|
1
|
Milana F, Procopio F, Calafiore E, Famularo S, Costa G, Galvanin J, Branciforte B, Torzilli G. Long-Term Outcomes According to Surgical Margin in Mass-Forming Cholangiocarcinoma: The Role of R1vasc. Ann Surg Oncol 2025; 32:4363-4373. [PMID: 40019600 DOI: 10.1245/s10434-025-17038-w] [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: 10/28/2024] [Accepted: 02/04/2025] [Indexed: 03/01/2025]
Abstract
BACKGROUND R0 resection is the standard for mass-forming cholangiocarcinoma (MFCCC). R1vasc resection (tumor-vessel detachment) yielded results comparable to R0 and superior to parenchymal-tumor exposure (R1par) for hepatocellular carcinoma and colorectal liver metastases. This study aims to clarify R1vasc outcomes for MFCCC. PATIENTS AND METHODS Margin status of patients with MFCCC undergoing resection between 2008 and 2022 was assessed to determine the oncological efficacy of R1vasc regarding survival and hepatic recurrence. RESULTS The study analyzed 125 patients: 68 (54.4%) R0, 18 (14.4%) R1vasc, 24 (19.2%) R1par, and 15 (12.0%) R1vasc + par. Tumor size was similar between R0 (4.4 cm, range 1.5-19.0) and R1vasc (4.3 cm, range 2.3-14.5, p = 0.754) but larger for R1par (8.2 cm, range 2.5-15.0, p = 0.005) and R1vasc + par (9.0 cm, range 5.0-17.0, p < 0.001). The median overall survival (OS) was comparable for R0 [64.8 months; 95% confidence interval (CI): 50.0-79.6], R1vasc (54.4 months; 95% CI 19.6-89.2; p = 0.932), and R1vasc + par (62.0 months; 95% CI 35.6-88.5; p = 0.989). R1par showed lower OS (26.8 months; 95% CI 16.1-37.6; p = 0.134). Local recurrence was higher for R1par (45.8%, p < 0.0001) compared with R0 (10.3%) and similar for R1vasc (16.6%) and R1vasc + par (20.0%). Survival after hepatic recurrence was higher for R1vasc compared with R1par (p = 0.041). CONCLUSIONS R1vasc is a valid option for increasing resectability in patients with MFCCC, with OS being comparable to R0. R1vasc + par may be necessary for larger tumors.
Collapse
Affiliation(s)
- Flavio Milana
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Fabio Procopio
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Eleonora Calafiore
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Simone Famularo
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Guido Costa
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Jacopo Galvanin
- Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Bruno Branciforte
- Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Guido Torzilli
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.
- Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Milan, Italy.
| |
Collapse
|
|
2
|
Tariq MA, Malik MK, Khan M, Majoka ZA, Asrar A. Rising Mortality of Intrahepatic Cholangiocarcinoma Among Older Adults in the United States: An Analysis of Demographic and Regional Trends. Liver Int 2025; 45:e16212. [PMID: 39679629 DOI: 10.1111/liv.16212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/21/2024] [Accepted: 12/02/2024] [Indexed: 12/17/2024]
Abstract
INTRODUCTION Intrahepatic cholangiocarcinoma (ICC) is the second most frequent primary liver malignancy after hepatocellular carcinoma. Contemporary mortality trends due to ICC are largely unknown. We aim to examine the temporal trends of ICC-related deaths among older adults in the United States from 1999 to 2022. METHODS We utilised the Centers for Disease Control and Prevention Wide-Ranging, Online Data for Epidemiologic Research (CDC WONDER) database, which provides information from death certificates of all US residents according to the International Classification of Diseases, Tenth Revision (ICD-10). RESULTS Between 1999 and 2022, there were 90 996 deaths attributed to ICC among individuals aged 65 and older. Overall, there is an increasing trend in ICC mortality; the total AAMR increased from 5.6 in 1999 to 14.3 in 2022 with an annual increase of 3.3%. Males had consistently higher AAMR than females across all years. For males, AAMR initially increased by 2.9% annually from 1999 to 2015, and since then, the rate has accelerated to a 3.9% annual increase. Conversely, females experienced a steady annual increase of 3.4% in AAMR from 1999 to 2022. When stratified by race, AAMR was highest among the Non-Hispanic (NH) Asian population, followed by Hispanic or Latino, NH Whites and NH Blacks. In brief, the AAMR has increased for all races; however, the NH Black population has experienced the greatest rise in AAMR during the study duration (APC: 4.0%; 95% CI, 3.5 to 4.8). Large metropolitan areas had a higher overall AAMR than small/medium metropolitan and non-metropolitan areas, though the rate of increase was comparable across all regions. States within the top 90th percentile of ICC-related deaths included Minnesota, Alaska, District of Columbia, Wisconsin, Massachusetts and Rhode Island. CONCLUSIONS Over the past two decades, there has been a consistent rise in mortality rates associated with intrahepatic cholangiocarcinoma in the United States. This upward trajectory underscores the imperative for additional research aimed at comprehending and delineating the underlying risk factors driving this increase.
Collapse
Affiliation(s)
- Muhammad Ali Tariq
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | | | - Madiha Khan
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | | | - Aeman Asrar
- Department of Medicine, Arnot Ogden Medical Center, Elmira, New York, USA
| |
Collapse
|
|
3
|
Haas CB, Shiels MS, Pfeiffer RM, D’Arcy M, Luo Q, Yu K, Austin AA, Cohen C, Miller P, Morawski BM, Pawlish K, Robinson WT, Engels EA. Cancers with epidemiologic signatures of viral oncogenicity among immunocompromised populations in the United States. J Natl Cancer Inst 2024; 116:1983-1991. [PMID: 38954841 PMCID: PMC11630524 DOI: 10.1093/jnci/djae159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/24/2024] [Accepted: 06/27/2024] [Indexed: 07/04/2024] Open
Abstract
BACKGROUND Immunosuppressed individuals have elevated risk of virus-related cancers. Identifying cancers with elevated risk in people with HIV and solid organ transplant recipients, 2 immunosuppressed populations, may help identify novel etiologic relationships with infectious agents. METHODS We used 2 linkages of population-based cancer registries with HIV and transplant registries in the United States. Cancer entities were systematically classified according to site and histology codes. Standardized incidence ratios were used to compare risk in people with HIV and solid organ transplant recipients with the general population. For selected cancer entities, incidence rate ratios were calculated for indicators of immunosuppression within each population. RESULTS We identified 38 047 cancer cases in solid organ transplant recipients and 53 592 in people with HIV, yielding overall standardized incidence ratios of 1.66 (95% confidence interval [CI] = 1.65 to 1.68) and 1.49 (95% CI = 1.47 to 1.50), respectively. A total of 43 cancer entities met selection criteria, including conjunctival squamous cell carcinoma (people with HIV standardized incidence ratio = 7.1, 95% CI = 5.5 to 9.2; solid organ transplant recipients standardized incidence ratio = 9.4, 95% CI = 6.8 to 12.6). Sebaceous adenocarcinoma was elevated in solid organ transplant recipients (standardized incidence ratio = 16.2, 95% CI = 14.0 to 18.6) and, among solid organ transplant recipients, associated with greater risk in lung and heart transplant recipients compared with recipients of other organs (incidence rate ratio = 2.3, 95% CI = 1.7 to 3.2). Salivary gland tumors, malignant fibrous histiocytoma, and intrahepatic cholangiocarcinoma showed elevated risk in solid organ transplant recipients (standardized incidence ratio = 3.9, 4.7, and 3.2, respectively) but not in people with HIV. However, risks for these cancers were elevated following an AIDS diagnosis among people with HIV (incidence rate ratio = 2.4, 4.3, and 2.0, respectively). CONCLUSIONS Elevated standardized incidence ratios among solid organ transplant recipients and people with HIV, and associations with immunosuppression within these populations, suggest novel infectious causes for several cancers including conjunctival squamous cell carcinoma, sebaceous adenocarcinoma, salivary gland tumors, malignant fibrous histiocytoma, and intrahepatic cholangiocarcinoma.
Collapse
Affiliation(s)
- Cameron B Haas
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Meredith S Shiels
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Ruth M Pfeiffer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Monica D’Arcy
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Qianlai Luo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Kelly Yu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | | | - Colby Cohen
- Florida Department of Health, Tallahassee, FL, USA
| | - Paige Miller
- Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, TX, USA
| | | | | | | | - Eric A Engels
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| |
Collapse
|
|
4
|
Tham EKJ, Lim RY, Koh B, Tan DJH, Ng CH, Law M, Cho E, Tang NSY, Tan CS, Sim BKL, Tan EY, Lim WH, Lim MC, Nakamura T, Danpanichkul P, Chirapongsathorn S, Wijarnpreecha K, Takahashi H, Morishita A, Zheng MH, Kow A, Muthiah M, Law JH, Huang DQ. Prevalence of Chronic Liver Disease in Cholangiocarcinoma: A Meta-Analysis. Clin Gastroenterol Hepatol 2024:S1542-3565(24)00971-6. [PMID: 39461458 DOI: 10.1016/j.cgh.2024.09.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 09/15/2024] [Accepted: 09/17/2024] [Indexed: 10/29/2024]
Abstract
BACKGROUND AND AIMS Chronic liver disease is a known risk factor for cholangiocarcinoma (CCA), but the proportion of people with CCA who have concurrent chronic liver disease is unclear. We aimed to evaluate the prevalence of chronic liver diseases in people with CCA. METHODS In this single-arm meta-analysis, we searched MEDLINE and EMBASE from inception to August 10, 2024, for articles in English containing data for CCA with and without chronic liver diseases. Data were pooled to obtain the prevalence of different chronic liver diseases, with further stratification by geographical location and tumor location. RESULTS In total, 118,068 individuals diagnosed with CCA were included, of whom 16,771 had chronic liver diseases. A pooled analysis of 109 studies determined that the prevalence of chronic liver disease was 25.23% (95% confidence interval [CI], 20.82%-30.23%; I2 = 99.0%), and 10.21% (7.75%-13.35%; I2 = 98.6%) of CCA patients had cirrhosis. Chronic liver diseases were associated more with intrahepatic CCAs, compared with extrahepatic CCAs (relative risk, 2.46; 95% CI, 2.37-2.55; P < .0001). This was observed across all etiologies of liver disease, except for primary sclerosing cholangitis, which was associated with extrahepatic CCAs (relative risk, 0.49; 95% CI, 0.43-0.57; P < .0001). CONCLUSIONS Around 1 in 4 people with CCA have chronic liver diseases, and 1 in 10 have cirrhosis.
