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Li H, Zhang J, Gu L. Efficacy and safety of maintenance therapy with anlotinib for advanced cholangiocarcinoma after first-line chemotherapy and the variations in efficacy based on different neutrophil-to-lymphocyte ratio (NLR). World J Surg Oncol 2024; 22:200. [PMID: 39075470 PMCID: PMC11285264 DOI: 10.1186/s12957-024-03472-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 07/17/2024] [Indexed: 07/31/2024] Open
Abstract
OBJECTIVE This study aimed to evaluate the clinical efficacy and safety of anlotinib as maintenance therapy in patients with advanced cholangiocarcinoma following first-line chemotherapy. METHODS This retrospective study enrolled 154 patients with advanced biliary tract cancer admitted to the hospital between January 2020 and December 2022. All patients received first-line intravenous chemotherapy with gemcitabine combined with cisplatin, oxaliplatin, or tegafur. Among the 106 patients who achieved disease control, 47 received oral anlotinib hydrochloride (12 mg daily, 2 weeks on/1 week off) as maintenance therapy. Clinical efficacy, including ORR, DCR, DOR, PFS, and OS, was compared between the anlotinib maintenance and non-maintenance groups. Subgroup analysis based on NLR levels was also performed. RESULTS Among the 47 anlotinib maintenance patients, the ORR was 21.28% and the DCR was 51.06%. The median DOR was 36 weeks, and the median PFS was 43 weeks in the anlotinib group, versus 28 weeks and 38 weeks in the non-maintenance group, respectively. The median OS was not reached in the anlotinib group but was 48 weeks in the non-maintenance group. Patients receiving anlotinib maintenance had significantly longer DOR, PFS, and OS (all p < 0.05). Patients with low NLR levels had better survival benefits from anlotinib. CONCLUSION Maintenance therapy with anlotinib demonstrates potential efficacy and a reliable safety profile in patients with advanced cholangiocarcinoma following first-line treatment. The efficacy of anlotinib therapy appears to be influenced by NLR levels. Further validation with larger sample sizes is warranted to strengthen the robustness and reliability of the results.
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Affiliation(s)
- Hui Li
- Department of Clinical Oncology, Affiliated Nanjing Tianyinshan Hospital, Pharmaceutical University, Nanjing, 210000, China
| | - Jue Zhang
- Department of Clinical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210000, China
| | - Lili Gu
- Department of General surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Xuanwu District, Nanjing City, 210000, Jiangsu Province, China.
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2
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Cillo U, Carraro A, Avolio AW, Cescon M, Di Benedetto F, Giannelli V, Magistri P, Nicolini D, Vivarelli M, Lanari J. Immunosuppression in liver transplant oncology: position paper of the Italian Board of Experts in Liver Transplantation (I-BELT). Updates Surg 2024; 76:725-741. [PMID: 38713396 DOI: 10.1007/s13304-024-01845-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 07/31/2023] [Indexed: 05/08/2024]
Abstract
Liver transplant oncology (TO) represents an area of increasing clinical and scientific interest including a heterogeneous group of clinical-pathological settings. Immunosuppressive management after LT is a key factor relevantly impacting result. However, disease-related guidance is still lacking, and many open questions remain in the field. Based on such a substantial lack of solid evidences, the Italian Board of Experts in Liver Transplantation (I-BELT) (a working group including representatives of all national transplant centers), unprecedently promoted a methodologically sound consensus conference on the topic, based on the GRADE approach. The group final recommendations are herein presented and commented. The 18 PICOs and Statements and their levels of evidence and grades of recommendation are reported and grouped into seven areas: (1) risk stratification by histopathological and bio-molecular parameters and role of mTORi post-LT; (2) steroids and HCC recurrence; (3) management of immunosuppression when HCC recurs after LT; (4) mTORi monotherapy; (5) machine perfusion and HCC recurrence after LT; (6) physiopathology of tumor-infiltrating lymphocytes and immunosuppression, the role of inflammation; (7) immunotherapy in liver transplanted patients. The interest in mammalian targets of rapamycin inhibitors (mTORi), for steroid avoidance and the need for a reduction to CNI exposure emerged from the consensus process. A selected list of unmet needs prompting further investigations have also been developed. The so far heterogeneous and granular approach to immunosuppression in oncologic patients deserves greater efforts for a more standardized therapeutic response to the different clinical scenarios. This consensus process makes a first unprecedented step in this direction, to be developed on a larger scale.
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Affiliation(s)
- Umberto Cillo
- Department of Surgical, Oncological and Gastroenterological Sciences, General Surgery 2 Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Padua University Hospital, Via Giustiniani 2, 34128, Padua, PD, Italy.
| | - Amedeo Carraro
- Liver Transplant Unit, Department of Surgery and Oncology, University Hospital Trust of Verona, Verona, Italy
| | - Alfonso W Avolio
- Department of General Surgery and Liver Transplantation, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Matteo Cescon
- General Surgery and Transplantation Unit, Department of Medical and Surgical Sciences, Azienda Ospedaliero-Universitaria-Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Fabrizio Di Benedetto
- Hepatopancreatobiliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Valerio Giannelli
- Liver Unit, Department of Liver Transplant, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - Paolo Magistri
- Hepatopancreatobiliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Daniele Nicolini
- Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Riuniti Hospital, Polytechnic University of Marche, Ancona, Italy
| | - Marco Vivarelli
- Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Riuniti Hospital, Polytechnic University of Marche, Ancona, Italy
| | - Jacopo Lanari
- Department of Surgical, Oncological and Gastroenterological Sciences, General Surgery 2 Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Padua University Hospital, Via Giustiniani 2, 34128, Padua, PD, Italy
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3
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Calvisi DF, Boulter L, Vaquero J, Saborowski A, Fabris L, Rodrigues PM, Coulouarn C, Castro RE, Segatto O, Raggi C, van der Laan LJW, Carpino G, Goeppert B, Roessler S, Kendall TJ, Evert M, Gonzalez-Sanchez E, Valle JW, Vogel A, Bridgewater J, Borad MJ, Gores GJ, Roberts LR, Marin JJG, Andersen JB, Alvaro D, Forner A, Banales JM, Cardinale V, Macias RIR, Vicent S, Chen X, Braconi C, Verstegen MMA, Fouassier L. Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance. Nat Rev Gastroenterol Hepatol 2023; 20:462-480. [PMID: 36755084 DOI: 10.1038/s41575-022-00739-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/20/2022] [Indexed: 02/10/2023]
Abstract
Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA.
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Affiliation(s)
- Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Scottish Centre, Institute of Genetics and Cancer, Edinburgh, UK
| | - Javier Vaquero
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Pedro M Rodrigues
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Cédric Coulouarn
- Inserm, Univ Rennes 1, OSS (Oncogenesis Stress Signalling), UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France
| | - Rui E Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Oreste Segatto
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Chiara Raggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC Transplantation Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Benjamin Goeppert
- Institute of Pathology and Neuropathology, Ludwigsburg, Germany
- Institute of Pathology, Kantonsspital Baselland, Liestal, Switzerland
| | - Stephanie Roessler
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Timothy J Kendall
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Ester Gonzalez-Sanchez
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - John Bridgewater
- Department of Medical Oncology, UCL Cancer Institute, London, UK
| | - Mitesh J Borad
- Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, AZ, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Jose J G Marin
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Alejandro Forner
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Liver Unit, Barcelona Clinic Liver Cancer (BCLC) Group, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Jesus M Banales
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Rocio I R Macias
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Silve Vicent
- University of Navarra, Centre for Applied Medical Research, Program in Solid Tumours, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, Instituto de Salud Carlos III), Madrid, Spain
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
| | - Chiara Braconi
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Monique M A Verstegen
- Department of Surgery, Erasmus MC Transplantation Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Laura Fouassier
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
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Lozano E, Sanchon-Sanchez P, Morente-Carrasco A, Chinchilla-Tábora LM, Mauriz JL, Fernández-Palanca P, Marin JJG, Macias RIR. Impact of Aberrant β-Catenin Pathway on Cholangiocarcinoma Heterogeneity. Cells 2023; 12:cells12081141. [PMID: 37190050 DOI: 10.3390/cells12081141] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/09/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
The poor prognosis of most cases of advanced cholangiocarcinoma (CCA) constitutes a severe problem in modern oncology, which is aggravated by the fact that the incidence of this liver cancer is increasing worldwide and is often diagnosed late, when surgical removal is not feasible. The difficulty of dealing with this deadly tumor is augmented by the heterogeneity of CCA subtypes and the complexity of mechanisms involved in enhanced proliferation, apoptosis avoidance, chemoresistance, invasiveness, and metastasis that characterize CCA. Among the regulatory processes implicated in developing these malignant traits, the Wnt/β-catenin pathway plays a pivotal role. Alteration of β-catenin expression and subcellular localization has been associated with worse outcomes in some CCA subtypes. This heterogeneity, which also affects cellular and in vivo models commonly used to study CCA biology and anticancer drug development, must be taken into account for CCA investigation to more accurately extrapolate basic laboratory research to the clinical situation. A better understanding of the altered Wnt/β-catenin pathway in relationship with the heterogeneous forms of CCA is mandatory for developing novel diagnostic tools and therapeutic strategies for patients suffering from this lethal disease.
