetter Str. 55, 79102, Freiburg, Germany,
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Thomas MB. Systemic and targeted therapy for biliary tract tumors and primary liver tumors. Surg Oncol Clin N Am 2013; 23:369-81. [PMID: 24560115 DOI: 10.1016/j.soc.2013.11.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Tumors of the biliary tract and hepatocellular carcinoma (HCC) are complex tumors with heterogeneous carcinogenic mechanisms. Patients with hepatobiliary cancer have advances disease and need systematic therapy to palliate symptoms and extend survival. Development of effective systematic therapy is a significant unmet medical need. It is hoped that current and future clinical trials will identify additional effective systemic agents, combination systemic therapies, and combined modality options. The HCC community needs validated biomarkers to help identify the patients who will benefit most from emerging treatment options.
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Affiliation(s)
- Melanie Byrne Thomas
- Hollings Cancer Center, College of Medicine, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
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Heldin CH. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal 2013; 11:97. [PMID: 24359404 PMCID: PMC3878225 DOI: 10.1186/1478-811x-11-97] [Citation(s) in RCA: 365] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Accepted: 12/11/2013] [Indexed: 01/15/2023] Open
Abstract
Platelet-derived growth factor (PDGF) isoforms and PDGF receptors have important functions in the regulation of growth and survival of certain cell types during embryonal development and e.g. tissue repair in the adult. Overactivity of PDGF receptor signaling, by overexpression or mutational events, may drive tumor cell growth. In addition, pericytes of the vasculature and fibroblasts and myofibroblasts of the stroma of solid tumors express PDGF receptors, and PDGF stimulation of such cells promotes tumorigenesis. Inhibition of PDGF receptor signaling has proven to useful for the treatment of patients with certain rare tumors. Whether treatment with PDGF/PDGF receptor antagonists will be beneficial for more common malignancies is the subject for ongoing studies.
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Affiliation(s)
- Carl-Henrik Heldin
- Ludwig Institute for Cancer Research, Science for life laboratory, Uppsala University, Box 595SE-751 24 Uppsala, Sweden.
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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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Herraez E, Lozano E, Macias RIR, Vaquero J, Bujanda L, Banales JM, Marin JJG, Briz O. Expression of SLC22A1 variants may affect the response of hepatocellular carcinoma and cholangiocarcinoma to sorafenib. Hepatology 2013; 58:1065-1073. [PMID: 23532667 DOI: 10.1002/hep.26425] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Accepted: 03/22/2013] [Indexed: 12/12/2022]
Abstract
UNLABELLED Reduced drug uptake is an important mechanism of chemoresistance. Down-regulation of SLC22A1 encoding the organic cation transporter-1 (OCT1) may affect the response of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CGC) to sorafenib, a cationic drug. Here we investigated whether SLC22A1 variants may contribute to sorafenib chemoresistance. Complete sequencing and selective variant identification were carried out to detect single nucleotide polymorphisms (SNPs) in SLC22A1 complementary DNA (cDNA). In HCC and CGC biopsies, in addition to previously described variants, two novel alternative spliced variants and three SNPs were identified. To study their functional consequences, these variants were mimicked by directed mutagenesis and expressed in HCC (Alexander and SK-Hep-1) and CGC (TFK1) cells. The two novel described variants, R61S fs*10 and C88A fs*16, encoded truncated proteins unable to reach the plasma membrane. Both variants abolished OCT1-mediated uptake of tetraethylammonium, a typical OCT1 substrate, and were not able to induce sorafenib sensitivity. In cells expressing functional OCT1 variants, OCT1 inhibition with quinine prevented sorafenib-induced toxicity. Expression of OCT1 variants in Xenopus laevis oocytes and determination of quinine-sensitive sorafenib uptake by high-performance liquid chromatography-dual mass spectrometry confirmed that OCT1 is able to transport sorafenib and that R61S fs*10 and C88A fs*16 abolish this ability. Screening of these SNPs in 23 HCC and 15 CGC biopsies revealed that R61S fs*10 was present in both HCC (17%) and CGC (13%), whereas C88A fs*16 was only found in HCC (17%). Considering all SLC22A1 variants, at least one inactivating SNP was found in 48% HCC and 40% CGC. CONCLUSION Development of HCC and CGC is accompanied by the appearance of aberrant OCT1 variants that, together with decreased OCT1 expression, may dramatically affect the ability of sorafenib to reach active intracellular concentrations in these tumors.
