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Zhang N, Sun L, Zhou S, Ji C, Cui T, Chu Q, Ye J, Liang S, Ma K, Liu Y, Li X, Guo X, Zhang W, Gu X, Cheng C, Zha Q, Tao S, Zhang Y, Chu J, Wu C, Zhang Y, Wang J, Liu Y, Liu L. Cholangiocarcinoma PDHA1 succinylation suppresses macrophage antigen presentation via alpha-ketoglutaric acid accumulation. Nat Commun 2025; 16:3177. [PMID: 40180922 PMCID: PMC11968997 DOI: 10.1038/s41467-025-58429-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 03/21/2025] [Indexed: 04/05/2025] Open
Abstract
Gemcitabine combined with cisplatin is the first-line chemotherapy for advanced cholangiocarcinoma, but drug resistance remains a challenge, leading to unsatisfactory therapeutic effect. Here, we elucidate the possibility of chemotherapy regimens sensitized by inhibiting succinylation in patients with cholangiocarcinoma from the perspective of post-translational modification. Our omics analysis reveals that succinylation of PDHA1 lysine 83, a key enzyme in the tricarboxylic acid cycle, alters PDH enzyme activity, modulates metabolic flux, and leads to alpha-ketoglutaric acid accumulation in the tumor microenvironment. This process activates the OXGR1 receptor on macrophages, triggering MAPK signaling and inhibiting MHC-II antigen presentation, which promotes immune escape and tumor progression. Moreover, we show that inhibiting PDHA1 succinylation with CPI-613 enhances the efficacy of gemcitabine and cisplatin. Targeting PDHA1 succinylation may be a promising strategy to improve treatment outcomes in cholangiocarcinoma and warrants further clinical exploration.
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Affiliation(s)
- Ning Zhang
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Linmao Sun
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Shuo Zhou
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China
| | - Changyong Ji
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Tianming Cui
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Qi Chu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Jiareng Ye
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Shuhang Liang
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
- Department of Gastrointestinal Surgery, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Kun Ma
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Yufeng Liu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Xianying Li
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
- Hepatobiliary Surgery Department, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Xinyu Guo
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, China
| | - Weizhi Zhang
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Xuetian Gu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Cheng Cheng
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Qingrui Zha
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Shengwei Tao
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Yunguang Zhang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Junhui Chu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Chenghui Wu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Yuchen Zhang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China
| | - Jiabei Wang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China.
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China.
| | - Yao Liu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China.
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China.
| | - Lianxin Liu
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
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Qu X, Wang Q, Zhu F, Liang H, Long Z, Wu Y, Jiang M, Liu Z, Dai X, Zhu Z. Research hotspots and trends in immunotherapy for cholangiocarcinoma: a bibliometric analysis (2014-2023). Front Immunol 2024; 15:1436315. [PMID: 39660136 PMCID: PMC11628549 DOI: 10.3389/fimmu.2024.1436315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 11/05/2024] [Indexed: 12/12/2024] Open
Abstract
Background Cholangiocarcinoma (CCA) is a malignant tumor of the gastrointestinal tract with a poor prognosis. Immunotherapy plays an important role in the treatment of CCA. This study aimed to investigate the research hotspots and trends in immunotherapy for CCA. Methods The Web of Science Core Collection was searched for literature related to CCA immunotherapy research from January 1, 2014, to December 31, 2023, and features such as country, institution, authors, references, and keywords in the included literature were quantitatively and visually analyzed using the VOS viewer and CiteSpace software. Results A total of 252 English publications published between 2014 and 2023 were included. The publications were mainly from China and the United States, with Fudan University being the institution that published the most papers. The highest number of publications came from Frontiers in Oncology. The most prolific authors were Jia Fan, Jian Zhou from China and Pa-Thai Yenchitsomanus from Thailand, while the Journal of Clinical Oncology ranked first in the number of citations among the co-cited journals. In recent years, the focus of research has shifted from "immune checkpoint" and "chemotherapy" to "immunotherapy combined therapy." Currently, the research frontiers are "microenvironment," "immune cells," and "macrophages." Conclusion Our study analyzes the research hotspots and trends in CCA to provide a knowledge map of immunotherapy research, which will serve as a reference and direction for future research.