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Affiliation(s)
- Elisa Lozano
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Paula Sanchon-Sanchez
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Ana Morente-Carrasco
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
- Area of Physiology, Faculty of Health Sciences, University Rey Juan Carlos, 28032 Alcorcón, Madrid, Spain
| | | | - José L Mauriz
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Institute of Biomedicine (IBIOMED), Universidad de León, 24071 León, Spain
| | - Paula Fernández-Palanca
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Institute of Biomedicine (IBIOMED), Universidad de León, 24071 León, Spain
| | - Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Rocio I R Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
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Haiaty S, Rashidi MR, Akbarzadeh M, Bazmany A, Mostafazadeh M, Nikanfar S, Shabkhizan R, Rezaeian R, Rahbarghazi R, Nouri M. Vandetanib alters the tumoricidal capacity of human breast cancer stem cells via inhibiting vasculogenic capacity. BIOIMPACTS : BI 2022; 13:405-413. [PMID: 37736340 PMCID: PMC10509738 DOI: 10.34172/bi.2022.24208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 08/24/2022] [Accepted: 09/12/2022] [Indexed: 09/23/2023]
Abstract
Introduction The inhibition of vascularization into tumor stroma as well as dynamic cell growth is the center of attention. Here, we aimed to examine the role of vandetanib on angiogenesis capacity of breast cancer stem cell (CSCs). Methods MDA-MB-231 cells were exposed to different doses of vandetanib and survival rate was monitored. Stimulatory effects of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF) were evaluated in vandetanib-treated MDA-MB-231 cells. In vitro tubulogenesis capacity was studied on the Matrigel surface. The synergistic effects of vandetanib on cell survival were also assessed after PI3K and/or Wnt3a inhibition. Vascular endothelial (VE)-cadherin, matrix metalloproteinase-2 (MMP-2), -9, Wnt3a, and p-Akt/Akt ratio were measured using western blotting. Results Vandetanib reduced survival rate in a dose-dependent manner (P<0.05). Proliferative effects associated with VEGF, FGF, and EGF were blunted in these cells pre-exposed to vandetanib (P<0.05). The microcirculation pattern's triple-negative breast cancer (TNBC) was suppressed by 1, 5 µM of vandetanib (P<0.05). Hence 1, 5 µM of vandetanib potentially decreased the population of CD24- cells. 1 and 5 µM of vandetanib inhibited cell proliferation by blocking PI3K and Wnt3a pathways and decreased the p-Akt/Akt ratio, Wnta3 protein levels (P<0.05). 1 and 5 µM vandetanib combined with PI3K inhibitor diminished metastatic markers including, MMP-2, and MMP-9. The concurrent treatment (PI3K, inhibitor+ 1, 5 µM vandetanib) also considerably reduced epithelial-mesenchymal transition (EMT) markers such as VE-cadherin (P<0.05). Conclusion Vandetanib suppressed vasculogenic mimicry (VM) networking through blunting stemness properties, coincided with suppression of VE-cadherin in CSCs.
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Affiliation(s)
- Sanya Haiaty
- Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran
- Research Center of Infectious Diseases and Tropical Medicine, Tabriz University of Medical Science, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad-Reza Rashidi
- Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Akbarzadeh
- Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Ahad Bazmany
- Research Center of Infectious Diseases and Tropical Medicine, Tabriz University of Medical Science, Tabriz, Iran
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University Of Mashhad, Mashhad, Iran
| | - Mostafa Mostafazadeh
- Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saba Nikanfar
- Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Roya Shabkhizan
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rostam Rezaeian
- Research Center of Infectious Diseases and Tropical Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Departmnt of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Nouri
- Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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6
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Zheng Q, Zhang B, Li C, Zhang X. Overcome Drug Resistance in Cholangiocarcinoma: New Insight Into Mechanisms and Refining the Preclinical Experiment Models. Front Oncol 2022; 12:850732. [PMID: 35372014 PMCID: PMC8970309 DOI: 10.3389/fonc.2022.850732] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/14/2022] [Indexed: 11/19/2022] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive tumor characterized by a poor prognosis. Therapeutic options are limited in patients with advanced stage of CCA, as a result of the intrinsic or acquired resistance to currently available chemotherapeutic agents, and the lack of new drugs entering into clinical application. The challenge in translating basic research to the clinical setting, caused by preclinical models not being able to recapitulate the tumor characteristics of the patient, seems to be an important reason for the lack of effective and specific therapies for CCA. So, there seems to be two ways to improve patient outcomes. The first one is developing the combination therapies based on a better understanding of the mechanisms contributing to the resistance to currently available chemotherapeutic agents. The second one is developing novel preclinical experimental models that better recapitulate the genetic and histopathological features of the primary tumor, facilitating the screening of new drugs for CCA patients. In this review, we discussed the evidence implicating the mechanisms underlying treatment resistance to currently investigated drugs, and the development of preclinical experiment models for CCA.
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Affiliation(s)
- Qingfan Zheng
- Department of Hepatobiliary and Pancreas Surgery, the Second Hospital of Jilin University, Changchun, China
| | - Bin Zhang
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Changfeng Li
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xuewen Zhang
- Department of Hepatobiliary and Pancreas Surgery, the Second Hospital of Jilin University, Changchun, China
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7
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Haiaty S, Rashidi MR, Akbarzadeh M, Bazmany A, Mostafazadeh M, Nikanfar S, Zibaei Z, Rahbarghazi R, Nouri M. Thymoquinone inhibited vasculogenic capacity and promoted mesenchymal-epithelial transition of human breast cancer stem cells. BMC Complement Med Ther 2021; 21:83. [PMID: 33663486 PMCID: PMC7931333 DOI: 10.1186/s12906-021-03246-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 02/11/2021] [Indexed: 02/07/2023] Open
Abstract
Background Vasculogenic mimicry (VM) is characterized by the formation of tubular structure inside the tumor stroma. It has been shown that a small fraction of cancer cells, namely cancer stem cells (CSCs), could stimulate the development of vascular units in the tumor niche, leading to enhanced metastasis to the remote sites. This study aimed to study the inhibitory effect of phytocompound, Thymoquinone (TQ), on human breast MDA-MB-231 cell line via monitoring Wnt/PI3K signaling pathway. Methods MDA-MB-231 CSCs were incubated with different concentrations of TQ for 48 h. The viability of CSCs was determined using the MTT assay. The combination of TQ and PI3K and Wnt3a inhibitors was examined in CSCs. By using the Matrigel assay, we measured the tubulogenesis capacity. The percent of CD24− CSCs and Rhodamine 123 efflux capacity was studied using flow cytometry analysis. Protein levels of Akt, p-Akt, Wnt3a, vascular endothelial-cadherin (VE-cadherin), and matrix metalloproteinases-2 and -9 (MMP-2 and -9) were detected by western blotting. Results TQ decreased the viability of CSCs in a dose-dependent manner. The combination of TQ with PI3K and Wnt3a inhibitors reduced significantly the survival rate compared to the control group (p < 0.05). TQ could blunt the stimulatory effect of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor (FGF) on CSCs (p < 0.05). The vasculogenic capacity of CSCs was reduced after being-exposed to TQ (p < 0.05). Western blotting revealed the decrease of CSCs metastasis by suppressing MMP-2 and -9. The protein level of VE-cadherin was also diminished in TQ-treated CSCs as compared to the control cell (p < 0.05), indicating inhibition of mesenchymal-endothelial transition (MendT). TQ could suppress Wnt3a and PI3K, which coincided with the reduction of the p-Akt/Akt ratio. TQ had the potential to decrease the number of CD24− CSCs and Rhodamine 123 efflux capacity after 48 h. Conclusion TQ could alter the vasculogenic capacity and mesenchymal-epithelial transition of human breast CSCs in vitro. Thus TQ together with anti-angiogenic therapies may be a novel therapeutic agent in the suppression of VM in breast cancer.