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Affiliation(s)
- Elisa Herraez
- Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
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Kim CH, Chung CW, Lee HM, Kim DH, Kwak TW, Jeong YIL, Kang DH. Synergistic effects of 5-aminolevulinic acid based photodynamic therapy and celecoxib via oxidative stress in human cholangiocarcinoma cells. Int J Nanomedicine 2013; 8:2173-86. [PMID: 23807846 PMCID: PMC3685402 DOI: 10.2147/ijn.s44394] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
5-Aminolevulinic acid (ALA)-based photodynamic therapy (PDT) has the potential to kill cancer cells via apoptotic or necrotic signals that are dependent on the generation of intracellular reactive oxygen species (ROS). Celecoxib is an anti-inflammatory drug that induces intracellular ROS generation. We investigated whether the combined application of celecoxib and ALA-PDT improved the efficacy of PDT in human cholangiocarcinoma cells and in tumor bearing mice. In vitro, combined treatment of celecoxib and ALA-PDT increased phototoxicity and intracellular ROS levels after irradiation with 0.75 J/cm(2) when compared to ALA-PDT alone. Even though ROS levels increased with 0.25 J/cm(2) of irradiation, it did not influence phototoxicity. When heme oxygenase-1, a defensive protein induced by oxidative stress, was inhibited in the combined treatment group, phototoxicity was increased at both 0.25 J/cm(2) and 0.75 J/cm(2) of irradiation. We identified the combined effect of ALA-PDT and celecoxib through the increase of oxidative stress such as ROS. In vivo, about 40% tumor growth inhibition was observed with combined application of ALA-PDT and celecoxib when compared to ALA-PDT alone. The combined application of ALA-PDT and celecoxib could be an effective therapy for human cholangiocarcinoma. Moreover, use of a heme oxygenase-1 inhibitor with PDT could play an important role for management of various tumors involving oxidative stress.
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Affiliation(s)
- Cy Hyun Kim
- National Research and Development Center for Hepatobiliary Cancer, Research Institute for Convergence of Biomedical Science and Technology, Yangsan, Republic of Korea
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Kim DH, Jeong YI, Chung CW, Kim CH, Kwak TW, Lee HM, Kang DH. Preclinical evaluation of sorafenib-eluting stent for suppression of human cholangiocarcinoma cells. Int J Nanomedicine 2013; 8:1697-711. [PMID: 23658488 PMCID: PMC3646502 DOI: 10.2147/ijn.s43508] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background Cholangiocarcinoma is a malignant tumor arising from the epithelium of the bile ducts. In this study, we prepared sorafenib-loaded biliary stents for potential application as drug-delivery systems for localized treatment of extrahepatic cholangiocarcinoma. Methods A sorafenib-coated metal stent was prepared using an electrospray system with the aid of poly(ɛ-caprolactone) (PCL), and then its anticancer activity was investigated using human cholangiocellular carcinoma (HuCC)-T1 cells in vitro and a mouse tumor xenograft model in vivo. Anticancer activity of sorafenib against HuCC-T1 cells was evaluated by the proliferation test, matrix metalloproteinase (MMP) activity, cancer cell invasion, and angiogenesis assay in vitro and in vivo. Results The drug-release study showed that the increased drug content on the PCL film induced a faster drug-release rate. The growth of cancer cells on the sorafenib-loaded PCL film surfaces decreased in a dose-dependent manner. MMP-2 expression of HuCC-T1 cells gradually decreased according to sorafenib concentration. Furthermore, cancer cell invasion and tube formation of human umbilical vein endothelial cells significantly decreased at sorafenib concentrations higher than 10 mM. In the mouse tumor xenograft model with HuCC-T1 cells, sorafenib-eluting PCL films significantly inhibited the growth of tumor mass and induced apoptosis of tumor cells. Various molecular signals, such as B-cell lymphoma (Bcl)-2, Bcl-2-associated death promoter, Bcl-x, caspase-3, cleaved caspase-3, Fas, signal transducer and activator of transcription 5, extracellular signal-regulated kinases, MMP-9 and pan-janus kinase/stress-activated protein kinase 1, indicated that apoptosis, inhibition of growth and invasion was cleared on sorafenib-eluting PCL films. Conclusion These sorafenib-loaded PCL films are effective in inhibiting angiogenesis, proliferation and invasion of cancer cells. We suggest that sorafenib-loaded PCL film is a promising candidate for the local treatment of cholangiocarcinoma.
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Affiliation(s)
- Do Hyung Kim
- National Research and Development Center for Hepatobiliary Cancer, Pusan National University Yangsan Hospital, Yangsan, Gyeongsangnam-do, South Korea
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Inhibition of the placental growth factor decreases burden of cholangiocarcinoma and hepatocellular carcinoma in a transgenic mouse model. Eur J Gastroenterol Hepatol 2012; 24:1020-32. [PMID: 22772092 DOI: 10.1097/meg.0b013e3283554219] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Hepatocellular carcinoma and cholangiocarcinoma form the majority of primary hepatic tumours and are the third most common cause of cancer-related deaths. These liver tumours rapidly outgrow their vascular supply and become hypoxic, resulting in the production of hypoxia inducible factors and triggering the angiogenic switch. Therefore, inhibiting angiogenesis has proven to be a valuable therapeutic strategy in hepatocellular carcinoma, yet less is known about its use in cholangiocarcinoma. In this study, we assess whether inhibiting the placental growth factor (PlGF) could offer a therapeutic option in mice with hepatocellular carcinoma and cholangiocarcinoma. PlGF is a homologue of the vascular endothelial growth factor, which is only involved in pathological angiogenesis, therefore, its inhibition does not induce adverse effects. METHODS We have used a chemically induced transgenic mouse model in which both hepatocellular carcinoma and cholangiocarcinoma develop after 25 weeks and are treated with murine monoclonal antibodies targeting PlGF. RESULTS This study has shown for the first time that inhibiting PlGF decreases the burden of cholangiocarcinoma, by affecting both angiogenesis and inflammation. CONCLUSION The use of monoclonal antibodies targeting PlGF could thus offer a potential systemic treatment for patients who suffer from primary liver tumours.