Collapse
Affiliation(s)
- Ethan Kai Jun Tham
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ryan Yanzhe Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Benjamin Koh
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Darren Jun Hao Tan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Cheng Han Ng
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Michelle Law
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Elina Cho
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Nicole Shu Ying Tang
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Claire Shiying Tan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore
| | - Benedix Kuan Loo Sim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore
| | - En Ying Tan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore
| | - Wen Hui Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Mei Chin Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Diagnostic Imaging, National University Health System, Singapore
| | - Toru Nakamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Research Division, Kurume University Research Center for Innovative Cancer Therapy, Kurume, Japan
| | - Pojsakorn Danpanichkul
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas
| | - Sakkarin Chirapongsathorn
- Division of Gastroenterology and Hepatology, Department of Medicine, Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand
| | - Karn Wijarnpreecha
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, New York
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University, Takamatsu, Japan
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Alfred Kow
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Mark Muthiah
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Jia Hao Law
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, National University Hospital, Singapore.
| | - Daniel Q Huang
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore.
| |
Collapse
|
|
5
|
Pu X, Li L, Xu F, Wang Z, Fu Y, Wu H, Ren J, Chen J, Sun B. HER2 amplification subtype intrahepatic cholangiocarcinoma exhibits high mutation burden and T cell exhaustion microenvironment. J Cancer Res Clin Oncol 2024; 150:403. [PMID: 39198311 PMCID: PMC11358322 DOI: 10.1007/s00432-024-05894-0] [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: 01/16/2024] [Accepted: 07/15/2024] [Indexed: 09/01/2024]
Abstract
OBJECTIVE This study aimed to establish a uniform standard for the interpretation of HER2 gene and protein statuses in intrahepatic cholangiocarcinoma (ICC). We also intended to explore the clinical pathological characteristics, molecular features, RNA expression and immune microenvironment of HER2-positive ICC. METHODS We analyzed a cohort of 304 ICCs using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) to identify HER2 status. Comprehensive analyses of the clinicopathological, molecular genetic, and RNA expression characterizations of ICCs with varying HER2 statuses were performed using next-generation sequencing. We further investigated the tumor microenvironment of ICCs with different HER2 statuses using IHC and multiplex immunofluorescence staining. RESULTS HER2/CEP17 ratio of ≥ 2.0 and HER2 copy number ≥ 4.0; or HER2 copy number ≥ 6.0 were setup as FISH positive criteria. Based on this criterion, 13 (4.27%, 13/304) samples were classified as having HER2 amplification. The agreement between FISH and IHC results in ICC was poor. HER2-amplified cases demonstrated a higher tumor mutational burden compared to non-amplified cases. No significant differences were observed in immune markers between the two groups. However, an increased density of CD8 + CTLA4 + and CD8 + FOXP3 + cells was identified in HER2 gene-amplified cases. CONCLUSION FISH proves to be more appropriate as the gold standard for HER2 evaluation in ICC. HER2 gene-amplified ICCs exhibit poorer prognosis, higher mutational burden, and T cell exhaustion and immune suppressed microenvironment.
Collapse
Affiliation(s)
- Xiaohong Pu
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Drum Tower Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu Province, China
| | - Lin Li
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Drum Tower Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu Province, China
| | - Feng Xu
- Department of Medical Imaging, The Affiliated Suqian First People's Hospital of Nanjing Medical University, 223800, Suqian, Jiangsu Province, China
| | - Ziyu Wang
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Drum Tower Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu Province, China
| | - Yao Fu
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Drum Tower Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu Province, China
| | - Hongyan Wu
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Drum Tower Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu Province, China
| | - Jun Ren
- Department of General Surgery, Northern Jiangsu People's Hospital, Yangzhou University, Yangzhou, 225000, Jiangsu Province, China.
| | - Jun Chen
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Drum Tower Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu Province, China.
| | - Beicheng Sun
- Medical School, Nanjing Drum Tower Hospital, The Affiliated Drum Tower Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu Province, China.
| |
Collapse
|
|
6
|
Li C, Dong Y, Zhang Y, Wu C. Clinical significance of lncRNA XIST expression in cholangiocarcinoma and its effect on cell migration and invasion. Clin Res Hepatol Gastroenterol 2024; 48:102398. [PMID: 38871250 DOI: 10.1016/j.clinre.2024.102398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 06/06/2024] [Accepted: 06/11/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND Cholangiocarcinoma is a malignant tumor that occurs in the bile duct system, and the prognosis of patients is poor. Currently, research suggests that long non-coding RNAs (lncRNAs) in the treatment and prevention of cholangiocarcinoma. This study primarily focuses on the regulation and potential mechanism of the lncRNA XIST (XIST) in cholangiocarcinoma. METHODS The levels of XIST and miR-126-3p in cholangiocarcinoma tissues and cells were detected using real-time quantitative polymerase chain reaction (RT-qPCR). Cell transfection status, including migration and invasion, was examined via the Transwell method. The relationship between XIST and miR-126-3p was observed by dual-luciferase gene reporter assay and verified by rescue assays. Additionally, the prognostic significance of XIST in cholangiocarcinoma was determined using Kaplan-Meier and multivariate Cox regression analyses. RESULTS XIST expression was increased in cholangiocarcinoma, while miR-126-3p was decreased, in both tissues and cells. The successful construction of silencing XIST was found to inhibit the count of cell migration and invasion. XIST directly targeted miR-126-3p to regulate the progression of cholangiocarcinoma. CONCLUSION XIST sponging miR-126-3p inhibited the progression of cholangiocarcinoma and improved the prognosis for patients. This finding provides new insights and opportunities for future studies on cholangiocarcinoma prognostic biomarkers.
Collapse
Affiliation(s)
- Chenxi Li
- Department of General Surgery, Wenling Hospital of Traditional Chinese Medicine, Wenling 317500, China
| | - Yifei Dong
- Department of Laboratory, The Eighth Hospital of Wuhan, Wuhan 430010, China
| | - Yichuan Zhang
- Minimally Invasive Endoscopy Center, Digestive Disease Center, The Affiliated Hospital of Panzhihua University, Panzhihua 617000, China.
| | - Caihong Wu
- Department of Anesthesiology, The Second Xiangya Hospital of Central South University, Changsha 421001, China; Anesthesia Medical Research Center of Central South University, Changsha 421001, China; Department of Clinical Nursing, The Second Xiangya Hospital of Central South University, Changsha 421001, China.
| |
Collapse
|
|
7
|
Kerdkumthong K, Nanarong S, Roytrakul S, Pitakpornpreecha T, Tantimetta P, Runsaeng P, Obchoei S. Quantitative proteomics analysis reveals possible anticancer mechanisms of 5'-deoxy-5'-methylthioadenosine in cholangiocarcinoma cells. PLoS One 2024; 19:e0306060. [PMID: 38923999 PMCID: PMC11206958 DOI: 10.1371/journal.pone.0306060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive cancer originating from bile duct epithelium, particularly prevalent in Asian countries with liver fluke infections. Current chemotherapy for CCA often fails due to drug resistance, necessitating novel anticancer agents. This study investigates the potential of 5'-deoxy-5'-methylthioadenosine (MTA), a naturally occurring nucleoside, against CCA. While MTA has shown promise against various cancers, its effects on CCA remain unexplored. We evaluated MTA's anticancer activity in CCA cell lines and drug-resistant sub-lines, assessing cell viability, migration, invasion, and apoptosis. The potential anticancer mechanisms of MTA were explored through proteomic analysis using LC-MS/MS and bioinformatic analysis. The results show a dose-dependent reduction in CCA cell viability, with enhanced effects on cancer cells compared to normal cells. Moreover, MTA inhibits growth, induces apoptosis, and suppresses cell migration and invasion. Additionally, MTA enhanced the anticancer effects of gemcitabine on drug-resistant CCA cells. Proteomics revealed the down-regulation of multiple proteins by MTA, affecting various molecular functions, biological processes, and cellular components. Network analysis highlighted MTA's role in inhibiting proteins related to mitochondrial function and energy derivation, crucial for cell growth and survival. Additionally, MTA suppressed proteins involved in cell morphology and cytoskeleton organization, important for cancer cell motility and metastasis. Six candidate genes, including ZNF860, KLC1, GRAMD1C, MAMSTR, TANC1, and TTC13, were selected from the top 10 most down-regulated proteins identified in the proteomics results and were subsequently verified through RT-qPCR. Further, KLC1 protein suppression by MTA treatment was confirmed through Western blotting. Additionally, based on TCGA data, KLC1 mRNA was found to be upregulated in the tissue of CCA patients compared to that of normal adjacent tissues. In summary, MTA shows promising anticancer potential against CCA by inhibiting growth, inducing apoptosis, and suppressing migration and invasion, while enhancing gemcitabine's effects. Proteomic analysis elucidates possible molecular mechanisms underlying MTA's anticancer activity, laying the groundwork for future research and development of MTA as a treatment for advanced CCA.
Collapse
Affiliation(s)
- Kankamol Kerdkumthong
- Faculty of Science, Division of Health and Applied Sciences, Biochemistry Graduate Program, Prince of Songkla University, Hatyai, Songkhla, Thailand
| | - Sutthipong Nanarong
- Faculty of Science, Division of Health and Applied Sciences, Biochemistry Graduate Program, Prince of Songkla University, Hatyai, Songkhla, Thailand
- Faculty of Pharmaceutical Sciences, Department of Pharmacognosy and Pharmaceutical Botany, Prince of Songkla University, Hatyai, Songkhla, Thailand
| | - Sittiruk Roytrakul
- National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathumtani, Thailand
| | - Thanawat Pitakpornpreecha
- Faculty of Science, Division of Health and Applied Sciences, Biochemistry Graduate Program, Prince of Songkla University, Hatyai, Songkhla, Thailand
- Faculty of Science, Center of Excellence for Biochemistry, Prince of Songkla University, Hatyai, Songkhla, Thailand
| | - Phonprapavee Tantimetta
- Faculty of Science, Division of Health and Applied Sciences, Biochemistry Graduate Program, Prince of Songkla University, Hatyai, Songkhla, Thailand
| | - Phanthipha Runsaeng
- Faculty of Science, Division of Health and Applied Sciences, Biochemistry Graduate Program, Prince of Songkla University, Hatyai, Songkhla, Thailand
- Faculty of Science, Center of Excellence for Biochemistry, Prince of Songkla University, Hatyai, Songkhla, Thailand
| | - Sumalee Obchoei
- Faculty of Science, Division of Health and Applied Sciences, Biochemistry Graduate Program, Prince of Songkla University, Hatyai, Songkhla, Thailand
- Faculty of Science, Center of Excellence for Biochemistry, Prince of Songkla University, Hatyai, Songkhla, Thailand
| |
Collapse
|
|
8
|
Qin HK, Xue DD, Guo HB. Lymphoepithelioma-Like Intrahepatic Cholangiocarcinoma Associated with Epstein-Barr Virus and Hepatitis Virus: Case Report and a Literature Review. Cancer Manag Res 2024; 16:395-402. [PMID: 38707744 PMCID: PMC11067915 DOI: 10.2147/cmar.s450575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 04/19/2024] [Indexed: 05/07/2024] Open
Abstract
Background Lymphoepithelioma-like carcinoma of the liver is a rare primary malignancy of the liver. The identification of lymphoepithelioma-like cholangiocarcinoma is very limited as there are currently very few reports of such cases. Although previous studies have reported the lymphoepithelioma-like cholangiocarcinoma pathologic features, few studies have revealed the clinic features, imaging characteristics, and clinical course and outcomes. This study was analyzed from multiple aspects such as contrast-enhanced ultrasound, magnetic resonance imaging, and pathological characteristics, aiming to improve the comprehensive understanding of this rare subtype of disease. Case Presentation A 43-year-old female with a history of hepatitis B for over 20 years presented with a lesion found in the right lobe of her liver. After discussion by a multidisciplinary team (MDT), malignant tumors cannot be excluded based on contrast-enhanced ultrasound and MRI. Thus, we decided to perform surgery for the patient. Postoperative pathology confirmed lymphoepithelioma-like intrahepatic cholangiocarcinoma. After 3 months of follow-up, the patient was still alive and no recurrence was observed. Conclusion The purpose of this article is to describe a rare case of lymphoepithelioma-like intrahepatic cholangiocarcinoma and analyze its contrast-enhanced ultrasound and contrast-enhanced MRI features, which will be helpful for physicians in diagnosing this disease. From the perspective of CEUS, the wedge-shaped highly enhanced area around the lesion in the arterial phase appears to be inflammatory but looks malignant based on the extremely fast washout. The lesion showed a low signal on T1WI, a high signal on T2WI and DWI, and an abnormal perfusion shadow can be seen behind the lesion. In particular, this subtype of cholangiocarcinoma has a good prognosis, the clinician should improve the recognition of the disease to strive for early diagnosis and therapy.