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Affiliation(s)
- Sanya Haiaty
- Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad-Reza Rashidi
- Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Akbarzadeh
- Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Biochemistry, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Ahad Bazmany
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University Of Mashhad, Mashhad, Iran.,Research Center of Infectious Diseases and Tropical Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Mostafa Mostafazadeh
- Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saba Nikanfar
- Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohre Zibaei
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Research Center of Infectious Diseases and Tropical Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran. .,Stem Cell Research Center, Tabriz University of Medical Sciences, Imam Reza St., Golgasht St, Tabriz, Iran. .,Departmnt of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohammad Nouri
- Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran. .,Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran. .,Stem Cell Research Center, Tabriz University of Medical Sciences, Imam Reza St., Golgasht St, Tabriz, Iran.
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8
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Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells. Sci Rep 2021; 11:2557. [PMID: 33510179 PMCID: PMC7844056 DOI: 10.1038/s41598-021-81172-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 12/29/2020] [Indexed: 12/12/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with marked resistance to chemotherapeutics without therapies. The tumour microenvironment of iCCA is enriched of Cancer-Stem-Cells expressing Epithelial-to-Mesenchymal Transition (EMT) traits, being these features associated with aggressiveness and drug resistance. Treatment with the anti-diabetic drug Metformin, has been recently associated with reduced incidence of iCCA. We aimed to evaluate the anti-cancerogenic effects of Metformin in vitro and in vivo on primary cultures of human iCCA. Our results showed that Metformin inhibited cell proliferation and induced dose- and time-dependent apoptosis of iCCA. The migration and invasion of iCCA cells in an extracellular bio-matrix was also significantly reduced upon treatments. Metformin increased the AMPK and FOXO3 and induced phosphorylation of activating FOXO3 in iCCA cells. After 12 days of treatment, a marked decrease of mesenchymal and EMT genes and an increase of epithelial genes were observed. After 2 months of treatment, in order to simulate chronic administration, Cytokeratin-19 positive cells constituted the majority of cell cultures paralleled by decreased Vimentin protein expression. Subcutaneous injection of iCCA cells previously treated with Metformin, in Balb/c-nude mice failed to induce tumour development. In conclusion, Metformin reverts the mesenchymal and EMT traits in iCCA by activating AMPK-FOXO3 related pathways suggesting it might have therapeutic implications.
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9
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Brandi G, Tavolari S. In Vitro and In Vivo Model Systems of Cholangiocarcinoma. DIAGNOSIS AND MANAGEMENT OF CHOLANGIOCARCINOMA 2021:471-494. [DOI: 10.1007/978-3-030-70936-5_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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10
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Lorenzo N, Sabina DM, Guido C, Ilaria Grazia Z, Samira S, Valeria A, Daniele C, Diletta O, Antonella G, Marco M, Daniela B, Valerio DP, Andrea O, Agostino Maria DR, Fabio M, Maria Consiglia B, Jessica F, Sara M, Gian Luca G, Pierluigi Benedetti P, Paquale Bartomeo B, Felice G, Vincenzo C, Pietro I, Giuseppina C, Eugenio G, Domenico A. DCLK1, a Putative Stem Cell Marker in Human Cholangiocarcinoma. Hepatology 2021; 73:144-159. [PMID: 32978808 PMCID: PMC8243252 DOI: 10.1002/hep.31571] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 08/20/2020] [Accepted: 09/02/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS Cholangiocarcinoma (CCA) is a very aggressive cancer showing the presence of high cancer stem cells (CSCs). Doublecortin-like kinase1 (DCLK1) has been demonstrated as a CSC marker in different gastroenterological solid tumors. Our aim was to evaluate in vitro the expression and the biological function of DCLK1 in intrahepatic CCA (iCCA) and perihilar CCA (pCCA). APPROACH AND RESULTS Specimens surgically resected of human CCA were enzymatically digested, submitted to immunosorting for specific CSC markers (LGR5 [leucine-rich repeat-containing G protein-coupled receptor], CD [clusters of differentiation] 90, EpCAM [epithelial cell adhesion molecule], CD133, and CD13), and primary cell cultures were prepared. DCLK1 expression was analyzed in CCA cell cultures by real-time quantitative PCR, western blot, and immunofluorescence. Functional studies have been performed by evaluating the effects of selective DCLK1 inhibitor (LRRK2-IN-1) on cell proliferation (MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay, cell population doubling time), apoptosis, and colony formation capacity. DCLK1 was investigated in situ by immunohistochemistry and real-time quantitative PCR. DCLK1 serum concentration was analyzed by enzyme-linked immunosorbent assay. We describe DCLK1 in CCA with an increased gene and protein DCLK1 expression in pCCALGR5+ and in iCCACD133+ cells compared with unsorted cells. LRRK2-IN-1 showed an anti-proliferative effect in a dose-dependent manner. LRRK2-IN-1 markedly impaired cell proliferation, induced apoptosis, and decreased colony formation capacity and colony size in both iCCA and pCCA compared with the untreated cells. In situ analysis confirmed that DCLK1 is present only in tumors, and not in healthy tissue. Interestingly, DCLK1 was detected in the human serum samples of patients with iCCA (high), pCCA (high), HCC (low), and cirrhosis (low), but it was almost undetectable in healthy controls. CONCLUSIONS DCLK1 characterizes a specific CSC subpopulation of iCCACD133+ and pCCALGR5+ , and its inhibition exerts anti-neoplastic effects in primary CCA cell cultures. Human DCLK1 serum might represent a serum biomarker for the early CCA diagnosis.
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Affiliation(s)
- Nevi Lorenzo
- Department of BiosciencesUniversity of MilanMilanItaly
- Department of Translational and Precision MedicineSapienza University of RomeRomeItaly
| | - Di Matteo Sabina
- Department of Translational and Precision MedicineSapienza University of RomeRomeItaly
- Department of ImmunologyBambino Gesù Children’s Hospital, IRCCSRomeItaly
| | - Carpino Guido
- Department of MovementHuman and Health SciencesUniversity of Rome “Foro Italico”RomeItaly
| | | | - Safarikia Samira
- Department of Translational and Precision MedicineSapienza University of RomeRomeItaly
| | - Ambrosino Valeria
- Department of Translational and Precision MedicineSapienza University of RomeRomeItaly
| | - Costantini Daniele
- Department of Translational and Precision MedicineSapienza University of RomeRomeItaly
| | - Overi Diletta
- Department of AnatomicalHistological, Forensic Medicine and Orthopedics SciencesSapienza University of RomeRomeItaly
| | - Giancotti Antonella
- Department of Maternal and Child Health and Urologic SciencesUmberto I HospitalSapienza University of RomeRomeItaly
| | - Monti Marco
- Department of Maternal and Child Health and Urologic SciencesUmberto I HospitalSapienza University of RomeRomeItaly
| | - Bosco Daniela
- Department of Pathological Anatomy and CytodiagnosticSapienza University of RomeRomeItaly
| | - De Peppo Valerio
- Hepatobiliary and Pancreatic Surgery IRCCSRegina Elena National Cancer InstituteRomeItaly
| | - Oddi Andrea
- Hepatobiliary and Pancreatic Surgery IRCCSRegina Elena National Cancer InstituteRomeItaly
| | - De Rose Agostino Maria
- Surgery, Hepatobiliary UnitCatholic University of the Sacred Heart School of Medicine and SurgeryRomeItaly
| | - Melandro Fabio
- Department of General Surgery and Organ TransplantationSapienza University of RomeRomeItaly
| | | | - Faccioli Jessica
- Department of Medico‐Surgical Sciences and BiotechnologiesSapienza University of RomeRomeItaly
| | - Massironi Sara
- Division of Gastroenterology and Center for Autoimmune Liver DiseasesDepartment of Medicine and SurgeryUniversity of Milan‐BicoccaMonzaItaly
- European Reference Network on Hepatological Diseases (ERN RARE‐LIVER)San Gerardo HospitalMonzaItaly
| | - Grazi Gian Luca
- Hepatobiliary and Pancreatic Surgery IRCCSRegina Elena National Cancer InstituteRomeItaly
| | - Panici Pierluigi Benedetti
- Department of Maternal and Child Health and Urologic SciencesUmberto I HospitalSapienza University of RomeRomeItaly
| | | | - Giuliante Felice
- Surgery, Hepatobiliary UnitCatholic University of the Sacred Heart School of Medicine and SurgeryRomeItaly
| | - Cardinale Vincenzo
- Department of Medico‐Surgical Sciences and BiotechnologiesSapienza University of RomeRomeItaly
| | - Invernizzi Pietro
- Division of Gastroenterology and Center for Autoimmune Liver DiseasesDepartment of Medicine and SurgeryUniversity of Milan‐BicoccaMonzaItaly
- European Reference Network on Hepatological Diseases (ERN RARE‐LIVER)San Gerardo HospitalMonzaItaly
| | | | - Gaudio Eugenio
- Department of AnatomicalHistological, Forensic Medicine and Orthopedics SciencesSapienza University of RomeRomeItaly
| | - Alvaro Domenico
- Department of Translational and Precision MedicineSapienza University of RomeRomeItaly
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11
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Martin Huertas R, Fuentes-Mateos R, Serrano Domingo JJ, Corral de la Fuente E, Rodríguez-Garrote M. Albumin-bound paclitaxel as new treatment for metastatic cholangiocarcinoma: A case report. World J Clin Oncol 2020; 11:844-853. [PMID: 33200077 PMCID: PMC7643189 DOI: 10.5306/wjco.v11.i10.844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/31/2020] [Accepted: 09/08/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cholangiocarcinomas are rare and very aggressive tumors. Most patients have advanced-stage or unresectable disease at presentation, and the systemic therapies have limited efficacy. Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free taxane that has been approved for the treatment of some cancers such as breast, non-small cell lung and pancreatic cancer, however it has not been applied to treat cholangiocarcinoma. We have both preclinical and clinical evidence of the efficacy of nab-paclitaxel in cholangiocarcinoma, yet no phase 3 trials have been made.