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Affiliation(s)
- Xilin Qu
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Qian Wang
- The First Affiliated Hospital, Gynecology & Obstetrics and Reproductive Medical Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Fengfeng Zhu
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Hao Liang
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Zhangtao Long
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yachen Wu
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Mengliang Jiang
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Zhaohai Liu
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Xiaoming Dai
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Zhu Zhu
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, China
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Zhang G, Li J, Li G, Zhang J, Yang Z, Yang L, Jiang S, Wang J. Strategies for treating the cold tumors of cholangiocarcinoma: core concepts and future directions. Clin Exp Med 2024; 24:193. [PMID: 39141161 PMCID: PMC11324771 DOI: 10.1007/s10238-024-01460-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 07/31/2024] [Indexed: 08/15/2024]
Abstract
Cholangiocarcinoma (CCA) is a rare type of digestive tract cancer originating from the epithelial cells of the liver and biliary tract. Current treatment modalities for CCA, such as chemotherapy and radiation therapy, have demonstrated limited efficacy in enhancing survival rates. Despite the revolutionary potential of immunotherapy in cancer management, its application in CCA remains restricted due to the minimal infiltration of immune cells in these tumors, rendering them cold and unresponsive to immune checkpoint inhibitors (ICIs). Cancer cells within cold tumors deploy various mechanisms for evading immune attack, thus impeding clinical management. Recently, combination immunotherapy has become increasingly essential to comprehend the mechanisms underlying cold tumors to enhance a deficient antitumor immune response. Therefore, a thorough understanding of the knowledge on the combination immunotherapy of cold CCA is imperative to leverage the benefits of immunotherapy in treating patients. Moreover, gut microbiota plays an essential role in the immunotherapeutic responses in CCA. In this review, we summarize the current concepts of immunotherapy in CCA and clarify the intricate dynamics within the tumor immune microenvironment (TIME) of CCA. We also delve into the evasion mechanisms employed by CCA tumors against the anti-tumor immune responses. The context of combination immunotherapies in igniting cold tumors of CCA and the critical function of gut microbiota in prompting immune responses have also been annotated. Furthermore, we have proposed future directions in the realm of CCA immunotherapy, aiming to improve the clinical prognosis of CCA patients.
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Affiliation(s)
- GuanBo Zhang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - JinSong Li
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - Gang Li
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - Jie Zhang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - Zhi Yang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - Lin Yang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - ShiJie Jiang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - JiaXing Wang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China.
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Wang J, Liu S, Cao Y, Chen Y. Overcoming treatment resistance in cholangiocarcinoma: current strategies, challenges, and prospects. Front Cell Dev Biol 2024; 12:1408852. [PMID: 39156971 PMCID: PMC11327014 DOI: 10.3389/fcell.2024.1408852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 06/26/2024] [Indexed: 08/20/2024] Open
Abstract
Significant advancements in our understanding and clinical treatment of cholangiocarcinoma (CCA) have been achieved over the past 5 years. Groundbreaking studies have illuminated the immune landscape and pathological characteristics of the tumor microenvironment in CCA. The development of immune- and metabolism-based classification systems has enabled a nuanced exploration of the tumor microenvironment and the origins of CCA, facilitating a detailed understanding of tumor progression modulation. Despite these insights, targeted therapies have not yet yielded satisfactory clinical results, highlighting the urgent need for innovative therapeutic strategies. This review delineates the complexity and heterogeneity of CCA, examines the current landscape of therapeutic strategies and clinical trials, and delves into the resistance mechanisms underlying targeted therapies. Finally, from a single-cell and spatial transcriptomic perspective, we address the challenge of therapy resistance, discussing emerging mechanisms and potential strategies to overcome this barrier and enhance treatment efficacy.