Collapse
Affiliation(s)
- Hao-Kun Qin
- Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Dong-Dong Xue
- Department of General Surgery, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Huai-Bin Guo
- Department of General Surgery, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| |
Collapse
|
|
9
|
Jagirdhar GSK, Bains Y, Surani S. Removal of intrahepatic bile duct stone could reduce the risk of cholangiocarcinoma. World J Clin Cases 2024; 12:1881-1884. [PMID: 38660555 PMCID: PMC11036522 DOI: 10.12998/wjcc.v12.i11.1881] [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: 02/14/2024] [Revised: 03/06/2024] [Accepted: 03/22/2024] [Indexed: 04/11/2024] Open
Abstract
Hepatolithiasis (HL) poses a significant risk for cholangiocarcinoma (CCA) development, with reported incidences ranging from 5%-13%. Risk factors include older age, smoking, hepatitis B infection, and prolonged HL duration. Chronic inflammation and mechanical stress on the biliary epithelium contribute to CCA pathogenesis. Hepatectomy reduces CCA risk by removing stones and atrophic liver segments. However, residual stones and incomplete removal increase CCA risk. Kim et al identified carbohydrate antigen 19-9, carcinoembryonic antigen, and stone laterality as CCA risk factors, reaffirming the importance of complete stone removal. Nonetheless, challenges remain in preventing CCA recurrence post-surgery. Longer-term studies are needed to elucidate CCA risk factors further.
Collapse
Affiliation(s)
| | - Yatinder Bains
- Department of Gastroenteroly, Saint Michaels Medical Center, Newark, NJ 07102, United States
| | - Salim Surani
- Department of Medicine and Pharmacology, Texas A&M University, College Station, TX 77843, United States
| |
Collapse
|
|
10
|
Cheo FY, Chan KS, Shelat VG. Outcomes of liver resection in hepatitis C virus-related intrahepatic cholangiocarcinoma: A systematic review and meta-analysis. World J Virol 2024; 13:88946. [PMID: 38616852 PMCID: PMC11008402 DOI: 10.5501/wjv.v13.i1.88946] [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: 10/16/2023] [Revised: 11/10/2023] [Accepted: 12/28/2023] [Indexed: 03/11/2024] Open
Abstract
BACKGROUND Cholangiocarcinoma is the second most common primary liver malignancy. Its incidence and mortality rates have been increasing in recent years. Hepatitis C virus (HCV) infection is a risk factor for development of cirrhosis and cholangiocarcinoma. Currently, surgical resection remains the only curative treatment option for cholangiocarcinoma. We aim to study the impact of HCV infection on outcomes of liver resection (LR) in intrahepatic cholangiocarcinoma (ICC). AIM To study the outcomes of curative resection of ICC in patients with HCV (i.e., HCV+) compared to patients without HCV (i.e., HCV-). METHODS We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies to assess the outcomes of LR in ICC in HCV+ patients compared to HCV- patients in tertiary care hospitals. PubMed, EMBASE, The Cochrane Library and Scopus were systematically searched from inception till August 2023. Included studies were RCTs and non-RCTs on patients ≥ 18 years old with a diagnosis of ICC who underwent LR, and compared outcomes between patients with HCV+ vs HCV-. The primary outcomes were overall survival (OS) and recurrence-free survival. Secondary outcomes include perioperative mortality, operation duration, blood loss, intrahepatic and extrahepatic recurrence. RESULTS Seven articles, published between 2004 and 2021, fulfilled the selection criteria. All of the studies were retrospective studies. Age, incidence of male patients, albumin, bilirubin, platelets, tumor size, incidence of multiple tumors, vascular invasion, bile duct invasion, lymph node metastases, and stage 4 disease were comparable between HCV+ and HCV- group. Alanine transaminase [MD 22.20, 95%confidence interval (CI): 13.75, 30.65, P < 0.00001] and aspartate transaminase levels (MD 27.27, 95%CI: 20.20, 34.34, P < 0.00001) were significantly higher in HCV+ group compared to HCV- group. Incidence of cirrhosis was significantly higher in HCV+ group [odds ratio (OR) 5.78, 95%CI: 1.38, 24.14, P = 0.02] compared to HCV- group. Incidence of poorly differentiated disease was significantly higher in HCV+ group (OR 2.55, 95%CI: 1.34, 4.82, P = 0.004) compared to HCV- group. Incidence of simultaneous hepatocellular carcinoma lesions was significantly higher in HCV+ group (OR 8.31, 95%CI: 2.36, 29.26, P = 0.001) compared to HCV- group. OS was significantly worse in the HCV+ group (hazard ratio 2.05, 95%CI: 1.46, 2.88, P < 0.0001) compared to HCV- group. CONCLUSION This meta-analysis demonstrated significantly worse OS in HCV+ patients with ICC who underwent curative resection compared to HCV- patients.
Collapse
Affiliation(s)
- Feng Yi Cheo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Kai Siang Chan
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - Vishal G Shelat
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
| |
Collapse
|
|
11
|
Zhang N, Shu L, Liu Z, Shi A, Zhao L, Huang S, Sheng G, Yan Z, Song Y, Huang F, Tang Y, Zhang Z. The role of extracellular vesicles in cholangiocarcinoma tumor microenvironment. Front Pharmacol 2024; 14:1336685. [PMID: 38269274 PMCID: PMC10805838 DOI: 10.3389/fphar.2023.1336685] [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: 11/11/2023] [Accepted: 12/26/2023] [Indexed: 01/26/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive malignant tumor that originates from the biliary system. With restricted treatment options at hand, the challenging aspect of early CCA diagnosis leads to a bleak prognosis. Besides the intrinsic characteristics of tumor cells, the generation and progression of CCA are profoundly influenced by the tumor microenvironment, which engages in intricate interactions with cholangiocarcinoma cells. Of notable significance is the role of extracellular vesicles as key carriers in enabling communication between cancer cells and the tumor microenvironment. This review aims to provide a comprehensive overview of current research examining the interplay between extracellular vesicles and the tumor microenvironment in the context of CCA. Specifically, we will emphasize the significant contributions of extracellular vesicles in molding the CCA microenvironment and explore their potential applications in the diagnosis, prognosis assessment, and therapeutic strategies for this aggressive malignancy.
Collapse
Affiliation(s)
- Nuoqi Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Lizhuang Shu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zengli Liu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
- Department of General Surgery, Qilu Hospital, Shandong University, Qingdao, Shandong, China
| | - Anda Shi
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Liming Zhao
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Shaohui Huang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Guoli Sheng
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zhangdi Yan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Yan Song
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Fan Huang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Yongchang Tang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zongli Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| |
Collapse
|
|
12
|
Caputo F, Gelsomino F, Spallanzani A, Pettorelli E, Benatti S, Ghidini M, Grizzi G, Ratti M, Merz V, Messina C, Tonelli R, Luppi G, Melisi D, Dominici M, Salati M. Multicentre match-paired analysis of advanced biliary cancer long-term survivors: The BILONG study. Clin Res Hepatol Gastroenterol 2022; 46:101955. [PMID: 35609824 DOI: 10.1016/j.clinre.2022.101955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 03/23/2022] [Accepted: 05/11/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Advanced biliary cancers (ABC) are aggressive malignancies with a median overall survival (mOS) <12 months when treated with first-line chemotherapy. Nevertheless, a subset of patients experiencing longer survival has been described in the updated analysis of ABC-02 trial. We aimed to provide a real-world description of ABC long-term survivors (LS), identifying which factors impact on survival. METHODS Patients diagnosed with ABC at three Institutions between 2002 and 2019, and who survived ≥18 months, were retrospectively identified. We compared them with a control cohort (C) with a mOS <18 months, matched on age, gender, ECOG PS, disease status, primary tumor site, prior surgery, and treatment modality. Their clinical features, treatments, and outcome were analyzed. RESULTS A total of 78 patients was included, 39 in each group. Both LS and C cohorts had superimposable baseline characteristics, without significant differences. mOS was 29 (95%CI 24.6-33.5) and 9 months (95%CI 6.6-12.9) in the two groups, respectively. After performing a logistic regression analysis, three factors were significantly associated with long-term outcome: low neutrophil-to-lymphocyte ratio (NLR < 3) (Odds Ratio [OR] 0.38), achievement of objective response to treatment (OR 0.16), and the number of lines received (OR 0.29). CONCLUSIONS We described a considerable subset of ABC experiencing long-term survival with conventional chemotherapy in a real-world scenario. Beyond clinical factors, we identified low NLR as a prognostic determinant that may allow for a more accurate selection of long survivors. While waiting for a deeper molecular characterization of this subgroup, we propose NLR as a stratification factor for daily practice and clinical trials.
Collapse
Affiliation(s)
- Francesco Caputo
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Fabio Gelsomino
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Andrea Spallanzani
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Elisa Pettorelli
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Stefania Benatti
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Michele Ghidini
- Division of Medical Oncology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giulia Grizzi
- Oncology Unit, Oncology Department, ASST of Cremona, Cremona, Italy
| | - Margherita Ratti
- Oncology Unit, Oncology Department, ASST of Cremona, Cremona, Italy
| | - Valeria Merz
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
| | - Carlo Messina
- Department of Medical Oncology, Santa Chiara Hospital, Trento, Italy
| | - Roberto Tonelli
- Department of Medical and Surgical Sciences, Respiratory Diseases Unit and Centre for Rare Lung Diseases, University Hospital of Modena, Modena, Italy; Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, Modena, Italy
| | - Gabriele Luppi
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Davide Melisi
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Massimiliano Salati
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy; PhD Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena Cancer Center, Via del Pozzo 71, Modena 41125, Italy.
| |
Collapse
|
|
13
|
Butsri S, Kukongviriyapan V, Senggunprai L, Kongpetch S, Prawan A. All- trans-retinoic acid induces RARB-dependent apoptosis via ROS induction and enhances cisplatin sensitivity by NRF2 downregulation in cholangiocarcinoma cells. Oncol Lett 2022; 23:179. [PMID: 35464301 PMCID: PMC9025595 DOI: 10.3892/ol.2022.13299] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 03/03/2022] [Indexed: 11/27/2022] Open
Abstract
All-trans-retinoic acid (ATRA) has been clinically used to treat acute promyelocytic leukemia and is being studied to treat other types of cancer; however, the therapeutic role and mechanism of ATRA against cholangiocarcinoma (CCA) remain unclear. The present study investigated the cytotoxic effect and underlying mechanisms of ATRA on CCA cell lines. Cell viability was evaluated by sulforhodamine B assay. Intracellular reactive oxygen species (ROS) levels were assessed by dihydroethidium assay. Apoptosis analysis was performed by flow cytometry. The pathways of apoptotic cell death induction were examined using enzymatic caspase activity assay. Proteins associated with apoptosis were evaluated by western blotting. The effects on gene expression were analyzed by reverse transcription-quantitative PCR analysis. ATRA induced a concentration- and time-dependent toxicity in CCA cells. Furthermore, when the cytotoxicity of ATRA against retinoic acid receptor (RAR)-deficient cells was assessed, it was revealed that ATRA cytotoxicity was RARB-dependent. Following ATRA treatment, there was a significant accumulation of cellular ROS and ATRA-induced ROS generation led to an increase in the expression levels of apoptosis-inducing proteins and intrinsic apoptosis. Pre-treatment with ROS scavengers could diminish the apoptotic effect of ATRA, suggesting that ROS and mitochondria may have an essential role in the induction of apoptosis. Furthermore, following ATRA treatment, an increase in cellular ROS content was associated with suppressing nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2) and NRF2-downstream active genes. ATRA also suppressed cisplatin-induced NRF2 expression, suggesting that the enhancement of cisplatin cytotoxicity by ATRA may be associated with the downregulation of NRF2 signaling. In conclusion, the results of the present study demonstrated that ATRA could be repurposed as an alternative drug for CCA therapy.