CASE SUMMARY A 63-year-old man was diagnosed in December 2016 with stage III B intrahepatic cholangiocarcinoma. Surgery was performed, followed by adjuvant chemotherapy treatment with capecitabine and gemcitabine; although, the gemcitabine was suspended due to allergic reaction after two cycles. In April 2019, metastatic cholangiocarcinoma relapse was diagnosed, and a first-line treatment with FOLFOX scheme was started. Eight cycles were administered, producing an initial clinical improvement and decrease in blood tumor marker levels. Radiological and serological progression was noted in September 2019. As a second-line treatment, FOLFIRI was not recommended due to risk of worsening the patient’s tumor-related diarrhea. A combination therapy with gemcitabine was not feasible, as the patient had previously suffered from an allergic reaction to this treatment. We decided to use nab-paclitaxel as a second-line treatment, and four cycles were administered. Both clinical and serological responses were observed, and a radiological mixed response was also noted.
CONCLUSION Advanced cholangiocarcinoma could be treated with nab-paclitaxel monotherapy, which should be studied in combination with other types of treatment (chemotherapy, fibroblast growth factor receptor inhibitors).
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Affiliation(s)
| | - Raquel Fuentes-Mateos
- Medical Oncology Department, Hospital Universitario Ramon y Cajal, Madrid 28034, Spain
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12
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Song F, Hu B, Cheng JW, Sun YF, Zhou KQ, Wang PX, Guo W, Zhou J, Fan J, Chen Z, Yang XR. Anlotinib suppresses tumor progression via blocking the VEGFR2/PI3K/AKT cascade in intrahepatic cholangiocarcinoma. Cell Death Dis 2020; 11:573. [PMID: 32709873 PMCID: PMC7381674 DOI: 10.1038/s41419-020-02749-7] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 06/28/2020] [Accepted: 06/30/2020] [Indexed: 12/15/2022]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor derived from bile duct epithelium. Its characteristics include an insidious onset and frequent recurrence or metastasis after surgery. Current chemotherapies and molecular target therapies provide only modest survival benefits to patients with ICC. Anlotinib is a novel multi-target tyrosine kinase inhibitor that has good antitumor effects in a variety of solid tumors. However, there are few studies of anlotinib-associated mechanisms and use as a treatment in ICC. In this study using in vitro experiments, we found that anlotinib had significant effects on proliferation inhibition, migration and invasion restraint, and cell-cycle arrestment. Anlotinib treatment affected induction of apoptosis and the mesenchymal-epithelial transition. Patient-derived xenograft models generated directly from patients with ICC revealed that anlotinib treatment dramatically hindered in vivo tumor growth. We also examined anlotinib's mechanism of action using transcriptional profiling. We found that anlotinib treatment might mainly inhibit tumor cell proliferation and invasion and promote apoptosis via cell-cycle arrestment by inactivating the VEGF/PI3K/AKT signaling pathway, as evidenced by significantly decreased phosphorylation levels of these kinases. The activation of vascular endothelial growth factor receptor 2 (VEGFR2) can subsequently activate PI3K/AKT signaling. We identified VEGRF2 as the main target of anlotinib. High VEGFR2 expression might serve as a promising indicator when used to predict a favorable therapeutic response. Taken together, these results indicated that anlotinib had excellent antitumor activity in ICC, mainly via inhibiting the phosphorylation level of VEGFR2 and subsequent inactivation of PIK3/AKT signaling. This work provides evidence and a rationale for using anlotinib to treat patients with ICC in the future.
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Grants
- National Key Research and Development Program (2016YFF0101405), the National Natural Science Foundation of China (81672839), the National Natural Science Foundation of China (81872355), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020103)。
- the Beijing Medical and Health Foundation (YWJKJJHKYJJ-F2093E), the Projects from the Shanghai Science and Technology Commission (19441905000)。
- the National Natural Science Foundation of China (81602543)。
- National Key Research and Development Program (2016YFC0902400), the State Key Program of National Natural Science of China (81830102), the National Natural Science Foundation of China (81572823), the National Natural Science Foundation of China (81772578)。
- the State Key Program of National Natural Science of China (81530077, the National Natural Science Foundation of China (81772551), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020105), the Shanghai Municipal Health Commission Collaborative Innovation Cluster Project (2019CXJQ02)。
- the National Natural Science Foundation of China (81871927), the Jiangsu Science and Technology Department Project (BL2014060), the Nantong Hepatobiliary and Pancreatic Surgery Disease Research Center Construction Project (HS2015001)。
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Affiliation(s)
- Fei Song
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, PR China
| | - Bo Hu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
| | - Jian-Wen Cheng
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
| | - Yun-Fan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
| | - Kai-Qian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
| | - Peng-Xiang Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
| | - Wei Guo
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, PR China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, PR China
| | - Zhong Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, PR China.
| | - Xin-Rong Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China.
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13
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Carpino G, Overi D, Melandro F, Grimaldi A, Cardinale V, Di Matteo S, Mennini G, Rossi M, Alvaro D, Barnaba V, Gaudio E, Mancone C. Matrisome analysis of intrahepatic cholangiocarcinoma unveils a peculiar cancer-associated extracellular matrix structure. Clin Proteomics 2019; 16:37. [PMID: 31687002 PMCID: PMC6821022 DOI: 10.1186/s12014-019-9257-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 10/24/2019] [Indexed: 12/18/2022] Open
Abstract
Background Intrahepatic cholangiocarcinoma (iCCA) is a malignancy that arises from the intrahepatic biliary tree, showing high mortality rates due to its late clinical presentation and limited treatment options. iCCA is characterized by a dense, reactive desmoplastic stroma marked by a dramatic accumulation of extracellular matrix (ECM). Although recent results strongly suggest a relationship between increasing desmoplastic stroma and the enhanced malignant behaviour of iCCA, the importance of ECM proteins in the pathogenesis of iCCA still have to be addressed. Methods iCCA ECM fibrillar structural organization was characterized by histological analysis. ECM proteome profiles from decellularized iCCA and surrounding noncancerous tissues were analysed by nLC coupled to MALDI-TOF/TOF analysis. Results iCCA tissues displayed high levels of collagen fibers and low abundance of reticular and elastic fibers, suggesting stiffness and loss of polarity. The ECM proteome profiles of iCCA samples, when compared to those obtained from the surrounding noncancerous tissues showed a dismantling of the basement membrane, a reduced angiogenesis and a downregulation of oncosuppressive activity. In particular, we focused on the effects of the overexpression of collagen type III alpha 1 chain (COL3A1) in iCCA, thus providing evidences that COL3A1 promotes iCCA cells migration and is a component of tumor-associated aligned collagen. Conclusions Overall, this study contributes to the understanding of molecular basis underlying desmoplasia in iCCA and indicates the type III collagen as a promising therapeutic target.