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Affiliation(s)
- Jiayi Wang
- International Medical College, Chongqing Medical University, Chongqing, China
| | - Siyan Liu
- International Medical College, Chongqing Medical University, Chongqing, China
| | - Yi Cao
- Second Clinical College, Chongqing Medical University, Chongqing, China
| | - Yong Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Barbato A, Piscopo F, Salati M, Pollastro C, Evangelista L, Ferrante L, Limongello D, Brillante S, Iuliano A, Reggiani-Bonetti L, Salatiello M, Iaccarino A, Pisapia P, Malapelle U, Troncone G, Indrieri A, Dominici M, Franco B, Carotenuto P. A MiR181/Sirtuin1 regulatory circuit modulates drug response in biliary cancers. Clin Exp Med 2024; 24:74. [PMID: 38598008 PMCID: PMC11006774 DOI: 10.1007/s10238-024-01332-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 03/14/2024] [Indexed: 04/11/2024]
Abstract
Despite recent advances, biliary tract cancer (BTC) remains one of the most lethal tumor worldwide due to late diagnosis, limited therapeutic strategies and resistance to conventional therapies. In recent years, high-throughput technologies have enabled extensive genome, and transcriptome sequencing unveiling, among others, the regulatory potential of microRNAs (miRNAs). Compelling evidence shown that miRNA are attractive therapeutic targets and promising candidates as biomarkers for various therapy-resistant tumors. The analysis of miRNA profile successfully identified miR-181c and -181d as significantly downregulated in BTC patients. Low miR-181c and -181d expression levels were correlated with worse prognosis and poor treatment efficacy. In fact, progression-free survival analysis indicated poor survival rates in miR-181c and -181d low expressing patients. The expression profile of miR-181c and -181d in BTC cell lines revealed that both miRNAs were dysregulated. Functional in vitro experiments in BTC cell lines showed that overexpression of miR-181c and -181d affected cell viability and increased sensitivity to chemotherapy compared to controls. In addition, by using bioinformatic tools we showed that the miR-181c/d functional role is determined by binding to their target SIRT1 (Sirtuin 1). Moreover, BTC patients expressing high levels of miR-181 and low SIRT1 shown an improved survival and treatment response. An integrative network analysis demonstrated that, miR-181/SIRT1 circuit had a regulatory effect on several important metabolic tumor-related processes. Our study demonstrated that miR-181c and -181d act as tumor suppressor miRNA in BTC, suggesting the potential use as therapeutic strategy in resistant cancers and as predictive biomarker in the precision medicine of BTC.
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Affiliation(s)
- Anna Barbato
- TIGEM, Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy
- Department of Translational Medical Science, Medical Genetics, University of Naples "Federico II", 80131, Naples, Italy
| | - Fabiola Piscopo
- TIGEM, Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy
- Department of Translational Medical Science, Medical Genetics, University of Naples "Federico II", 80131, Naples, Italy
| | - Massimiliano Salati
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, 41125, Modena, Italy
| | - Carla Pollastro
- TIGEM, Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy
- Department of Translational Medical Science, Medical Genetics, University of Naples "Federico II", 80131, Naples, Italy
| | - Lorenzo Evangelista
- TIGEM, Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy
| | - Luigi Ferrante
- TIGEM, Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy
| | - Davide Limongello
- TIGEM, Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy
| | - Simona Brillante
- TIGEM, Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy
- IRGB, Institute for Genetic and Biomedical Research, National Research Council (CNR), Milan, Italy
| | - Antonella Iuliano
- Department of Mathematics, Computer Science and Economics (DIMIE), University of Basilicata, 85100, Potenza, Italy
| | - Luca Reggiani-Bonetti
- Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, 41125, Modena, Italy
| | - Maria Salatiello
- Department of Public Health, Universita' degli Studi di Napoli-AOU Federico II, 80131, Naples, Italy
| | - Antonino Iaccarino
- Department of Public Health, Universita' degli Studi di Napoli-AOU Federico II, 80131, Naples, Italy
| | - Pasquale Pisapia
- Department of Public Health, Universita' degli Studi di Napoli-AOU Federico II, 80131, Naples, Italy
| | - Umberto Malapelle
- Department of Public Health, Universita' degli Studi di Napoli-AOU Federico II, 80131, Naples, Italy
| | - Giancarlo Troncone
- Department of Public Health, Universita' degli Studi di Napoli-AOU Federico II, 80131, Naples, Italy
| | - Alessia Indrieri
- TIGEM, Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy
- IRGB, Institute for Genetic and Biomedical Research, National Research Council (CNR), Milan, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, 41125, Modena, Italy
| | - Brunella Franco
- TIGEM, Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy
- Department of Translational Medical Science, Medical Genetics, University of Naples "Federico II", 80131, Naples, Italy
- Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine Program, 80078, Naples, Italy
| | - Pietro Carotenuto
- TIGEM, Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy.
- Department of Translational Medical Science, Medical Genetics, University of Naples "Federico II", 80131, Naples, Italy.