Collapse
Affiliation(s)
- Siriwoot Butsri
- Department of Pharmacology, Faculty of Medicine, Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Veerapol Kukongviriyapan
- Department of Pharmacology, Faculty of Medicine, Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Laddawan Senggunprai
- Department of Pharmacology, Faculty of Medicine, Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Sarinya Kongpetch
- Department of Pharmacology, Faculty of Medicine, Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Auemduan Prawan
- Department of Pharmacology, Faculty of Medicine, Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| |
Collapse
|
|
14
|
Salati M, Marcheselli L, Messina C, Merz V, Messina M, Carotenuto P, Caputo F, Gelsomino F, Spallanzani A, Reggiani Bonetti L, Caramaschi S, Luppi G, Dominici M, Ghidini M. Development and Multicentre Validation of the Modena Score to Predict Survival in Advanced Biliary Cancers Undergoing Second-Line Chemotherapy. Cancer Manag Res 2022; 14:983-993. [PMID: 35283642 PMCID: PMC8906899 DOI: 10.2147/cmar.s346235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 02/23/2022] [Indexed: 12/24/2022] Open
Abstract
Background The role of second-line chemotherapy in advanced biliary cancers (ABCs) has only recently been established in phase III randomized trial and the optimal selection of patients most likely to benefit from it remains challenging. Methods A cohort of 98 ABC treated second-line chemotherapy was used as a developmental dataset to identify covariates independently associated with overall survival (OS). Kaplan–Meier analysis was used to investigate the association between variables and OS and those retaining statistically significance were combined in a multiplexed score. Results The following pretreatment variables were independently associated with OS: ECOG PS > 0, peritoneal disease, LDH > 430 UI/L, albumin <3.5 gr/dL, gamma-GT >100 UI/L, sodium <140 mEq/L, absolute lymphocyte count <1000/mmc, and PFS to first-line <6 months. Based on these results, a scoring system was developed that identified three subgroups with statistically different OS: low-risk (mOS 18 months), intermediate-risk (mOS 9.4 months) and high-risk (mOS 2.9 months) (p < 0.001). The prognostic model was both internally and externally validated in a multicentre cohort of 120 ABCs. Conclusion The Modena score is a multiplexed scoring system capable of accurately risk-stratified ABCs treated with second-line chemotherapy. Based on its reproducibility, usability and generalizability, it has the potential for assisting therapeutic decision-making in the clinic and risk-stratification in future trials.
Collapse
Affiliation(s)
- Massimiliano Salati
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
- PhD Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
- Correspondence: Massimiliano Salati, PhD Program Clinical and Experimental Medicine, University Hospital of Modena, Modena Cancer Centre, via del Pozzo 71, Modena, 41125, Italy, Tel +39/0594223808, Fax +39/0594222647, Email
| | - Luigi Marcheselli
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Carlo Messina
- Department of Medical Oncology, Santa Chiara Hospital, Trento, Italy
| | - Valeria Merz
- Department of Medical Oncology, Santa Chiara Hospital, Trento, Italy
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
| | - Marco Messina
- Oncology Unit, Fondazione San Raffaele-Giglio, Cefalu’, Palermo, Italy
| | - Pietro Carotenuto
- Telethon Institute of Genetics and Medicine, Pozzuoli, 80078, Napoli, Italy
| | - Francesco Caputo
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Fabio Gelsomino
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Andrea Spallanzani
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | | | | | - Gabriele Luppi
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Michele Ghidini
- Medical Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| |
Collapse
|
|
15
|
Understanding the genetic basis for cholangiocarcinoma. Adv Cancer Res 2022; 156:137-165. [DOI: 10.1016/bs.acr.2022.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
|
|
16
|
Salati M, Rizzo A, Merz V, Messina C, Francesco C, Gelsomino F, Spallanzani A, Ricci AD, Palloni A, Frega G, De Lorenzo S, Carotenuto P, Pettorelli E, Benatti S, Luppi G, Melisi D, Brandi G, Dominici M. Third-line chemotherapy in advanced biliary cancers (ABC): pattern of care, treatment outcome and prognostic factors from a multicenter study. Expert Rev Gastroenterol Hepatol 2022; 16:73-79. [PMID: 34890512 DOI: 10.1080/17474124.2022.2017772] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVES Here, we aim at describing the pattern of care, survival outcome and prognostic factors of ABC patients (pts) receiving third-line chemotherapy. METHODS Institutional registries across three academic medical centers were retrospectively reviewed. Kaplan-Meier estimators were used to calculate survival, the log-rank test to make comparisons, and the Cox proportional hazard models to assess the progostic impact of variables. RESULTS Among 101 pts included in the analysis. 68 (67.3%), 19 (18.8%) and 14 (13.8%) had intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer, respectively. Atotal of 63 (62.3%) pts received monochemotherapy, while 38 (37.6%) were treated with adoublet. The median OS and PFS were 5 and 3 months, respectively. Disease control rate was achieved in 23 (22.7%) pts, with 2 (2%) partial responses. Grade 3-4 treatment-related adverse events were reported in 22 (21.7%) pts. At multivariate analysis, ECOG PS (p < 0.001), tumor burden (p = 0.01) and lymphocyte-to-monocyte ratio (p =0.02) were independent predictors of survival. CONCLUSIONS Third-line chemotherapy displayed limited activity in this real-world cohort, although prognostic factors have been identified that may assist in treatment decision. The results of this multicenter experience, highlight the need for more effective therapies and provide a benchmark for future trials in this setting.
Collapse
Affiliation(s)
- Massimiliano Salati
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy.,PhD Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandro Rizzo
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Valeria Merz
- Department of Medical Oncology, Santa Chiara Hospital, Trento, Italy.,Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
| | - Carlo Messina
- Department of Medical Oncology, Santa Chiara Hospital, Trento, Italy
| | - Caputo Francesco
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Fabio Gelsomino
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Andrea Spallanzani
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Angela Dalia Ricci
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Andrea Palloni
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Giorgio Frega
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Stefania De Lorenzo
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Pietro Carotenuto
- Department of Cell and Disease Mechanisms, Telethon Institute of Genetics and Medicine, Pozzuoli, Napoli, Italy.,Medical Genetics, Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Elisa Pettorelli
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Stefania Benatti
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Gabriele Luppi
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | | | - Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| |
Collapse
|
|
17
|
Dana P, Kariya R, Lert-itthiporn W, Seubwai W, Saisomboon S, Wongkham C, Okada S, Wongkham S, Vaeteewoottacharn K. Homophilic Interaction of CD147 Promotes IL-6-Mediated Cholangiocarcinoma Invasion via the NF-κB-Dependent Pathway. Int J Mol Sci 2021; 22:13496. [PMID: 34948304 PMCID: PMC8706168 DOI: 10.3390/ijms222413496] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/13/2021] [Accepted: 12/13/2021] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinoma (CCA), an aggressive cancer of bile ducts, is a well-known chronic inflammation-related disease. The major impediment in CCA treatment is limited treatment options for advanced disease; hence, an alternative is urgently required. The role of CD147 on cytokine production has been observed in inflammation-related diseases, but not in CCA. Therefore, this study was focused on CD147-promoting proinflammatory cytokine production and functions. Proinflammatory cytokine profiles were compared between CD147 expressing CCA cells and CD147 knockout cells (CD147 KO). Three cytokines, namely interleukin (IL)-6, IL-8, and granulocyte-monocyte colony-stimulating factor (GM-CSF), were dramatically diminished in CD147 KO clones. The involvement of the CD147-related cytokines in CCA invasion was established. CD147-promoted IL-6, IL-8, and GM-CSF secretions were regulated by NF-κB nuclear translocation, Akt activation, and p38 phosphorylation. CD147-fostering IL-6 production was dependent on soluble CD147, CD147 homophilic interaction, and NF-κB function. The overexpression of specific genes in CCA tissues compared to normal counterparts emphasized the clinical importance of these molecules. Altogether, CD147-potentiated proinflammatory cytokine production leading to CCA cell invasion is shown for the first time in the current study. This suggests that modulation of CD147-related inflammation might be a promising choice for advanced CCA treatment.
Collapse
Affiliation(s)
- Paweena Dana
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.D.); (W.L.-i.); (S.S.); (C.W.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Ryusho Kariya
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; (R.K.); (S.O.)
| | - Worachart Lert-itthiporn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.D.); (W.L.-i.); (S.S.); (C.W.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Wunchana Seubwai
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand;
- Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Saowaluk Saisomboon
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.D.); (W.L.-i.); (S.S.); (C.W.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand;
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; (R.K.); (S.O.)
| | - Chaisiri Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.D.); (W.L.-i.); (S.S.); (C.W.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; (R.K.); (S.O.)
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.D.); (W.L.-i.); (S.S.); (C.W.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand;
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; (R.K.); (S.O.)
| | - Kulthida Vaeteewoottacharn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.D.); (W.L.-i.); (S.S.); (C.W.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand;
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; (R.K.); (S.O.)
| |
Collapse
|
|
18
|
Xing L, Lv HT, Liu SG, Wang WB, Zhang TF, Liu JH, Bian W. The effect of gemcitabine combined with AMD3100 applying to cholangiocarcinoma RBE cell lines to CXCR4/CXCL12 axis. Scand J Gastroenterol 2021; 56:914-919. [PMID: 34165373 DOI: 10.1080/00365521.2021.1906944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
PURPOSE To evaluate the effect of AMD3100 treatment to cholangiocarcinoma by analyzing the relationship between them, and provide experimental evidence for whether AMD3100 can become a clinical treatment drug for cholangiocarcinoma. MATERIALS AND METHODS Cholangiocarcinoma RBE cell lines were used in this study. MTT cell proliferation test was used for evaluating the effect of gemcitabine and AMD3100 to cell. CXCR4, N-cadherin, VEGF-C and MMP-9 were detect by RT-PCR and western. Transwell was used for evaluating the invasion effect. RESULTS We demonstrated that as the concentration of gemcitabine increasing from 0.33, 3.33 to 33.33 uM, the cell survival rate was 76.65%, 71.40%, 52.25%, respectively. RT-PCR and Western blot that gemcitabine could affect the expression of CXCR4 protein and the level of mRNA transcription in a dose-dependent manner. N-cadherin VEGF-C, MMP-9 mRNA transcription level showed a significant upward trend in gemcitabine group. In Transwell test, the number of cells in the gemcitabine group was significantly higher than that in the no-medication group (p < .05), the AMD3100 group and the combination group of gemcitabine and AMD3100, the difference between the no-medication group and the AMD3100 monotherapy group was not significant, and the combination group was between them. CONCLUSIONS This study showed that gemcitabine significantly inhibited the growth of cholangiocarcinoma RBE cells in a dose-dependent manner, and gemcitabine can affect the expression of CXCR4, N-cadherin, VEGF-C, MMP-9 protein and mRNA. Cell invasion and metastasis-related factors decreased after AMD3100 combined with gemcitabine.