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Affiliation(s)
- Guido Carpino
- 1Division of Health Sciences, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro de Bosis 6, 00135 Rome, Italy
| | - Diletta Overi
- 2Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Borelli 50, 00161 Rome, Italy
| | - Fabio Melandro
- 3Department of General Surgery and Organ Transplantation "P. Stefanini", Sapienza University of Rome, Viale del Policlinico 151, 00161 Rome, Italy
| | - Alessio Grimaldi
- 4Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 151, 00161 Rome, Italy
| | - Vincenzo Cardinale
- 5Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100 Latina, Italy
| | - Sabina Di Matteo
- 6Department of Translational and Precision Medicine, Sapienza University of Rome, Viale del Policlinico 151, 00161 Rome, Italy
| | - Gianluca Mennini
- 3Department of General Surgery and Organ Transplantation "P. Stefanini", Sapienza University of Rome, Viale del Policlinico 151, 00161 Rome, Italy
| | - Massimo Rossi
- 3Department of General Surgery and Organ Transplantation "P. Stefanini", Sapienza University of Rome, Viale del Policlinico 151, 00161 Rome, Italy
| | - Domenico Alvaro
- 6Department of Translational and Precision Medicine, Sapienza University of Rome, Viale del Policlinico 151, 00161 Rome, Italy
| | - Vincenzo Barnaba
- 4Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 151, 00161 Rome, Italy
| | - Eugenio Gaudio
- 2Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Borelli 50, 00161 Rome, Italy
| | - Carmine Mancone
- 7Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy
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14
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Models for Understanding Resistance to Chemotherapy in Liver Cancer. Cancers (Basel) 2019; 11:cancers11111677. [PMID: 31671735 PMCID: PMC6896032 DOI: 10.3390/cancers11111677] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 10/23/2019] [Accepted: 10/24/2019] [Indexed: 12/19/2022] Open
Abstract
The lack of response to pharmacological treatment constitutes a substantial limitation in the handling of patients with primary liver cancers (PLCs). The existence of active mechanisms of chemoresistance (MOCs) in hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma hampers the usefulness of chemotherapy. A better understanding of MOCs is needed to develop strategies able to overcome drug refractoriness in PLCs. With this aim, several experimental models are commonly used. These include in vitro cell-free assays using subcellular systems; studies with primary cell cultures; cancer cell lines or heterologous expression systems; multicellular models, such as spheroids and organoids; and a variety of in vivo models in rodents, such as subcutaneous and orthotopic tumor xenografts or chemically or genetically induced liver carcinogenesis. Novel methods to perform programmed genomic edition and more efficient techniques to isolate circulating microvesicles offer new opportunities for establishing useful experimental tools for understanding the resistance to chemotherapy in PLCs. In the present review, using three criteria for information organization: (1) level of research; (2) type of MOC; and (3) type of PLC, we have summarized the advantages and limitations of the armamentarium available in the field of pharmacological investigation of PLC chemoresistance.
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15
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Gentilini A, Caligiuri A, Raggi C, Rombouts K, Pinzani M, Lori G, Correnti M, Invernizzi P, Rovida E, Navari N, Di Matteo S, Alvaro D, Banales JM, Rodrigues P, Raschioni C, Donadon M, Di Tommaso L, Marra F. CXCR7 contributes to the aggressive phenotype of cholangiocarcinoma cells. Biochim Biophys Acta Mol Basis Dis 2019; 1865:2246-2256. [PMID: 31059778 DOI: 10.1016/j.bbadis.2019.04.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 12/20/2018] [Accepted: 01/06/2019] [Indexed: 12/15/2022]
Abstract
Development of cholangiocarcinoma (CCA) is dependent on a cross-talk with stromal cells, which release different chemokines including CXCL12, that interacts with two different receptors, CXCR4 and CXCR7. The aim of the present study was to investigate the role of CXCR7 in CCA cells. CXCR7 is overexpressed by different CCA cell lines and in human CCA specimens. Knock-down of CXCR7 in HuCCT-1 cells reduced migration, invasion, and CXCL12-induced adhesion to collagen I. Survival of CCA was also reduced in CXCR7-silenced cells. The ability of CXCL12 to induce cell migration and survival was also blocked by CCX733, a CXCR7 antagonist. Similar effects of CXCR7 activation were observed in CCLP-1 cells and in primary iCCA cells. Enrichment of tumor stem-like cells by a 3D culture system resulted in increased CXCR7 expression compared to cells grown in monolayers, and genetic knockdown of CXCR7 robustly reduced sphere formation both in HuCCT-1 and in CCLP-1 cells. In HuCCT-1 cells CXCR7 was found to interact with β-arrestin 2, which was necessary to mediate CXCL12-induced migration, but not survival. In conclusion, CXCR7 is widely expressed in CCA, and contributes to the aggressive phenotype of CCA cells, inducing cell migration, invasion, adhesion, survival, growth and stem cell-like features. Cell migration induced by CXCR7 requires interaction with β-arrestin 2.
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Affiliation(s)
- Alessandra Gentilini
- Department of Experimental and Clinical Medicine, University of Florence, Italy.
| | - Alessandra Caligiuri
- Department of Experimental and Clinical Medicine, University of Florence, Italy.
| | - Chiara Raggi
- Department of Experimental and Clinical Medicine, University of Florence, Italy; Center for Autoimmune Liver Diseases IRCCS Istituto Clinico Humanitas, Rozzano, MI, Italy.
| | - Krista Rombouts
- University College London (UCL), Institute for Liver and Digestive Health, Royal Free Hospital, London, UK.
| | - Massimo Pinzani
- University College London (UCL), Institute for Liver and Digestive Health, Royal Free Hospital, London, UK.
| | - Giulia Lori
- Department of Experimental and Clinical Medicine, University of Florence, Italy.
| | - Margherita Correnti
- Center for Autoimmune Liver Diseases IRCCS Istituto Clinico Humanitas, Rozzano, MI, Italy.
| | | | - Elisabetta Rovida
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Italy.
| | - Nadia Navari
- Department of Experimental and Clinical Medicine, University of Florence, Italy.
| | - Sabina Di Matteo
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy.
| | - Domenico Alvaro
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy.
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, CIBERehd, Ikerbasque, San Sebastian, Spain.
| | - Pedro Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, CIBERehd, Ikerbasque, San Sebastian, Spain.
| | - Carlotta Raschioni
- Oncology Experimental Therapeutics, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
| | - Matteo Donadon
- Department of Pathology, IRCCS Humanitas Clinical Institute, Rozzano, MI, Italy.
| | - Luca Di Tommaso
- Pathology Unit, Humanitas Clinical and Research Center, Rozzano, MI, Italy; Department of Biomedical Sciences, Humanitas University, Rozzano, MI, Italy.
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Italy.
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16
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Xin P, Xu W, Zhu X, Li C, Zheng Y, Zheng T, Cheng W, Peng Q. Protective autophagy or autophagic death: effects of BEZ235 on chronic myelogenous leukemia. Cancer Manag Res 2019; 11:7933-7951. [PMID: 31686909 PMCID: PMC6709803 DOI: 10.2147/cmar.s204472] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 07/05/2019] [Indexed: 12/11/2022] Open
Abstract
Purpose To investigate the effects of BEZ235 on chronic myeloid leukemia (CML) cells. Methods MTS assay was used to detect the proliferation of CML cells. The proteins expression were detected by Western blot assay. The effects of BEZ235 on autophagy in CML cells were verified through transmission electron microscopy and evaluated by laser confocal microscopy. Annexin V-FITC/PI double staining flow cytometry was used to detect apoptosis. A xenograft model was established to observe the therapeutic effect of BEZ235 in vivo. Results BEZ235 could inhibit the proliferation of CML cells; CQ and 3-MA could increase the proliferation inhibition and Z-VAD-FMK can reduce the proliferation inhibition of BEZ235 on CML cells (P<0.05). Results of TEM showed that the autophagosomes of CML cells treated with BEZ235 increased (P<0.05). The results by confocal microscopy showed that the autophagic activity of K562 cells increased with BEZ235 treatment. When BEZ235 combined with CQ, BEZ235-induced autophagic flow was blocked. FCM results showed that BEZ235 could induces apoptosis in CML cells. Z-VAD-FMK could decrease the apoptosis of CML cells induced by BEZ235. CQ increased the apoptosis of CML cells induced by BEZ235 (P<0.05). Western blot showed that BEZ235 inhibited the phosphorylation of AKT and S6K. BEZ235 alone could upregulate the expression of cleaved caspase-3 and LC3II. When combined with Z-VAD-FMK, the expression of cleaved caspase-3 was lower than that of BEZ235 alone. When combined with CQ, the expression of cleaved caspase-3 and LC3II were higher than those of BEZ235 alone (P<0.05). BEZ235 could inhibit the growth of xenografts of CML cell line. Conclusion BEZ235 can inhibit the proliferation of CML cells, induce apoptosis, and enhance autophagy activity. It induces protective autophagy. The combination of CQ can enhance the apoptosis and proliferation inhibition of CML cells induced by BEZ235.