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Yáñez-Bartolomé M, Serra-Camprubí Q, Arenas EJ, Escorihuela M, Castet F, Fabregat-Franco C, Querol J, Arribas J, Peiró S, Macarulla T, Tian TV. Generation of Metastatic Cholangiocarcinoma Patient-Derived Xenograft Models. Methods Mol Biol 2024; 2806:139-151. [PMID: 38676801 DOI: 10.1007/978-1-0716-3858-3_11] [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] [Indexed: 04/29/2024]
Abstract
Cholangiocarcinoma (CCA) poses a substantial clinical hurdle as it is often detected at advanced metastatic stages with limited therapeutic options. To enhance our understanding of advanced CCA, it is imperative to establish preclinical models that faithfully recapitulate the disease's characteristics. Patient-derived xenograft (PDX) models have emerged as a valuable approach in cancer research, offering an avenue to reproduce and study the genomic, histologic, and molecular features of the original human tumors. By faithfully preserving the heterogeneity, microenvironmental interactions, and drug responses observed in human tumors, PDX models serve as highly relevant and predictive preclinical tools. Here, we present a comprehensive protocol that outlines the step-by-step process of generating and maintaining PDX models using biopsy samples from patients with advanced metastatic CCA. The protocol encompasses crucial aspects such as tissue processing, xenograft transplantation, and subsequent monitoring of the PDX models. By employing this protocol, we aim to establish a robust collection of PDX models that accurately reflect the genomic landscape, histologic diversity, and therapeutic responses observed in advanced CCA, thereby enabling improved translational research, drug development, and personalized treatment strategies for patients facing this challenging disease.
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Affiliation(s)
- Mariana Yáñez-Bartolomé
- Upper GI and Endocrine Tumor Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Queralt Serra-Camprubí
- Upper GI and Endocrine Tumor Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Enrique J Arenas
- Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
| | - Marta Escorihuela
- Growth Factor Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Florian Castet
- Upper GI and Endocrine Tumor Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Carles Fabregat-Franco
- Upper GI and Endocrine Tumor Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Jessica Querol
- Upper GI and Endocrine Tumor Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Joaquín Arribas
- Growth Factor Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer, Monforte de Lemos, Madrid, Spain
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain
- Cancer Research Program, Hospital de Mar Medical Research Institute (IMIM), Barcelona, Spain
- Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain
| | - Sandra Peiró
- Upper GI and Endocrine Tumor Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Teresa Macarulla
- Upper GI and Endocrine Tumor Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
| | - Tian V Tian
- Upper GI and Endocrine Tumor Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
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7
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Wu G, Wang D, Xiong F, Liu W, Wang Q, Chen J, Wang B, Chen Y. Upregulation of RSPO3 via targeted promoter DNA demethylation inhibits the progression of cholangiocarcinoma. Clin Epigenetics 2023; 15:177. [PMID: 37932819 PMCID: PMC10629118 DOI: 10.1186/s13148-023-01592-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/25/2023] [Indexed: 11/08/2023] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA) refers to a collection of malignant tumors that develop from the biliary epithelium. Extensive clinical evidence and epidemiological observations indicate a concerning increase in both the incidence and mortality rates of CCA. Surgical resection is currently the sole available cure for CCA. However, it is unfortunate that only a fraction of patients has access to surgery at the time of diagnosis. Moreover, there is a high incidence of cancer recurrence after resection, and systemic treatments have limited efficacy. Therefore, the identification of novel biomarkers for CCA-targeted molecular therapy remains a crucial task in oncology research. RESULTS Our study demonstrated that low expression of RSPO3 was associated with poorer survival rates in patients with CCA. We found that the RSPO3 promoter DNA was hypermethylated in CCA, which was correlated with the low expression of RSPO3. The expression of RSPO3 was influenced by the balance between the DNA methyltransferase DNMT3a and the DNA demethylase TET1 in CCA. In vitro and in vivo experiments showed that targeting RSPO3 promoter DNA methylation using dCas9DNMT3a promoted tumorigenicity of CCA, while targeted RSPO3 promoter DNA demethylation using dCas9TET1CD inhibited CCA tumorigenicity. Additionally, in our primary CCA model, knockdown of Rspo3 promoted CCA progression, whereas overexpression of Rspo3 inhibited CCA progression. CONCLUSIONS Our findings suggest that increased methylation and decreased expression of RSPO3 may indicate a poor prognosis in CCA. Restoring RSPO3 expression by targeting promoter DNA demethylation could offer insights for precise treatment of CCA.