Collapse
Affiliation(s)
- Li Xing
- Department of Gastrointestinal Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, PR China
| | - Hai-Tao Lv
- Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, PR China
| | - San-Guang Liu
- Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, PR China
| | - Wen-Bin Wang
- Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, PR China
| | - Teng-Fei Zhang
- Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, PR China
| | - Jian-Hua Liu
- Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, PR China
| | - Wei Bian
- Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, PR China
| |
Collapse
|
|
19
|
Clinicopathologic features, tumor immune microenvironment and genomic landscape of Epstein-Barr virus-associated intrahepatic cholangiocarcinoma. J Hepatol 2021; 74:838-849. [PMID: 33212090 DOI: 10.1016/j.jhep.2020.10.037] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 10/07/2020] [Accepted: 10/30/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Little is known about Epstein-Barr virus (EBV)-associated intrahepatic cholangiocarcinoma (EBVaICC) because of its rarity. We aimed to comprehensively investigate the clinicopathology, tumor immune microenvironment (TIME) and genomic landscape of this entity in southern China. METHODS We evaluated 303 intrahepatic cholangiocarcinomas (ICCs) using in situ hybridization for EBV. We compared clinicopathological parameters between EBVaICC and nonEBVaICC, and we analyzed EBV infection status, tumor-infiltrating lymphocytes (TILs) and genomic features of EBVaICC by immunohistochemistry, double staining, nested PCR, multiplex immunofluorescence staining, fluorescence in situ hybridization and whole-exome sequencing. RESULTS EBVaICC accounted for 6.6% of ICCs and was associated with EBV latency type I infection and clonal EBV isolates. Patients with EBVaICC were more often female and younger, with solitary tumors, higher HBV infection rates and less frequent cirrhosis; the lymphoepithelioma-like (LEL) subtype was more common in EBVaICC. EBVaICC was associated with a significantly larger TIME component than nonEBVaICC. The LEL subtype of EBVaICC - associated with a significantly increased density and proportion of CD20+ B cells and CD8+ T cells - was associated with significantly higher 2-year survival rates than conventional EBVaICC and nonEBVaICC. Both PD-1 and PD-L1 in TILs, and PD-L1 in tumor cells, were overexpressed in EBVaICC. High PD-L1 expression in tumor cells and high CD8+ TIL densities were significantly more common in EBVaICC than in nonEBVaICC. Seven genes (MUC4, DNAH1, GLI2, LIPE, MYH7, RP11-766F14.2 and WDR36) were mutated in at least 3 patients. EBVaICC had a different mutational pattern to liver fluke-associated cholangiocarcinoma and HBV-associated ICC. CONCLUSIONS EBVaICC, as a subset of ICC, has unique etiological, clinicopathological and genetic characteristics, with a significantly larger TIME component. Paradoxically, patients with EBVaICC could be candidates for immune checkpoint therapy. LAY SUMMARY Epstein-Barr virus (EBV) is associated with a subtype of intrahepatic cholangiocarcinoma, with unique clinicopathological and genetic characteristics. The tumor immune microenvironment is also different in this tumor subtype and patients with EBV-associated intrahepatic cholangiocarcinoma may respond well to immune checkpoint inhibitors.
Collapse
|
|
20
|
Zhuang L, Meng Z, Yang Z. MRPL27 contributes to unfavorable overall survival and disease-free survival from cholangiocarcinoma patients. Int J Med Sci 2021; 18:936-943. [PMID: 33456351 PMCID: PMC7807179 DOI: 10.7150/ijms.50782] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 12/22/2020] [Indexed: 02/05/2023] Open
Abstract
Objective: This study aimed to investigate the roles of MRPL27 in survival from cholangiocarcinoma patients in The Cancer Genome Atlas (TCGA) database. Methods: In TCGA-CHOL profile, MRPL27 gene expression and clinical data were obtained. Cox regression models were used to evaluate the potential links between MRPL27 and cholangiocarcinoma survival. Enrichment analysis of MRPL27 was conducted in Metascape and Gene Set Enrichment Analysis (GSEA) databases. Results: 36 cholangiocarcinoma patients were included in this analysis. MRPL27 mRNA was significantly upregulated in tumor tissues in cholangiocarcinoma patients including intrahepatic, distal and hilar/perihilar cholangiocarcinoma cases (all p < 0.01). Cholangiocarcinoma patients with high MRPL27 had worse overall survival (OS) and disease-free survival (DFS) compared to those with low MRPL27 (all p < 0.05). Univariate and multivariate Cox models indicated that MRPL27 should be a risk factor for the OS and DFS in cholangiocarcinoma patients (both p < 0.01). Bioinformatic analysis revealed that MRPL27 mainly involved in the processes of mitochondrial translation elongation, respiratory electron transport, ATP synthesis, and inner mitochondrial membrane organization. No mutations of MRPL27 were screened in cholangiocarcinoma patients. Conclusion: Upregulated in tumors, MRPL27 contributes to unfavorable survival in cholangiocarcinoma patients.
Collapse
Affiliation(s)
- Liping Zhuang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Zhiqiang Meng
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Zongguo Yang
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| |
Collapse
|
|
21
|
Kasemsuk T, Saehlim N, Arsakhant P, Sittithumcharee G, Okada S, Saeeng R. A novel synthetic acanthoic acid analogues and their cytotoxic activity in cholangiocarcinoma cells. Bioorg Med Chem 2021; 29:115886. [PMID: 33290909 DOI: 10.1016/j.bmc.2020.115886] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/01/2020] [Accepted: 11/07/2020] [Indexed: 12/15/2022]
Abstract
A novel series of acanthoic acid analogues containing triazole moiety were synthesized through esterification and CuAAC reaction. Evaluation of their biological activities against four cell lines of cholangiocarcinoma cells showed that 3d exhibited the strongest activity with an IC50 value of 18 µM against KKU-213 cell line, which was 8 fold more potent than acanthoic acid. Interestingly, the triazole ring and nitro group on benzyl ring play very significant role in cytotoxic activity. The computational studies revealed that 3d occupies the binding energy of -12.7 and -10.8 kcal/mol with CDK-2 and EGFR protein kinases, respectively. This result might provide a beginning for the development of acanthoic acid analogues as an anticancer agent.
Collapse
Affiliation(s)
- Teerapich Kasemsuk
- Department of Chemistry, Faculty of Science and Technology, Rambhai Barni Rajabhat University, Chanthaburi 22000, Thailand
| | - Natthiya Saehlim
- Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand
| | - Patcharee Arsakhant
- Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand
| | - Gunya Sittithumcharee
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection & Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection & Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Rungnapha Saeeng
- Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand; The Research Unit in Synthetic Compounds and Synthetic Analogues from Natural Product for Drug Discovery (RSND), Burapha University, Chonburi 20131, Thailand.
| |
Collapse
|
|
22
|
Li J, Yang Z, Huang S, Li D. BIRC7 and STC2 Expression Are Associated With Tumorigenesis and Poor Outcome in Extrahepatic Cholangiocarcinoma. Technol Cancer Res Treat 2020; 19:1533033820971676. [PMID: 33234031 PMCID: PMC7705185 DOI: 10.1177/1533033820971676] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Background: Extrahepatic cholangiocarcinoma (EHCC) is a highly aggressive epithelial malignancy and has a poor prognosis for the insensitivity to therapies and difficulty in detection. Novel targets and biomarkers are urgently needed to develop for functional, diagnostic and prognostic application on EHCC. Methods: Immunohistochemical staining technique using the EnVision antibody complex was performed on the samples obtained from 100 EHCC, 30 peritumoral extrahepatic biliary tract (EHBT), 10 EHBT adenomas and 15 normal EHBT tissues. Results: The positive rates of BIRC7 and STC2 expression in tissues obtained from peritumoral EHBT, EHBT adenomas and normal EHBT were significantly lower than those in EHCC tissues. BIRC7 and STC2 proteins were expressed at significantly higher levels in patients with lymph node metastasis, invasion of adjacent tissues, and higher TNM stage (III and/or IV) and unable to undergo resection (biopsy only). Kaplan-Meier survival curves indicated that significantly decreased overall survival rate in patients with positive-BIRC7 or positive-STC2 expression compared with patients of negative-BIRC7 or negative-STC2 expression, respectively. Cox-proportional regression analysis demonstrated that positive-BIRC7 and positive-STC2 expression, along with poor differentiation of EHCC, tumor size >3 cm, lymph node metastasis, invasion of adjacent tissues and unable to undergo resection are independent prognostic factors of EHCC patients. Conclusions: The levels of BIRC7 and STC2 expression were correlated with clinicopathological characteristics of EHCC, and positive expression of BIRC7 and STC2 are associated with progression and poor clinical outcomes of EHCC. BIRC7 and STC2 might be a potential biomarker for EHCC in clinic.
Collapse
Affiliation(s)
- Jiequn Li
- Department of Liver Transplantation, 70566The Second Xiangya Hospital, Central South University, Changsha, China
| | - Zhulin Yang
- Department of General Surgery, 70566The Second Xiangya Hospital, Central South University, Changsha, China
| | - Shengfu Huang
- Department of General Surgery, 70566The Second Xiangya Hospital, Central South University, Changsha, China
| | - Daiqiang Li
- Department of Pathology, 70566The Second Xiangya Hospital, Central South University, Changsha, China
| |
Collapse
|
|
23
|
Carotenuto P, Hedayat S, Fassan M, Cardinale V, Lampis A, Guzzardo V, Vicentini C, Scarpa A, Cascione L, Costantini D, Carpino G, Alvaro D, Ghidini M, Trevisani F, Te Poele R, Salati M, Ventura S, Vlachogiannis G, Hahne JC, Boulter L, Forbes SJ, Guest RV, Cillo U, Said‐Huntingford I, Begum R, Smyth E, Michalarea V, Cunningham D, Rimassa L, Santoro A, Roncalli M, Kirkin V, Clarke P, Workman P, Valeri N, Braconi C. Modulation of Biliary Cancer Chemo-Resistance Through MicroRNA-Mediated Rewiring of the Expansion of CD133+ Cells. Hepatology 2020; 72:982-996. [PMID: 31879968 PMCID: PMC7590111 DOI: 10.1002/hep.31094] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 12/15/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Changes in single microRNA (miRNA) expression have been associated with chemo-resistance in biliary tract cancers (BTCs). However, a global assessment of the dynamic role of the microRNome has never been performed to identify potential therapeutic targets that are functionally relevant in the BTC cell response to chemotherapy. APPROACH AND RESULTS High-throughput screening (HTS) of 997 locked nucleic acid miRNA inhibitors was performed in six cholangiocarcinoma cell lines treated with cisplatin and gemcitabine (CG) seeking changes in cell viability. Validation experiments were performed with mirVana probes. MicroRNA and gene expression was assessed by TaqMan assay, RNA-sequencing, and in situ hybridization in four independent cohorts of human BTCs. Knockout of microRNA was achieved by CRISPR-CAS9 in CCLP cells (MIR1249KO) and tested for effects on chemotherapy sensitivity in vitro and in vivo. HTS revealed that MIR1249 inhibition enhanced chemotherapy sensitivity across all cell lines. MIR1249 expression was increased in 41% of cases in human BTCs. In validation experiments, MIR1249 inhibition did not alter cell viability in untreated or dimethyl sulfoxide-treated cells; however, it did increase the CG effect. MIR1249 expression was increased in CD133+ biliary cancer cells freshly isolated from the stem cell niche of human BTCs as well as in CD133+ chemo-resistant CCLP cells. MIR1249 modulated the chemotherapy-induced enrichment of CD133+ cells by controlling their clonal expansion through the Wnt-regulator FZD8. MIR1249KO cells had impaired expansion of the CD133+ subclone and its enrichment after chemotherapy, reduced expression of cancer stem cell markers, and increased chemosensitivity. MIR1249KO xenograft BTC models showed tumor shrinkage after exposure to weekly CG, whereas wild-type models showed only stable disease over treatment. CONCLUSIONS MIR1249 mediates resistance to CG in BTCs and may be tested as a target for therapeutics.