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Affiliation(s)
- Pengliang Xin
- Department of Haematology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, People's Republic of China
| | - Wenqian Xu
- Department of Haematology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, People's Republic of China
| | - Xiongpeng Zhu
- Department of Haematology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, People's Republic of China
| | - Chuntuan Li
- Department of Haematology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, People's Republic of China
| | - Yan Zheng
- Department of Haematology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, People's Republic of China
| | - Tingjin Zheng
- Central Laboratory, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, People's Republic of China
| | - Wenzhao Cheng
- Stem Cell Translational Research Center, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, People's Republic of China
| | - Qunyi Peng
- Department of Haematology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, People's Republic of China
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17
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Vicent S, Lieshout R, Saborowski A, Verstegen MMA, Raggi C, Recalcati S, Invernizzi P, van der Laan LJW, Alvaro D, Calvisi DF, Cardinale V. Experimental models to unravel the molecular pathogenesis, cell of origin and stem cell properties of cholangiocarcinoma. Liver Int 2019; 39 Suppl 1:79-97. [PMID: 30851232 DOI: 10.1111/liv.14094] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 02/10/2019] [Accepted: 02/25/2019] [Indexed: 12/11/2022]
Abstract
Human cholangiocarcinoma (CCA) is an aggressive tumour entity arising from the biliary tree, whose molecular pathogenesis remains largely undeciphered. Over the last decade, the advent of high-throughput and cell-based techniques has significantly increased our knowledge on the molecular mechanisms underlying this disease while, at the same time, unravelling CCA complexity. In particular, it becomes clear that CCA displays pronounced inter- and intratumoural heterogeneity, which is presumably the consequence of the interplay between distinct tissues and cells of origin, the underlying diseases, and the associated molecular alterations. To better characterize these events and to design novel and more effective therapeutic strategies, a number of CCA experimental and preclinical models have been developed and are currently generated. This review summarizes the current knowledge and understanding of these models, critically underlining their translational usefulness and limitations. Furthermore, this review aims to provide a comprehensive overview on cells of origin, cancers stem cells and their dynamic interplay within CCA tissue.
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Affiliation(s)
- Silvestre Vicent
- Program in Solid Tumors, Center for Applied Applied Medical Research, University of Navarra, Pamplona, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Ruby Lieshout
- Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Monique M A Verstegen
- Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Chiara Raggi
- Humanitas Clinical and Research Center, Rozzano, Italy.,Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Stefania Recalcati
- Department of Biomedical Sciences for Health, University of Milan, Milano, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center of Autoimmune Liver Diseases, Department of Medicine and Surgery, San Gerardo Hospita, l, University of Milano, Bicocca, Italy
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
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18
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Varamo C, Peraldo-Neia C, Ostano P, Basiricò M, Raggi C, Bernabei P, Venesio T, Berrino E, Aglietta M, Leone F, Cavalloni G. Establishment and Characterization of a New Intrahepatic Cholangiocarcinoma Cell Line Resistant to Gemcitabine. Cancers (Basel) 2019; 11:cancers11040519. [PMID: 30979003 PMCID: PMC6520787 DOI: 10.3390/cancers11040519] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 04/05/2019] [Accepted: 04/07/2019] [Indexed: 12/19/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is one of the most lethal liver cancers. Late diagnosis and chemotherapy resistance contribute to the scarce outfit and poor survival. Resistance mechanisms are still poorly understood. Here, we established a Gemcitabine (GEM) resistant model, the MT-CHC01R1.5 cell line, obtained by a GEM gradual exposure (up to 1.5 µM) of the sensitive counterpart, MT-CHC01. GEM resistance was irreversible, even at high doses. The in vitro and in vivo growth was slower than MT-CHC01, and no differences were highlighted in terms of migration and invasion. Drug prediction analysis suggested that Paclitaxel and Doxycycline might overcome GEM resistance. Indeed, in vitro MT-CHC01R1.5 growth was reduced by Paclitaxel and Doxycycline. Importantly, Doxycycline pretreatment at very low doses restored GEM sensitivity. To assess molecular mechanisms underlying the acquisition of GEM resistance, a detailed analysis of the transcriptome in MT-CHC01R1.5 cells versus the corresponding parental counterpart was performed. Transcriptomic analysis showed that most up-regulated genes were involved in cell cycle regulation and in the DNA related process, while most down-regulated genes were involved in the response to stimuli, xenobiotic metabolism, and angiogenesis. Furthermore, additional panels of drug resistance and epithelial to mesenchymal transition genes (n = 168) were tested by qRT-PCR and the expression of 20 genes was affected. Next, based on a comparison between qRT-PCR and microarray data, a list of up-regulated genes in MT-CHC01R1.5 was selected and further confirmed in a primary cell culture obtained from an ICC patient resistant to GEM. In conclusion, we characterized a new GEM resistance ICC model that could be exploited either to study alternative mechanisms of resistance or to explore new therapies.
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Affiliation(s)
- Chiara Varamo
- Department of Oncology, University of Turin, 10100 Torino, Italy.
- Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Center for Cancer Biology, KU Leuven, B3000 Leuven, Belgium.
| | | | - Paola Ostano
- Cancer Genomics Lab, Fondazione Edo ed Elvo Tempia, 13900 Biella, Italy.
| | - Marco Basiricò
- Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy.
| | - Chiara Raggi
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
- Dept. Medicina Sperimentale e Clinica, Università di Firenze, 50100 Florence, Italy.
| | - Paola Bernabei
- Flow Cytometry Center, Candiolo Cancer Institute FPO-IRCCS, 10060 Candiolo, Torino, Italy.
| | - Tiziana Venesio
- Molecular Pathology Lab, Unit of Pathology, Candiolo Cancer Institute FPO-IRCCS, 10060 Candiolo, Torino, Italy.
| | - Enrico Berrino
- Molecular Pathology Lab, Unit of Pathology, Candiolo Cancer Institute FPO-IRCCS, 10060 Candiolo, Torino, Italy.
- Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy.
| | - Massimo Aglietta
- Department of Oncology, University of Turin, 10100 Torino, Italy.
- Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy.
| | - Francesco Leone
- Department of Oncology, University of Turin, 10100 Torino, Italy.
- Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy.
| | - Giuliana Cavalloni
- Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy.
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19
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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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20
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Carpino G, Cardinale V, Folseraas T, Overi D, Grzyb K, Costantini D, Berloco PB, Di Matteo S, Karlsen TH, Alvaro D, Gaudio E. Neoplastic Transformation of the Peribiliary Stem Cell Niche in Cholangiocarcinoma Arisen in Primary Sclerosing Cholangitis. Hepatology 2019; 69:622-638. [PMID: 30102768 DOI: 10.1002/hep.30210] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 07/26/2018] [Indexed: 02/06/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic inflammatory cholangiopathy frequently complicated by cholangiocarcinoma (CCA). Massive proliferation of biliary tree stem/progenitor cells (BTSCs), expansion of peribiliary glands (PBGs), and dysplasia were observed in PSC. The aims of the present study were to evaluate the involvement of PBGs and BTSCs in CCA which emerged in PSC patients. Specimens from normal liver (n = 5), PSC (n = 20), and PSC-associated CCA (n = 20) were included. Samples were processed for histology, immunohistochemistry, and immunofluorescence. In vitro experiments were performed on human BTSCs, human mucinous primary CCA cell cultures, and human cholangiocyte cell lines (H69). Our results indicated that all CCAs emerging in PSC patients were mucin-producing tumors characterized by PBG involvement and a high expression of stem/progenitor cell markers. Ducts with neoplastic lesions showed higher inflammation, wall thickness, and PBG activation compared to nonneoplastic PSC-affected ducts. CCA showed higher microvascular density and higher expression of nuclear factor kappa B, interleukin-6, interleukin-8, transforming growth factor β, and vascular endothelial growth factor-1 compared to nonneoplastic ducts. CCA cells were characterized by a higher expression of epithelial-to-mesenchymal transition (EMT) traits and by the absence of primary cilia compared to bile ducts and PBG cells in controls and patients with PSC. Our in vitro study demonstrated that lipopolysaccharide and oxysterols (PSC-related stressors) induced the expression of EMT traits, the nuclear factor kappa B pathway, autophagy, and the loss of primary cilia in human BTSCs. Conclusion: CCA arising in patients with PSC is characterized by extensive PBG involvement and by activation of the BTSC niche in these patients, the presence of duct lesions at different stages suggests a progressive tumorigenesis.