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Affiliation(s)
- Guanhua Wu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China
| | - Da Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China
| | - Fei Xiong
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China
| | - Wenzheng Liu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China
| | - Qi Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China
| | - Junsheng Chen
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China
| | - Bing Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China.
| | - Yongjun Chen
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China.
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8
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Ilyas SI, Affo S, Goyal L, Lamarca A, Sapisochin G, Yang JD, Gores GJ. Cholangiocarcinoma - novel biological insights and therapeutic strategies. Nat Rev Clin Oncol 2023; 20:470-486. [PMID: 37188899 PMCID: PMC10601496 DOI: 10.1038/s41571-023-00770-1] [Citation(s) in RCA: 81] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/24/2023] [Indexed: 05/17/2023]
Abstract
In the past 5 years, important advances have been made in the scientific understanding and clinical management of cholangiocarcinoma (CCA). The cellular immune landscape of CCA has been characterized and tumour subsets with distinct immune microenvironments have been defined using molecular approaches. Among these subsets, the identification of 'immune-desert' tumours that are relatively devoid of immune cells emphasizes the need to consider the tumour immune microenvironment in the development of immunotherapy approaches. Progress has also made in identifying the complex heterogeneity and diverse functions of cancer-associated fibroblasts in this desmoplastic cancer. Assays measuring circulating cell-free DNA and cell-free tumour DNA are emerging as clinical tools for detection and monitoring of the disease. Molecularly targeted therapy for CCA has now become a reality, with three drugs targeting oncogenic fibroblast growth factor receptor 2 (FGFR2) fusions and one targeting neomorphic, gain-of-function variants of isocitrate dehydrogenase 1 (IDH1) obtaining regulatory approval. By contrast, immunotherapy using immune-checkpoint inhibitors has produced disappointing results in patients with CCA, underscoring the requirement for novel immune-based treatment strategies. Finally, liver transplantation for early stage intrahepatic CCA under research protocols is emerging as a viable therapeutic option in selected patients. This Review highlights and provides in-depth information on these advances.
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Affiliation(s)
- Sumera I Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
- Department of Immunology, Mayo Clinic, Rochester, MN, USA
| | - Silvia Affo
- Liver, Digestive System and Metabolism Research, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Lipika Goyal
- Department of Medicine, Mass General Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Angela Lamarca
- Department of Oncology, OncoHealth Institute, Fundación Jiménez Díaz University Hospital, Madrid, Spain
- Department of Medical Oncology, The Christie NHS Foundation, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Gonzalo Sapisochin
- Ajmera Transplant Program and HPB Surgical Oncology, Toronto General Hospital, University of Toronto, Toronto, Canada
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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Milardi G, Lleo A. Tumor-Infiltrating B Lymphocytes: Promising Immunotherapeutic Targets for Primary Liver Cancer Treatment. Cancers (Basel) 2023; 15:2182. [PMID: 37046842 PMCID: PMC10093314 DOI: 10.3390/cancers15072182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/23/2023] [Accepted: 04/03/2023] [Indexed: 04/14/2023] Open
Abstract
Hepatocellular carcinoma and cholangiocarcinoma are the fourth most lethal primary cancers worldwide. Therefore, there is an urgent need for therapeutic strategies, including immune cell targeting therapies. The heterogeneity of liver cancer is partially explained by the characteristics of the tumor microenvironment (TME), where adaptive and innate immune system cells are the main components. Pioneering studies of primary liver cancers revealed that tumor-infiltrating immune cells and their dynamic interaction with cancer cells significantly impacted carcinogenesis, playing an important role in cancer immune evasion and responses to immunotherapy treatment. In particular, B cells may play a prominent role and have a controversial function in the TME. In this work, we highlight the effect of B lymphocytes as tumor infiltrates in relation to primary liver cancers and their potential prognostic value. We also present the key pathways underlying B-cell interactions within the TME, as well as the way that a comprehensive characterization of B-cell biology can be exploited to develop novel immune-based therapeutic approaches.