Collapse
|
|
24
|
The A.L.A.N. score identifies prognostic classes in advanced biliary cancer patients receiving first-line chemotherapy. Eur J Cancer 2019; 117:84-90. [PMID: 31276980 DOI: 10.1016/j.ejca.2019.05.030] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 05/23/2019] [Accepted: 05/29/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Chemotherapy is the mainstay treatment for advanced biliary cancer (ABC). Best supportive care and clinical trials are currently alternative options. The identification of a prognostic score that can be widely applied to daily practice has the potential to better inform clinical management of ABC patients. METHODS A cohort of 123 ABC patients undergoing first-line chemotherapy was used as an exploratory cohort to define the prognostic value of laboratory tests routinely performed in clinical practice. Kaplan-Meier analysis was used to investigate the association between the variables and overall survival (OS). Those variables that were statistically significant at the multivariate analysis were combined in a multiplex score. Performance of the novel prognostic score was confirmed in a validation cohort of 60 ABC patients. RESULTS Baseline actual neutrophil count, lymphocytes-monocytes ratio, neutrophil-lymphocytes ratio and albumin (A.L.A.N.) correlated with OS at the multivariate analysis in the exploratory cohort. When combined in the multiplex, A.L.A.N. score was able to identify three classes of ABC patients with significantly different OS (high-risk: median OS, 5 months; intermediate-risk: median OS, 12 months and low-risk: median OS, 22 months; p:<0.001). The score performed well in the different subtypes of ABC and was independent of stage, performance status and chemotherapy regimen. The performance of the A.L.A.N. score was confirmed in a validation cohort of cholangiocarcinoma patients (high-risk: median OS, 4.3 months; intermediate-risk: median OS 9.3 months, low-risk: median OS 13 months; p:0.005). CONCLUSIONS The A.L.A.N score can be derived by variables routinely recorded in clinical practice and can provide prognostic assessment of ABC patients considered for first-line treatment.
Collapse
|
|
25
|
Braconi C, Roessler S, Kruk B, Lammert F, Krawczyk M, Andersen JB. Molecular perturbations in cholangiocarcinoma: Is it time for precision medicine? Liver Int 2019; 39 Suppl 1:32-42. [PMID: 30829432 DOI: 10.1111/liv.14085] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/26/2019] [Accepted: 02/26/2019] [Indexed: 12/11/2022]
Abstract
The complexity of cholangiocarcinoma (CCA) cellularity and the molecular perturbation mechanisms that underlie the diversity of growth patterns of this malignancy remain a clinical concern. Tumours of the biliary system display significant intrinsic chemoresistance, caused by significant stromal involvement and genome-wide tumour heterogeneity, hampering disease remission and palliation as well as promoting the metastatic behaviour. It is crucial to advance our present understanding of the risk and molecular pathogenesis of CCA. This will facilitate the delineation of patient subsets based on molecular perturbations and adjust for precision therapies.
Collapse
Affiliation(s)
- Chiara Braconi
- Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.,Gastrointestinal and Lymphoma Unit, The Royal Marsden NHS Trust, Surrey and London, UK
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg and Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
| | - Beata Kruk
- Department of General, Transplant and Liver Surgery, Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Marcin Krawczyk
- Department of General, Transplant and Liver Surgery, Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland.,Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Jesper B Andersen
- Department of Health and Medical Sciences, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N, Denmark
| |
Collapse
|
|
26
|
Labib PL, Goodchild G, Pereira SP. Molecular Pathogenesis of Cholangiocarcinoma. BMC Cancer 2019; 19:185. [PMID: 30819129 PMCID: PMC6394015 DOI: 10.1186/s12885-019-5391-0] [Citation(s) in RCA: 201] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 02/20/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cholangiocarcinomas are a heterogeneous group of malignancies arising from a number of cells of origin along the biliary tree. Although most cases in Western countries are sporadic, large population-based studies have identified a number of risk factors. This review summarises the evidence behind reported risk factors and current understanding of the molecular pathogenesis of cholangiocarcinoma, with a focus on inflammation and cholestasis as the driving forces in cholangiocarcinoma development. RISK FACTORS FOR CHOLANGIOCARCINOGENESIS Cholestatic liver diseases (e.g. primary sclerosing cholangitis and fibropolycystic liver diseases), liver cirrhosis, and biliary stone disease all increase the risk of cholangiocarcinoma. Certain bacterial, viral or parasitic infections such as hepatitis B and C and liver flukes also increase cholangiocarcinoma risk. Other risk factors include inflammatory disorders (such as inflammatory bowel disease and chronic pancreatitis), toxins (e.g. alcohol and tobacco), metabolic conditions (diabetes, obesity and non-alcoholic fatty liver disease) and a number of genetic disorders. MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA Regardless of aetiology, most risk factors cause chronic inflammation or cholestasis. Chronic inflammation leads to increased exposure of cholangiocytes to the inflammatory mediators interleukin-6, Tumour Necrosis Factor-ɑ, Cyclo-oxygenase-2 and Wnt, resulting in progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair genes. Accumulating bile acids from cholestasis lead to reduced pH, increased apoptosis and activation of ERK1/2, Akt and NF-κB pathways that encourage cell proliferation, migration and survival. Other mediators upregulated in cholangiocarcinoma include Transforming Growth Factor-β, Vascular Endothelial Growth Factor, Hepatocyte Growth Factor and several microRNAs. Increased expression of the cell surface receptor c-Met, the glucose transporter GLUT-1 and the sodium iodide symporter lead to tumour growth, angiogenesis and cell migration. Stromal changes are also observed, resulting in alterations to the extracellular matrix composition and recruitment of fibroblasts and macrophages that create a microenvironment promoting cell survival, invasion and metastasis. CONCLUSION Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholangiocarcinogenesis. An understanding of the molecular pathogenesis of cholangiocarcinoma is vital when developing new diagnostic biomarkers and targeted therapies for this disease.
Collapse
Affiliation(s)
- Peter L. Labib
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
| | - George Goodchild
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
| | - Stephen P. Pereira
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
| |
Collapse
|
|
27
|
Franca A, Filho ACML, Guerra MT, Weerachayaphorn J, dos Santos ML, Njei B, Robert M, Lima CX, Vidigal PVT, Banales JM, Ananthanarayanam M, Leite MF, Nathanson MH. Effects of Endotoxin on Type 3 Inositol 1,4,5-Trisphosphate Receptor in Human Cholangiocytes. Hepatology 2019; 69:817-830. [PMID: 30141207 PMCID: PMC6351171 DOI: 10.1002/hep.30228] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 08/13/2018] [Indexed: 12/16/2022]
Abstract
Clinical conditions that result in endotoxemia, such as sepsis and alcoholic hepatitis (AH), often are accompanied by cholestasis. Although hepatocellular changes in response to lipopolysaccharide (LPS) have been well characterized, less is known about whether and how cholangiocytes contribute to this form of cholestasis. We examined effects of endotoxin on expression and function of the type 3 inositol trisphosphate receptor (ITPR3), because this is the main intracellular Ca2+ release channel in cholangiocytes, and loss of it impairs ductular bicarbonate secretion. Bile duct cells expressed the LPS receptor, Toll-like receptor 4 (TLR4), which links to activation of nuclear factor-κB (NF-κB). Analysis of the human ITPR3 promoter revealed five putative response elements to NF-κB, and promoter activity was inhibited by p65/p50. Nested 0.5- and 1.0-kilobase (kb) deletion fragments of the ITPR3 promoter were inhibited by NF-κB subunits. Chromatin immunoprecipitation (ChIP) assay showed that NF-κB interacts with the ITPR3 promoter, with an associated increase in H3K9 methylation. LPS decreased ITPR3 mRNA and protein expression and also decreased sensitivity of bile duct cells to calcium agonist stimuli. This reduction was reversed by inhibition of TLR4. ITPR3 expression was decreased or absent in cholangiocytes from patients with cholestasis of sepsis and from those with severe AH. Conclusion: Stimulation of TLR4 by LPS activates NF-κB to down-regulate ITPR3 expression in human cholangiocytes. This may contribute to the cholestasis that can be observed in conditions such as sepsis or AH.
Collapse
Affiliation(s)
- Andressa Franca
- Federal University of Minas Gerais (UFMG), Belo Horizonte, MG
| | | | - Mateus T. Guerra
- Section of Digestive Disease, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
| | - Jittima Weerachayaphorn
- Section of Digestive Disease, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT,Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | | | - Basile Njei
- Section of Digestive Disease, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
| | - Marie Robert
- Department of Pathology, Yale University School of Medicine, New Haven, CT
| | | | | | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | | | - M. Fatima Leite
- Federal University of Minas Gerais (UFMG), Belo Horizonte, MG
| | - Michael H. Nathanson
- Section of Digestive Disease, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
| |
Collapse
|
|
28
|
Fibroinflammatory Liver Injuries as Preneoplastic Condition in Cholangiopathies. Int J Mol Sci 2018; 19:ijms19123875. [PMID: 30518128 PMCID: PMC6321547 DOI: 10.3390/ijms19123875] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 11/29/2018] [Accepted: 12/01/2018] [Indexed: 02/08/2023] Open
Abstract
The cholangipathies are a class of liver diseases that specifically affects the biliary tree. These pathologies may have different etiologies (genetic, autoimmune, viral, or toxic) but all of them are characterized by a stark inflammatory infiltrate, increasing overtime, accompanied by an excess of periportal fibrosis. The cellular types that mount the regenerative/reparative hepatic response to the damage belong to different lineages, including cholagiocytes, mesenchymal and inflammatory cells, which dynamically interact with each other, exchanging different signals acting in autocrine and paracrine fashion. Those messengers may be proinflammatory cytokines and profibrotic chemokines (IL-1, and 6; CXCL1, 10 and 12, or MCP-1), morphogens (Notch, Hedgehog, and WNT/β-catenin signal pathways) and finally growth factors (VEGF, PDGF, and TGFβ, among others). In this review we will focus on the main molecular mechanisms mediating the establishment of a fibroinflammatory liver response that, if perpetuated, can lead not only to organ dysfunction but also to neoplastic transformation. Primary Sclerosing Cholangitis and Congenital Hepatic Fibrosis/Caroli’s disease, two chronic cholangiopathies, known to be prodrome of cholangiocarcinoma, for which several murine models are also available, were also used to further dissect the mechanisms of fibroinflammation leading to tumor development.
Collapse
|
|
29
|
Macharia LW, Mureithi MW, Anzala O. Burden of cancer in Kenya: types, infection-attributable and trends. A national referral hospital retrospective survey. AAS Open Res 2018; 1:25. [PMID: 32382698 PMCID: PMC7185250 DOI: 10.12688/aasopenres.12910.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2018] [Indexed: 11/14/2023] Open
Abstract
Background: Cancer in Africa is an emerging health problem. In Kenya it ranks third as a cause of death after infectious and cardiovascular diseases. Approximately 15% of the global cancer burden is attributable to infectious agents, with higher percentages in developing countries. Therefore, this study aimed to provide comprehensive hospital based data to inform policies Method: A retrospective survey was conducted at Kenyatta National Hospital (KNH) and Moi Teaching and Referral Hospital (MTRH) from 2008 to 2012. Data was obtained from the patients files using a pre-designed data collection form. The study was approved by the KNH/University of Nairobi and MTRH Ethics and Research Committees. Results: In KNH, the five most common cancers in females (n=300) were cervical 62 (20.7%), breast 59 (19.7%), ovarian 22 (7.3%), chronic leukemia 16 (5.3%), endometrial and gastric both with 15 (5%). In males (n=200) they were prostate 23 (11.5%), laryngeal 19 (9.5%), colorectal 17 (8.5%), esophageal 14 (7.0%) and nasopharyngeal carcinoma 12 (6%). The top infection-attributable cancers were: cervical 62 (12.4%), colorectal 31 (6.2%), gastric 26 (5.2%), prostate 23 (4.6%) and nasopharyngeal carcinoma 17 (3.4%). In contrast, in MTRH the five most common cancers in females (n=282) were breast cancer 74 (26.2%), cervical 41 (14.5%), Kaposi's sarcoma 38 (13.5%), non-Hodgkin's lymphoma 15(5.3%) and ovarian 14 (5%) while in males (n=218) they were Kaposi's sarcoma 55 (25.2%), non-Hodgkin's lymphoma 22 (10.1%), chronic leukemia 17 (7.8%), colorectal and esophageal cancers both with 16 (7.3%). The top infection-attributable cancers were: Kaposi's sarcoma 93 (18.6%), cervical 41 (8.2%), non-Hodgkin's lymphoma 37 (7.4%), colorectal 27 (5.4%) and liver cancer 16 (3.2%). Conclusion: This study presents a picture of the burden of cancer and infection-attributable cancer from two referral hospitals in Kenya. Reducing the burden of infection-attributable cancers can translate to a reduction of the overall cancer burden.