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El-Khoueiry AB, Rankin CJ, Ben-Josef E, Lenz HJ, Gold PJ, Hamilton RD, Govindarajan R, Eng C, Blanke CD. SWOG 0514: a phase II study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma. Invest New Drugs 2012; 30:1646-51. [PMID: 21748296 PMCID: PMC3490705 DOI: 10.1007/s10637-011-9719-0] [Citation(s) in RCA: 121] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2011] [Accepted: 07/05/2011] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Gallbladder and cholangiocarcinomas represent a heterogeneous group of malignant diseases that commonly present at an advanced stage and have limited therapeutic options. Based on the role of the Ras-Raf-Mek-Erk pathway and the VEGF axis in biliary carcinomas, we conducted a phase II study of sorafenib in patients with advanced biliary cancers. METHODS Eligible patients had no prior therapy for metastatic or unresectable disease. Sorafenib was administered at 400 mg po twice daily continuously. RESULTS The study was terminated after the first stage of accrual due to failure to meet the primary objective. A confirmed response rate of 0% (0%-11%) was observed. Thirty-nine percent of patients demonstrated stable disease (including 2 with unconfirmed PR). PFS was 3 months (95% CI: 2-4 months) and OS 9 months (95% CI: 4-12 months). The most common grade 3 and 4 toxicities included hand-foot skin reaction (13%), bilirubin elevation (13%), venous thromboembolism (10%), AST/ALT elevation (10%) and elevated alkaline phosphatase (10%). CONCLUSION While treatment with sorafenib did not result in objective responses, patients with biliary cancers receiving this drug had some therapeutic benefit. Additional studies with sorafenib in combination with chemotherapy or other targeted agents may be warranted.
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Affiliation(s)
- Anthony B El-Khoueiry
- University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Ave, Suite 3459, Los Angeles, CA 90033, USA.
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Igarashi S, Matsubara T, Harada K, Ikeda H, Sato Y, Sasaki M, Matsui O, Nakanuma Y. Bile duct expression of pancreatic and duodenal homeobox 1 in perihilar cholangiocarcinogenesis. Histopathology 2012; 61:266-76. [PMID: 22594685 DOI: 10.1111/j.1365-2559.2012.04218.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
AIMS Pancreatic and duodenal homeobox 1 (Pdx1) is a transcription factor that is crucial in embryogenic development and differentiation of pancreas, and its overexpression is reportedly involved in the progression of many malignancies, including pancreatic carcinoma. In this study, the role of Pdx1 was examined in cholangiocarcinogenesis. METHODS AND RESULTS Forty-three cases of human cholangiocarcinoma (CC) and 66 cases of hepatolithiasis or primary sclerosing cholangitis (PSC) with biliary intraepithelial neoplasia (BilIN) lesions and also eight fetal and 20 adult normal livers were examined immunohistochemically. Pdx1 was constantly expressed in the nuclei of fetal bile ducts, but was virtually absent in the large bile ducts of adults. By contrast, Hairy and enhancer of split 1 (Hes1), which represses pancreatic exocrine and endocrine differentiation, was expressed frequently in the adult bile ducts. Pdx1 was expressed in 67% of invasive CCs. In large bile ducts, expression of Pdx1 increased while that of Hes1 decreased during the progression of BilIN lesions to CC. Expression of Pdx1 correlated with proliferative activities in CCs. In an in vitro study, all three CC cell lines expressed Pdx1 mRNA and protein. CONCLUSION Up-regulation of Pdx1 is a feature of cholangiocarcinogenesis associated with chronic cholangitis. Furthermore, expression of Pdx1 in CC is related to increased proliferative activity in CCs.
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Affiliation(s)
- Saya Igarashi
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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Zhang Y, Zhao J, Du YJ. Progress in understanding the relationship between vascular endothelial growth factor and digestive tumors. Shijie Huaren Xiaohua Zazhi 2011; 19:2703-2708. [DOI: 10.11569/wcjd.v19.i26.2703] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Digestive tumors account for a large portion of human malignancies, and their incidence and mortality are on the rise. Neovascularization plays a critical role in the metastasis of tumors. Vascular endothelial growth factor (VEGF) is one of the best characterized angiogenic regulators. There is close relationship between VEGF and tumor growth, invasion and metastasis. VEGF has become a research hot for diagnosis, targeted therapy and prognosis of tumors. The purpose of this review is to review the recent progress in understanding the relationship between VEGF and digestive tumors.
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