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Affiliation(s)
- Giulia Milardi
- Hepatobiliary Immunopathology Labaratory, IRCCS Humanitas Research Hospital, 20089 Milan, Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, 20072 Milan, Italy
- Department of Gastroenterology, Division of Internal Medicine and Hepatology, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
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Mariotti V, Fiorotto R, Cadamuro M, Fabris L, Strazzabosco M. New insights on the role of vascular endothelial growth factor in biliary pathophysiology. JHEP Rep 2021; 3:100251. [PMID: 34151244 PMCID: PMC8189933 DOI: 10.1016/j.jhepr.2021.100251] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/06/2021] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
The family of vascular endothelial growth factors (VEGFs) includes 5 members (VEGF-A to -D, and placenta growth factor), which regulate several critical biological processes. VEGF-A exerts a variety of biological effects through high-affinity binding to tyrosine kinase receptors (VEGFR-1, -2 and -3), co-receptors and accessory proteins. In addition to its fundamental function in angiogenesis and endothelial cell biology, VEGF/VEGFR signalling also plays a role in other cell types including epithelial cells. This review provides an overview of VEGF signalling in biliary epithelial cell biology in both normal and pathologic conditions. VEGF/VEGFR-2 signalling stimulates bile duct proliferation in an autocrine and paracrine fashion. VEGF/VEGFR-1/VEGFR-2 and angiopoietins are involved at different stages of biliary development. In certain conditions, cholangiocytes maintain the ability to secrete VEGF-A, and to express a functional VEGFR-2 receptor. For example, in polycystic liver disease, VEGF secreted by cystic cells stimulates cyst growth and vascular remodelling through a PKA/RAS/ERK/HIF1α-dependent mechanism, unveiling a new level of complexity in VEFG/VEGFR-2 regulation in epithelial cells. VEGF/VEGFR-2 signalling is also reactivated during the liver repair process. In this context, pro-angiogenic factors mediate the interactions between epithelial, mesenchymal and inflammatory cells. This process takes place during the wound healing response, however, in chronic biliary diseases, it may lead to pathological neo-angiogenesis, a condition strictly linked with fibrosis progression, the development of cirrhosis and related complications, and cholangiocarcinoma. Novel observations indicate that in cholangiocarcinoma, VEGF is a determinant of lymphangiogenesis and of the immune response to the tumour. Better insights into the role of VEGF signalling in biliary pathophysiology might help in the search for effective therapeutic strategies.
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Key Words
- ADPKD, adult dominant polycystic kidney disease
- Anti-Angiogenic therapy
- BA, biliary atresia
- BDL, bile duct ligation
- CCA, cholangiocarcinoma
- CCl4, carbon tetrachloride
- CLDs, chronic liver diseases
- Cholangiocytes
- Cholangiopathies
- DP, ductal plate
- DPM, ductal plate malformation
- DRCs, ductular reactive cells
- Development
- HIF-1α, hypoxia-inducible factor type 1α
- HSCs, hepatic stellate cells
- IHBD, intrahepatic bile ducts
- IL-, interleukin-
- LECs, lymphatic endothelial cells
- LSECs, liver sinusoidal endothelial cells
- Liver repair
- MMPs, matrix metalloproteinases
- PBP, peribiliary plexus
- PC, polycystin
- PDGF, platelet-derived growth factor
- PIGF, placental growth factor
- PLD, polycystic liver diseases
- Polycystic liver diseases
- SASP, senescence-associated secretory phenotype
- TGF, transforming growth factor
- VEGF, vascular endothelial growth factors
- VEGF-A
- VEGF/VEGFR-2 signalling
- VEGFR-1/2, vascular endothelial growth factor receptor 1/2
- mTOR, mammalian target of rapamycin
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Affiliation(s)
- Valeria Mariotti
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA
| | - Romina Fiorotto
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA
| | - Massimiliano Cadamuro
- Department of Molecular Medicine, University of Padua, School of Medicine, Padua, Italy
| | - Luca Fabris
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA.,Department of Molecular Medicine, University of Padua, School of Medicine, Padua, Italy
| | - Mario Strazzabosco
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA
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11
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Tovoli F, Guerra P, Iavarone M, Veronese L, Renzulli M, De Lorenzo S, Benevento F, Brandi G, Stefanini F, Piscaglia F. Surveillance for Hepatocellular Carcinoma Also Improves Survival of Incidentally Detected Intrahepatic Cholangiocarcinoma Arisen in Liver Cirrhosis. Liver Cancer 2020; 9:744-755. [PMID: 33442543 PMCID: PMC7768136 DOI: 10.1159/000509059] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 05/29/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Due to its poor survival, intrahepatic cholangiocarcinoma (ICC) is held to be a much more aggressive cancer than hepatocellular carcinoma (HCC). In most published series, patients were diagnosed when symptomatic. However, ICC is now increasingly being discovered during the surveillance for HCC in cirrhosis. Whether