Collapse
Affiliation(s)
- Lucy Wanjiku Macharia
- Department of medical Microbiology, Faculty of Medicine, University of Nairobi, Nairobi, Kenya
| | - Marianne Wanjiru Mureithi
- Department of medical Microbiology, Faculty of Medicine, University of Nairobi, Nairobi, Kenya
- KAVI-Institute of Clinical Research (KAVI-ICR), College of Health Sciences, University of Nairobi, Nairobi, Kenya
| | - Omu Anzala
- Department of medical Microbiology, Faculty of Medicine, University of Nairobi, Nairobi, Kenya
- KAVI-Institute of Clinical Research (KAVI-ICR), College of Health Sciences, University of Nairobi, Nairobi, Kenya
| |
Collapse
|
|
30
|
Siripongsakun S, Vidhyarkorn S, Charuswattanakul S, Mekraksakit P, Sungkasubun P, Yodkhunnathum N, Tangruangkiat S, Ritlumlert N, Sricharunrat T, Jaroenpatarapesaj S, Soonklang K, Kulthanmanusorn A, Auewarakul CU, Mahidol C. Ultrasound surveillance for cholangiocarcinoma in an endemic area: A prove of survival benefits. J Gastroenterol Hepatol 2018; 33:1383-1388. [PMID: 29247982 DOI: 10.1111/jgh.14074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 12/03/2017] [Accepted: 12/11/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Cholangiocarcinoma (CCA) is an aggressive malignancy with rapid progression and poor prognosis. Abdominal ultrasound surveillance may detect early-stage malignancy and improve surgical outcome. However, little data exist on the benefits of abdominal ultrasound surveillance in populations at high risk for CCA development in an endemic area. This study compared survival outcomes of CCA patients recruited through abdominal ultrasound surveillance program and those presented to the hospital independent of surveillance. METHODS The surveillance population-based cohort was 4225 villagers in Northern Thailand, aged 30-60 years, who consented to a 5-year abdominal ultrasound surveillance program, which included interval ultrasound examinations every 6 months. The non-surveillance cohort was hospital-based CCA patients diagnosed during April 2007 to November 2015. Numbers of operable tumors, percentages of R0 resection, and survival analyses were compared between the two cohorts. RESULTS There were 48 and 192 CCA patients in the surveillance and the non-surveillance cohorts, respectively. Of these, 37/48 (77.1%) and 22/192 (11.5%) were in an operable stage and R0 resections performed in 36/48 (97.3%) and 14/192 (63.6%), respectively. The median survival in each group was 31.8 and 6.7 months, respectively (with correction of lead time bias) (P < 0.0001). By multivariate analysis, abdominal ultrasound surveillance (hazard ratio [HR] = 0.41; P = 0.012), operable stage (HR = 0.11; P < 0.001), and serum albumin ≥ 3.5 g/dL (HR = 0.42; P < 0.001) were significantly associated with decreased mortality, whereas size of CCA (HR = 1.11; P < 0.001), serum alanine aminotransferase > 40 IU/L (HR = 1.71; P = 0.017), and tumor recurrence (HR = 4.86; P = 0.017) were associated with increased mortality. CONCLUSION Abdominal ultrasound surveillance provided survival benefits and should be considered in areas highly endemic for CCA to reduce mortality.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Kamonwan Soonklang
- Data Management Unit, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand
| | | | - Chirayu U Auewarakul
- School of Medicine and Public Health, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand.,Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Chulabhorn Mahidol
- Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.,HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand
| |
Collapse
|
|
31
|
Lampis A, Carotenuto P, Vlachogiannis G, Cascione L, Hedayat S, Burke R, Clarke P, Bosma E, Simbolo M, Scarpa A, Yu S, Cole R, Smyth E, Mateos JF, Begum R, Hezelova B, Eltahir Z, Wotherspoon A, Fotiadis N, Bali MA, Nepal C, Khan K, Stubbs M, Hahne JC, Gasparini P, Guzzardo V, Croce CM, Eccles S, Fassan M, Cunningham D, Andersen JB, Workman P, Valeri N, Braconi C. MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma. Gastroenterology 2018; 154:1066-1079.e5. [PMID: 29113809 PMCID: PMC5863695 DOI: 10.1053/j.gastro.2017.10.043] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 10/12/2017] [Accepted: 10/27/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small-molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors. METHODS We performed a high-throughput screen of 484 small-molecule compounds to identify those that reduced viability of 6 human CCA cell lines. We tested the effects of HSP90 inhibitors on cells with disruption of the MIR21 gene, cells incubated with MIR21 inhibitors, and stable cell lines with inducible expression of MIR21. We obtained CCA biopsies from patients, cultured them as organoids (patient-derived organoids). We assessed their architecture, mutation and gene expression patterns, response to compounds in culture, and when grown as subcutaneous xenograft tumors in mice. RESULTS Cells with IDH1 and PBRM1 mutations had the highest level of sensitivity to histone deacetylase inhibitors. HSP90 inhibitors were effective in all cell lines, irrespective of mutations. Sensitivity of cells to HSP90 inhibitors correlated inversely with baseline level of MIR21. Disruption of MIR21 increased cell sensitivity to HSP90 inhibitors. CCA cells that expressed transgenic MIR21 were more resistant to HSP90 inhibitors than cells transfected with control vectors; inactivation of MIR21 in these cells restored sensitivity to these agents. MIR21 was shown to target the DnaJ heat shock protein family (Hsp40) member B5 (DNAJB5). Transgenic expression of DNAJB5 in CCA cells that overexpressed MIR21 re-sensitized them to HSP90 inhibitors. Sensitivity of patient-derived organoids to HSP90 inhibitors, in culture and when grown as xenograft tumors in mice, depended on expression of miRNA21. CONCLUSIONS miRNA21 appears to mediate resistance of CCA cells to HSP90 inhibitors by reducing levels of DNAJB5. HSP90 inhibitors might be developed for the treatment of CCA and miRNA21 might be a marker of sensitivity to these agents.
Collapse
Affiliation(s)
| | | | | | - Luciano Cascione
- Bioinformatics Core Unit, Institute of Oncology Research, Bellinzona, Switzerland
| | | | | | - Paul Clarke
- The Institute of Cancer Research, London, UK
| | - Else Bosma
- The Institute of Cancer Research, London, UK
| | - Michele Simbolo
- ARC-Net Research Centre and Department of Pathology and Diagnostics, University of Verona, Verona, Italy
| | - Aldo Scarpa
- ARC-Net Research Centre and Department of Pathology and Diagnostics, University of Verona, Verona, Italy
| | - Sijia Yu
- The Institute of Cancer Research, London, UK
| | | | | | | | | | | | | | | | | | | | - Chirag Nepal
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Khurum Khan
- The Royal Marsden NHS Trust, London and Surrey, UK
| | - Mark Stubbs
- The Institute of Cancer Research, London, UK
| | | | | | | | | | | | - Matteo Fassan
- ARC-Net Research Centre and Department of Pathology and Diagnostics, University of Verona, Verona, Italy; Department of Medicine, University of Padua, Padua, Italy
| | | | - Jesper B Andersen
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Nicola Valeri
- The Institute of Cancer Research, London, UK; The Royal Marsden NHS Trust, London and Surrey, UK
| | - Chiara Braconi
- The Institute of Cancer Research, London, UK; The Royal Marsden NHS Trust, London and Surrey, UK.
| |
Collapse
|
|
32
|
Ghidini M, Cascione L, Carotenuto P, Lampis A, Trevisani F, Previdi MC, Hahne JC, Said-Huntingford I, Raj M, Zerbi A, Mescoli C, Cillo U, Rugge M, Roncalli M, Torzilli G, Rimassa L, Santoro A, Valeri N, Fassan M, Braconi C. Characterisation of the immune-related transcriptome in resected biliary tract cancers. Eur J Cancer 2017; 86:158-165. [PMID: 28988016 PMCID: PMC5699791 DOI: 10.1016/j.ejca.2017.09.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 08/08/2017] [Accepted: 09/04/2017] [Indexed: 12/30/2022]
Abstract
UNLABELLED Although biliary tract cancers (BTCs) are known to have an inflammatory component, a detailed characterisation of immune-related transcripts has never been performed. In these studies, nCounter PanCancer Immune Profiling Panel was used to assess the expression of 770 immune-related transcripts in the tumour tissues (TTs) and matched adjacent tissues (ATs) of resected BTCs. Cox regression analysis and Kaplan-Meier methods were used to correlate findings with relapse-free survival (RFS). The first analysis in the TT and AT of an exploratory set (n = 22) showed deregulation of 39 transcripts associated with T-cell activation. Risk of recurrence was associated with a greater number of genes deregulated in AT in comparison to TT. Analysis in the whole set (n = 53) showed a correlation between AT cytotoxic T-lymphocyte antigen-4 (CTLA4) expression and RFS, which maintained statistical significance at multivariate analysis. CTLA4 expression correlated with forkhead box P3 (FOXP3) expression, suggesting enrichment in T regulatory cells. CTLA4 is known to act by binding to the cluster of differentiation 80 (CD80). No association was seen between AT CD80 expression and RFS. However, CD80 expression differentiated prognosis in patients who received adjuvant chemotherapy. We showed that the immunomodulatory transcriptome is deregulated in resected BTCs. Our study includes a small number of patients and does not enable to draw definitive conclusions; however, it provides useful insights into potential transcripts that may deserve further investigation in larger cohorts of patients. TRANSCRIPT PROFILING Nanostring data have been submitted to GEO repository: GSE90698 and GSE90699.