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Affiliation(s)
- Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Trine Folseraas
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Krzysztof Grzyb
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Daniele Costantini
- Department of Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | | | - Sabina Di Matteo
- Department of Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Tom Hemming Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Domenico Alvaro
- Department of Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
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21
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Wu CE, Chen MH, Yeh CN. mTOR Inhibitors in Advanced Biliary Tract Cancers. Int J Mol Sci 2019; 20:E500. [PMID: 30682771 PMCID: PMC6386826 DOI: 10.3390/ijms20030500] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 01/19/2019] [Accepted: 01/22/2019] [Indexed: 12/19/2022] Open
Abstract
Patients with advanced biliary tract cancers (BTCs), including cholangiocarcinoma (CCA), have poor prognosis so novel treatment is warranted for advanced BTC. In current review, we discuss the limitations of current treatment in BTC, the importance of mTOR signalling in BTC, and the possible role of mTOR inhibitors as a future treatment in BTC. Chemotherapy with gemcitabine-based chemotherapy is still the standard of care and no targeted therapy has been established in advanced BTC. PI3K/AKT/mTOR signaling pathway linking to several other pathways and networks regulates cancer proliferation and progression. Emerging evidences reveal mTOR activation is associated with tumorigenesis and drug-resistance in BTC. Rapalogs, such as sirolimus and everolimus, partially inhibit mTOR complex 1 (mTORC1) and exhibit anti-cancer activity in vitro and in vivo in BTC. Rapalogs in clinical trials demonstrate some activity in patients with advanced BTC. New-generation mTOR inhibitors against ATP-binding pocket inhibit both TORC1 and TORC2 and demonstrate more potent anti-tumor effects in vitro and in vivo, however, prospective clinical trials are warranted to prove its efficacy in patients with advanced BTC.
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Affiliation(s)
- Chao-En Wu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou branch, Chang Gung University, Taoyuan 333, Taiwan.
| | - Ming-Huang Chen
- School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
- Department of Oncology, Taipei Veterans General Hospital, Taipei 112, Taiwan.
| | - Chun-Nan Yeh
- Department of General Surgery and Liver Research Center, Chang Gung Memorial Hospital, Linkou branch, Chang Gung University, Taoyuan 333, Taiwan.
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22
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The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma. PLoS One 2019; 14:e0210077. [PMID: 30677052 PMCID: PMC6345424 DOI: 10.1371/journal.pone.0210077] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 12/17/2018] [Indexed: 12/15/2022] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive cancer with high resistance to chemotherapeutics. CCA is enriched in cancer stem cells, which correlate with aggressiveness and prognosis. FXR, a member of the metabolic nuclear receptor family, is markedly down-regulated in human CCA. Our aim was to evaluate, in primary cultures of human intrahepatic CCA (iCCA), the effects of the FXR agonist obeticholic acid (OCA), a semisynthetic bile acid derivative, on their cancerogenic potential. Primary human iCCA cell cultures were prepared from surgical specimens of mucinous or mixed iCCA subtypes. Increasing concentrations (0-2.5 μM) of OCA were added to culture media and, after 3-10 days, effects on proliferation (MTS assay, cell population doubling time), apoptosis (annexin V-FITC/propidium iodide), cell migration and invasion (wound healing response and Matrigel invasion assay), and cancerogenic potential (spheroid formation, clonogenic assay, colony formation capacity) were evaluated. Results: FXR gene expression was downregulated (RT-qPCR) in iCCA cells vs normal human biliary tree stem cells (p < 0.05) and in mucinous iCCA vs mixed iCCA cells (p < 0.05) but was upregulated by addition of OCA. OCA significantly (p < 0.05) inhibited proliferation of both mucinous and mixed iCCA cells, starting at a concentration as low as 0.05 μM. Also, CDCA (but not UDCA) inhibited cell proliferation, although to a much lower extent than OCA, consistent with its different affinity for FXR. OCA significantly induced apoptosis of both iCCA subtypes and decreased their in vitro cancerogenic potential, as evaluated by impairment of colony and spheroid formation capacity and delayed wound healing and Matrigel invasion. In general, these effects were more evident in mixed than mucinous iCCA cells. When tested together with Gemcitabine and Cisplatin, OCA potentiated the anti-proliferative and pro-apoptotic effects of these chemotherapeutics, but mainly in mixed iCCA cells. OCA abolished the capacity of both mucinous and mixed iCCA cells to form colonies when administered together with Gemcitabine and Cisplatin. In subcutaneous xenografts of mixed iCCA cells, OCA alone or combined with Gemcitabine or Cisplatin markedly reduced the tumor size after 5 weeks of treatment by inducing necrosis of tumor mass and inhibiting cell proliferation. In conclusion, FXR is down-regulated in iCCA cells, and its activation by OCA results in anti-cancerogenic effects against mucinous and mixed iCCA cells, both in vitro and in vivo. The effects of OCA predominated in mixed iCCA cells, consistent with the lower aggressiveness and the higher FXR expression in this CCA subtype. These results, showing the FXR-mediated capacity of OCA to inhibit cholangiocarcinogenesis, represent the basis for testing OCA in clinical trials of CCA patients.
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23
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Li L, Knutsdottir H, Hui K, Weiss MJ, He J, Philosophe B, Cameron AM, Wolfgang CL, Pawlik TM, Ghiaur G, Ewald AJ, Mezey E, Bader JS, Selaru FM. Human primary liver cancer organoids reveal intratumor and interpatient drug response heterogeneity. JCI Insight 2019; 4:121490. [PMID: 30674722 DOI: 10.1172/jci.insight.121490] [Citation(s) in RCA: 150] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 12/05/2018] [Indexed: 12/28/2022] Open
Abstract
Liver cancer is the fourth leading cause of cancer-related mortality and is distinguished by a relative paucity of chemotherapy options. It has been hypothesized that intratumor genetic heterogeneity may contribute to the high failure rate of chemotherapy. Here, we evaluated functional heterogeneity in a cohort of primary human liver cancer organoid lines. Each primary human liver cancer surgical specimen was used to generate multiple cancer organoid lines, obtained from distinct regions of the tumor. A total of 27 liver cancer lines were established and tested with 129 cancer drugs, generating 3,483 cell survival data points. We found a rich intratumor, functional (drug response) heterogeneity in our liver cancer patients. Furthermore, we established that the majority of drugs were either ineffective, or effective only in select organoid lines. In contrast, we found that a subset of drugs appeared pan-effective, displaying at least moderate activity in the majority of these cancer organoid lines. These drugs, which are FDA approved for indications other than liver cancers, deserve further consideration as either systemic or local therapeutics. Of note, molecular profiles, obtained for a reduced sample set, did not correlate with the drug response heterogeneity of liver cancer organoid lines. Taken together, these findings lay the foundation for in-depth studies of pan-effective drugs, as well as for functional personalized oncology approaches. Lastly, these functional studies demonstrate the utility of cancer organoid drug testing as part of a drug discovery pipeline.
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Affiliation(s)
- Ling Li
- Division of Gastroenterology and Hepatology
| | | | - Ken Hui
- Division of Gastroenterology and Hepatology
| | - Matthew J Weiss
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jin He
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Benjamin Philosophe
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Andrew M Cameron
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Christopher L Wolfgang
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, Wexner Medical Center, James Cancer Hospital, Solove Research Institute, Health Services Management and Policy, The Ohio State University Ohio, USA
| | | | - Andrew J Ewald
- Departments of Cell Biology and Oncology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Joel S Bader
- Department of Biomedical Engineering and High-Throughput Biology Center
| | - Florin M Selaru
- Division of Gastroenterology and Hepatology.,Department of Oncology, Sidney Kimmel Cancer Center
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24
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Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives. Cancer Treat Rev 2018; 72:45-55. [PMID: 30476750 DOI: 10.1016/j.ctrv.2018.11.001] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 11/07/2018] [Accepted: 11/08/2018] [Indexed: 02/07/2023]
Abstract
Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches. The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes. Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy. This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.
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25
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Bragazzi MC, Ridola L, Safarikia S, Matteo SD, Costantini D, Nevi L, Cardinale V. New insights into cholangiocarcinoma: multiple stems and related cell lineages of origin. Ann Gastroenterol 2017; 31:42-55. [PMID: 29333066 PMCID: PMC5759612 DOI: 10.20524/aog.2017.0209] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 09/14/2017] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that may develop at any level of the biliary tree. CCA is currently classified into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) on the basis of its anatomical location. Notably, although these three CCA subtypes have common features, they also have important inter- and intra-tumor differences that can affect their pathogenesis and outcome. A unique feature of CCA is that it manifests in the hepatic parenchyma or large intrahepatic and extrahepatic bile ducts, furnished by two distinct stem cell niches: the canals of Hering and the peribiliary glands, respectively. The complexity of CCA pathogenesis highlights the need for a multidisciplinary, translational, and systemic approach to this malignancy. This review focuses on advances in the knowledge of CCA histomorphology, risk factors, molecular pathogenesis, and subsets of CCA.