this earlier detection of ICC is associated with an equally dismal prognosis or not is unknown. METHODS This is amulticenter retrospective study of consecutive ICC patients. Patients were stratified into subgroups according to the absence/presence of cirrhosis. A propensity score matching was performed to reduce the potential biases. Cirrhotic patients were further stratified according to their surveillance status. The lead-time bias and its potential effects were also estimated. RESULTS We gathered 184 patients. Eighty-five patients (46.2%) were cirrhotic. Liver cirrhosis was not related to a worse overall survival (33.0 vs. 32.0 months, p = 0.800) even after the propensity score analysis (43.0 in vs. 44.0 months in 54 pairs of patients, p = 0.878). Among the cirrhotic population, 47 (55.3%) patients had received a diagnosis of ICC during a surveillance programme. The 2 subgroups differed in maximum tumour dimensions (30 vs. 48 mm in surveyed and non-surveyed patients, respectively). Surveyed patients were more likely to receive surgical treatments (59.8 vs. 28.9%, p = 0.003). Overall survival was higher in surveyed patients (51.0 vs. 21.0 months, p < 0.001). These benefits were confirmed after correcting for the lead-time bias. CONCLUSIONS Cirrhotic patients have different clinical presentation and outcomes of ICC according to their surveillance status. In our series, ICC in cirrhosis was not associated with worse OS. Cirrhosis itself should not discourage either surgical or non-surgical treatments.
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Affiliation(s)
- Francesco Tovoli
- Division of Internal Medicine, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Pietro Guerra
- Division of Internal Medicine, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Massimo Iavarone
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy
| | - Letizia Veronese
- III Medical Clinic, Department of Internal Medicine, IRCCS − Policlinico San Matteo Foundation, Pavia, Italy
| | - Matteo Renzulli
- Radiology Unit, Azienda Ospedaliero Universitaria S.Orsola-Malpighi di Bologna, Bologna, Italy
| | - Stefania De Lorenzo
- Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Francesca Benevento
- Division of Internal Medicine, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giovanni Brandi
- Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Federico Stefanini
- Division of Internal Medicine, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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12
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Polidoro MA, Mikulak J, Cazzetta V, Lleo A, Mavilio D, Torzilli G, Donadon M. Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells. World J Gastroenterol 2020; 26:4900-4918. [PMID: 32952338 PMCID: PMC7476172 DOI: 10.3748/wjg.v26.i33.4900] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/24/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
In the last years, several studies have been focused on elucidate the role of tumor microenvironment (TME) in cancer development and progression. Within TME, cells from adaptive and innate immune system are one of the main abundant components. The dynamic interactions between immune and cancer cells lead to the activation of complex molecular mechanisms that sustain tumor growth. This important cross-talk has been elucidate for several kind of tumors and occurs also in patients with liver cancer, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Liver is well-known to be an important immunological organ with unique microenvironment. Here, in normal conditions, the rich immune-infiltrating cells cooperate with non-parenchymal cells, such as liver sinusoidal endothelial cells and Kupffer cells, favoring self-tolerance against gut antigens. The presence of underling liver immunosuppressive microenvironment highlights the importance to dissect the interaction between HCC and iCCA cells with immune infiltrating cells, in order to understand how this cross-talk promotes tumor growth. Deeper attention is, in fact, focused on immune-based therapy for these tumors, as promising approach to counteract the intrinsic anti-tumor activity of this microenvironment. In this review, we will examine the key pathways underlying TME cell-cell communications, with deeper focus on the role of natural killer cells in primary liver tumors, such as HCC and iCCA, as new opportunities for immune-based therapeutic strategies.
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Affiliation(s)
- Michela Anna Polidoro
- Hepatobiliary Immunopathology Laboratory, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
| | - Joanna Mikulak
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Rozzano 20089, Milan, Italy
| | - Valentina Cazzetta
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
| | - Ana Lleo
- Hepatobiliary Immunopathology Laboratory, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Internal Medicine, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
| | - Domenico Mavilio
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Rozzano 20089, Milan, Italy
| | - Guido Torzilli
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
| | - Matteo Donadon
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
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