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Affiliation(s)
- Maria Consiglia Bragazzi
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Lorenzo Ridola
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Samira Safarikia
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Sabina Di Matteo
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Daniele Costantini
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Lorenzo Nevi
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
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26
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Activation of Fas/FasL pathway and the role of c-FLIP in primary culture of human cholangiocarcinoma cells. Sci Rep 2017; 7:14419. [PMID: 29089545 PMCID: PMC5663931 DOI: 10.1038/s41598-017-14838-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 10/16/2017] [Indexed: 12/13/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) represents a heterogeneous group of malignancies emerging from the biliary tree, often in the context of chronic bile ducts inflammation. The immunological features of iCCA cells and their capability to control the lymphocytes response have not yet been investigated. The aims of the present study were to evaluate the interaction between iCCA cells and human peripheral blood mononuclear cells (PBMCs) and the role of Fas/FasL in modulating T-cells and NK-cells response after direct co-culture. iCCA cells express high levels of Fas and FasL that increase after co-culture with PBMCs inducing apoptosis in CD4+, CD8+ T-cells and in CD56+ NK-cells. In vitro, c-FLIP is expressed in iCCA cells and the co-culture with PBMCs induces an increase of c-FLIP in both iCCA cells and biliary tree stem cells. This c-FLIP increase does not trigger the caspase cascade, thus hindering apoptotis of iCCA cells which, instead, underwent proliferation. The increased expression of Fas, FasL and c-FLIP is confirmed in situ, in human CCA and in primary sclerosing cholangitis. In conclusion our data indicated that iCCA cells have immune-modulatory properties by which they induce apoptosis of T and NK cells, via Fas/FasL pathway, and escape inflammatory response by up-regulating c-FLIP system.
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Lustri AM, Di Matteo S, Fraveto A, Costantini D, Cantafora A, Napoletano C, Bragazzi MC, Giuliante F, De Rose AM, Berloco PB, Grazi GL, Carpino G, Alvaro D. TGF-β signaling is an effective target to impair survival and induce apoptosis of human cholangiocarcinoma cells: A study on human primary cell cultures. PLoS One 2017; 12:e0183932. [PMID: 28873435 PMCID: PMC5584931 DOI: 10.1371/journal.pone.0183932] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 08/14/2017] [Indexed: 12/15/2022] Open
Abstract
Cholangiocarcinoma (CCA) and its subtypes (mucin- and mixed-CCA) arise from the neoplastic transformation of cholangiocytes, the epithelial cells lining the biliary tree. CCA has a high mortality rate owing to its aggressiveness, late diagnosis and high resistance to radiotherapy and chemotherapeutics. We have demonstrated that CCA is enriched for cancer stem cells which express epithelial to mesenchymal transition (EMT) traits, with these features being associated with aggressiveness and drug resistance. TGF-β signaling is upregulated in CCA and involved in EMT. We have recently established primary cell cultures from human mucin- and mixed-intrahepatic CCA. In human CCA primary cultures with different levels of EMT trait expression, we evaluated the anticancer effects of: (i) CX-4945, a casein kinase-2 (CK2) inhibitor that blocks TGF-β1-induced EMT; and (ii) LY2157299, a TGF-β receptor I kinase inhibitor. We tested primary cell lines expressing EMT trait markers (vimentin, N-cadherin and nuclear catenin) but negative for epithelial markers, and cell lines expressing epithelial markers (CK19-positive) in association with EMT traits. Cell viability was evaluated by MTS assays, apoptosis by Annexin V FITC and cell migration by wound-healing assay. Results: at a dose of 10 μM, CX4945 significantly decreased cell viability of primary human cell cultures from both mucin and mixed CCA, whereas in CK19-positive cell cultures, the effect of CX4945 on cell viability required higher concentrations (>30μM). At the same concentrations, CX4945 also induced apoptosis (3- fold increase vs controls) which correlated with the expression level of CK2 in the different CCA cell lines (mucin- and mixed-CCA). Indeed, no apoptotic effects were observed in CK19-positive cells expressing lower CK2 levels. The effects of CX4945 on viability and apoptosis were associated with an increased number of γ-H2ax (biomarker for DNA double-strand breaks) foci, suggesting the active role of CK2 as a repair mechanism in CCAs. LY2157299 failed to influence cell proliferation or apoptosis but significantly inhibited cell migration. At a 50 μM concentration, in fact, LY2157299 significantly impaired (at 24, 48 and 120 hrs) the wound-healing of primary cell cultures from both mucin-and mixed-CCA. In conclusion, we demonstrated that CX4945 and LY2157299 exert relevant but distinct anticancer effects against human CCA cells, with CX4945 acting on cell viability and apoptosis, and LY2157299 impairing cell migration. These results suggest that targeting the TGF-β signaling with a combination of CX-4945 and LY2157299 could have potential benefits in the treatment of human CCA.
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Affiliation(s)
- Anna Maria Lustri
- Medico-surgical Sciences and Biotechnologies, Sapienza University of Rome, RM, ROMA, Italy
| | - Sabina Di Matteo
- Medico-surgical Sciences and Biotechnologies, Sapienza University of Rome, RM, ROMA, Italy
| | - Alice Fraveto
- Medico-surgical Sciences and Biotechnologies, Sapienza University of Rome, RM, ROMA, Italy
| | - Daniele Costantini
- Medico-surgical Sciences and Biotechnologies, Sapienza University of Rome, RM, ROMA, Italy
| | - Alfredo Cantafora
- Medico-surgical Sciences and Biotechnologies, Sapienza University of Rome, RM, ROMA, Italy
| | - Chiara Napoletano
- Department of Experimental Medicine, University of Rome Sapienza, Roma, Italy
| | | | - Felice Giuliante
- Catholic University of the Sacred Heart School of Medicine, Roma, Italy
| | | | - Pasquale B. Berloco
- Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Roma, Italy
| | - Gian Luca Grazi
- Regina Elena National Cancer Institute, the Gastroenterology Unit, Roma, Italy
| | - Guido Carpino
- Department of Health Science, University of Rome Foro Italico, Roma, Italy
| | - Domenico Alvaro
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, RM, ROMA, Italy
- * E-mail:
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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: 92] [Impact Index Per Article: 11.5] [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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29
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Tian D, Shi Y, Chen D, Liu Q, Fan F. The Wnt inhibitor LGK-974 enhances radiosensitivity of HepG2 cells by modulating Nrf2 signaling. Int J Oncol 2017. [PMID: 28627706 DOI: 10.3892/ijo.2017.4042] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of antioxidant and detoxification activities that can eliminate reactive oxygen species (ROS) produced via irradiation. However, Nrf2 overexpression in liver cancer cells may cause both radioresistance and chemoresistance. Reducing Nrf2 levels can enhance the radiosensitivity of HepG2 cells. Wingless/int-3A (Wnt3A) is a Wnt family protein that mainly activates the canonical Wnt signaling pathway. Recent studies showed that the Axin1-GSK-3β protein complex, a component of the canonical Wnt signaling pathway, can capture Nrf2 and facilitate its ubiquitination and proteasomal degradation in the cytoplasm. This protein complex is degraded upon activation of the Wnt signaling pathway. In the present study, we treated HepG2 cells with the Wnt3A inhibitor LGK-974, an effective and specific PORCN inhibitor that can prevent the formation of a proper folding of the Wnt protein in the endoplasmic reticulum. We found that HepG2 cells became more sensitive to radiation with increasing LGK-974 concentrations. Upon 2 Gy or 4 Gy irradiation, the cells treated with LGK-974 more frequently underwent apoptosis and grew less rapidly. PCR and western blot results showed that inhibiting the secretion of Wnt3A blocked the Wnt signaling pathway and prevented Nrf2 signaling. Notably, the Wnt inhibitor may serve as a radiosensitizing drug.
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Affiliation(s)
- Dan Tian
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Tianjin 300192, P.R. China
| | - Ying Shi
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Dexi Chen
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Qiang Liu
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Tianjin 300192, P.R. China
| | - Feiyue Fan
- Institute of Laboratory Animal Sciences, Peking Union Medical College (PUMC) and Chinese Academy of Medical Sciences (CAMS), Beijing 100069, P.R. China
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30
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Hornfeldt CS, Tran E, Schwartz M. Emerging therapies for the treatment of cholangiocarcinoma. INTERNATIONAL JOURNAL OF HEPATOBILIARY AND PANCREATIC DISEASES 2017. [DOI: 10.5348/ijhpd-2017-72-ra-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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