Collapse
Affiliation(s)
- Michele Ghidini
- The Institute of Cancer Research, Cotswold Road, London, SM2 5NG, UK; Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni, 113, Rozzano, Milan, 20089, Italy; ASST Hospital of Cremona, Viale Concordia, 1, Cremona, 26100, Italy
| | - Luciano Cascione
- Institute of Oncology Research, Via Vela 6, Bellinzona, 6500, Switzerland
| | - Pietro Carotenuto
- The Institute of Cancer Research, Cotswold Road, London, SM2 5NG, UK
| | - Andrea Lampis
- The Institute of Cancer Research, Cotswold Road, London, SM2 5NG, UK
| | - Francesco Trevisani
- The Institute of Cancer Research, Cotswold Road, London, SM2 5NG, UK; San Raffaele Scientific Institute, Via Olgettina, Milan, 20132, Italy
| | | | - Jens C Hahne
- The Institute of Cancer Research, Cotswold Road, London, SM2 5NG, UK
| | | | - Maya Raj
- The Institute of Cancer Research, Cotswold Road, London, SM2 5NG, UK
| | - Alessandro Zerbi
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni, 113, Rozzano, Milan, 20089, Italy; Humanitas University, Via Manzoni, 113, Rozzano, Milan, 20089, Italy
| | | | - Umberto Cillo
- University of Padua, Via Gabelli 61, Padova, 35100, Italy
| | - Massimo Rugge
- University of Padua, Via Gabelli 61, Padova, 35100, Italy
| | - Massimo Roncalli
- Humanitas University, Via Manzoni, 113, Rozzano, Milan, 20089, Italy
| | - Guido Torzilli
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni, 113, Rozzano, Milan, 20089, Italy; Humanitas University, Via Manzoni, 113, Rozzano, Milan, 20089, Italy
| | - Lorenza Rimassa
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni, 113, Rozzano, Milan, 20089, Italy
| | - Armando Santoro
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni, 113, Rozzano, Milan, 20089, Italy; Humanitas University, Via Manzoni, 113, Rozzano, Milan, 20089, Italy
| | - Nicola Valeri
- The Institute of Cancer Research, Cotswold Road, London, SM2 5NG, UK; The Royal Marsden NHS Foundation Trust, London and Surrey, Downs Road, SM2 5PT, UK
| | - Matteo Fassan
- University of Padua, Via Gabelli 61, Padova, 35100, Italy
| | - Chiara Braconi
- The Institute of Cancer Research, Cotswold Road, London, SM2 5NG, UK; The Royal Marsden NHS Foundation Trust, London and Surrey, Downs Road, SM2 5PT, UK.
| |
Collapse
|
|
33
|
He J, Chen X, Li B, Zhou W, Xiao J, He K, Zhang J, Xiang G. Chaetocin induces cell cycle arrest and apoptosis by regulating the ROS-mediated ASK-1/JNK signaling pathways. Oncol Rep 2017; 38:2489-2497. [PMID: 28849240 DOI: 10.3892/or.2017.5921] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Accepted: 08/07/2017] [Indexed: 12/11/2022] Open
Abstract
The present study demonstrated that chaetocin, a natural small-molecule product produced by Chaetomium fungal species and a potential anticancer agent, inhibited the viability and invasive ability of the human intrahepatic cholangio-carcinoma cell line CCLP-1 in vivo and in vitro as revealed by CCK-8 and Transwell invasion assays and mouse xenograft tumor experiments. As determined using flow cytometry and intracellular ROS assays, chaetocin was found to induce cell cycle arrest and oxidative stress, leading to CCLP-1 cell apoptosis. Cell apoptosis can be initiated via different apoptotic signaling pathways under oxidative stress. As determined by western blot analysis, expression levels of the apoptosis signal-regulating kinase 1 (ASK-1) signalosome and its downstream c-Jun N-terminal kinase (JNK) signaling pathway were increased under oxidative stress stimulation. These findings indicate that chaetocin arrests the cell cycle and induces apoptosis by regulating the reactive oxygen species-mediated ASK-1/JNK signaling pathways.
Collapse
Affiliation(s)
- Jingliang He
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Xiaoxun Chen
- Department of Gastrointestinal Surgery, The Guigang City People's Hospital, Guigang, Guangxi 537100, P.R. China
| | - Bowei Li
- The Third Clinical Medical College of Southern Medical University, Guangzhou, Guangdong 510317, P.R. China
| | - Wenjie Zhou
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Jinfeng Xiao
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Ke He
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Jinqian Zhang
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Guoan Xiang
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| |
Collapse
|
|
34
|
Lo CH, Vunnam N, Lewis AK, Chiu TL, Brummel BE, Schaaf TM, Grant BD, Bawaskar P, Thomas DD, Sachs JN. An Innovative High-Throughput Screening Approach for Discovery of Small Molecules That Inhibit TNF Receptors. SLAS DISCOVERY 2017; 22:950-961. [PMID: 28530838 DOI: 10.1177/2472555217706478] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Tumor necrosis factor receptor 1 (TNFR1) is a transmembrane receptor that binds tumor necrosis factor or lymphotoxin-alpha and plays a critical role in regulating the inflammatory response. Upregulation of these ligands is associated with inflammatory and autoimmune diseases. Current treatments reduce symptoms by sequestering free ligands, but this can cause adverse side effects by unintentionally inhibiting ligand binding to off-target receptors. Hence, there is a need for new small molecules that specifically target the receptors, rather than the ligands. Here, we developed a TNFR1 FRET biosensor expressed in living cells to screen compounds from the NIH Clinical Collection. We used an innovative high-throughput fluorescence lifetime screening platform that has exquisite spatial and temporal resolution to identify two small-molecule compounds, zafirlukast and triclabendazole, that inhibit the TNFR1-induced IκBα degradation and NF-κB activation. Biochemical and computational docking methods were used to show that zafirlukast disrupts the interactions between TNFR1 pre-ligand assembly domain (PLAD), whereas triclabendazole acts allosterically. Importantly, neither compound inhibits ligand binding, proving for the first time that it is possible to inhibit receptor activation by targeting TNF receptor-receptor interactions. This strategy should be generally applicable to other members of the TNFR superfamily, as well as to oligomeric receptors in general.
Collapse
Affiliation(s)
- Chih Hung Lo
- 1 Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Nagamani Vunnam
- 1 Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Andrew K Lewis
- 1 Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Ting-Lan Chiu
- 1 Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Benjamin E Brummel
- 1 Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Tory M Schaaf
- 2 Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | | | - Prachi Bawaskar
- 2 Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - David D Thomas
- 2 Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.,4 Photonic Pharma LLC, Minneapolis, MN, USA
| | - Jonathan N Sachs
- 1 Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| |
Collapse
|
|
35
|
Zhang C, Wang H, Ning Z, Xu L, Zhuang L, Wang P, Meng Z. Serum liver enzymes serve as prognostic factors in patients with intrahepatic cholangiocarcinoma. Onco Targets Ther 2017; 10:1441-1449. [PMID: 28331337 PMCID: PMC5348058 DOI: 10.2147/ott.s124161] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Objective Liver functions, reflective of the overall status of the host, have been reported to be important factors affecting the prognosis in many types of cancers. In this study, we explored the influences of liver enzymes albumin (ALB), globulin (GELO), total protein (TP), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), gamma glutamyltranspeptidase (GGT), and lactate dehydrogenase (LDH) on the overall survival (OS) in a number of 173 patients with intrahepatic cholangiocarcinoma (ICC). Patients and methods Between 2011 and 2015, we enrolled patients with pathologically proven locally advanced or metastatic ICC. The impact of ALB, GELO, TP, ALP, ALT, AST, TBIL, DBIL, GGT, and LDH on OS were analyzed using Kaplan–Meier analysis. Next, the associations between these liver enzymes and OS were evaluated by univariate and multivariate analyses. Finally, the role of these enzymes in OS was evaluated in the subgroups. Results Elevated liver enzymes were linked with OS. We revealed that independent prognostic factors of poor outcome were ALP, TBIL, DBIL, and GGT, whereas ALB is a protective factor in ICC patients. Conclusion Our results demonstrate that these liver enzymes may serve as valuable predictive markers in ICC patients.
Collapse
Affiliation(s)
- Chenyue Zhang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Haiyong Wang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Radiation Oncology, Shandong Cancer Hospita & Institute, Jinan, People's Republic of China
| | - Zhouyu Ning
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Litao Xu
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Liping Zhuang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Peng Wang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Zhiqiang Meng
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| |
Collapse
|
|
36
|
Liu H, Zhang Y, Ai M, Wang J, Jin B, Teng Z, Wang Y, Li L. Body Mass Index Can Increase the Risk of Gallbladder Cancer: A Meta-Analysis of 14 Cohort Studies. Med Sci Monit Basic Res 2016; 22:146-155. [PMID: 27899789 PMCID: PMC5134363 DOI: 10.12659/msmbr.901651] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND This study sought to appraise the association between raised body mass index (BMI) and the risk of gallbladder cancer (GBC) by performing a meta-analysis of 14 cohort studies. MATERIAL AND METHODS Eligible cohort studies were selected by searching PubMed and EMBASE from their inception to May 26, 2016, and the reference lists of retrieved articles were also consulted. The information was screened by two authors separately. We used a fixed-effects model to calculate the overall pooled risk estimates. A random-effects model was used to identify heterogeneity. RESULTS The meta-analysis incorporated 14 cohort studies. Nine papers were deemed to be of high quality based on the Newcastle-Ottawa Scale (NOS). Compared with normal weight (BMI 18.5-24.9 kg/m²), the overall pooled relative risks (RR) of GBC was 1.45 (95% CI 1.30-1.61) for excess body weight individuals (BMI ≥25 kg/m²); 1.10 (95% CI 1.02-1.18) for overweight persons (BMI 25-29.9 kg/m²) and 1.69(95% CI 1.54-1.86) for obese folks (BMI ≥30 kg/m²). A higher risk of GBC was presented in obese women (women: RR 1.78, 95% CI 1.59-1.99; men: RR 1.50, 95% CI 1.25-1.79). And a positive relationship between overweight and GBC risk was also displayed in female (RR 1.25, 95% CI 1.11-1.40), but not in male (RR 1.01, 95% CI 0.93-1.11). The sensitivity analysis indicated stable results, and no publication bias was observed. CONCLUSIONS This meta-analysis of 14 cohort studies demonstrated that raised BMI has a dramatic association with risk of GBC, especially in women. But, no association between overweight and GBC in men was found.
Collapse
Affiliation(s)
- Hao Liu
- Department of General Surgery, The 6th Affiliated Hospital of Kunming Medical University, The People's Hospital of Yuxi City, Yuxi, Yunan, China (mainland)
| | - Yong Zhang
- Department of General Surgery, The 6th Affiliated Hospital of Kunming Medical University, The People's Hospital of Yuxi City, Yuxi, Yunan, China (mainland)
| | - Min Ai
- Department of Health Statistics and Epidemiology, Dali University, Dali, Yunnan, China (mainland)
| | - Jun Wang
- Department of General Surgery, The 6th Affiliated Hospital of Kunming Medical University, The People's Hospital of Yuxi City, Yuxi, Yunan, China (mainland)
| | - Bo Jin
- Department of General Surgery, The 6th Affiliated Hospital of Kunming Medical University, Yuxi, Yunan, China (mainland)
| | - Zhaowei Teng
- Department of Orthopedic Surgery, The 6th Affiliated Hospital of Kunming Medical University, The People's Hospital of Yuxi City, Yuxi, Yunan, China (mainland)
| | - Yansheng Wang
- Department of General Surgery, The 6th Affiliated Hospital of Kunming Medical University, The People's Hospital of Yuxi City, Yuxi, Yunan, China (mainland)
| | - Li Li
- Department of General Surgery, The 6th Affiliated Hospital of Kunming Medical University, The People's Hospital of Yuxi City, Yuxi, Yunan, China (mainland)
| |
Collapse
|
|
37
|
Deregulated MicroRNAs in Biliary Tract Cancer: Functional Targets and Potential Biomarkers. BIOMED RESEARCH INTERNATIONAL 2016; 2016:4805270. [PMID: 27957497 PMCID: PMC5120202 DOI: 10.1155/2016/4805270] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 10/10/2016] [Indexed: 02/07/2023]
Abstract
Biliary tract cancer (BTC) is still a fatal disease with very poor prognosis. The lack of reliable biomarkers for early diagnosis and of effective therapeutic targets is a major demanding problem in diagnosis and management of BTC. Due to the clinically silent and asymptomatic characteristics of the tumor, most patients are diagnosed at an already advanced stage allowing only for a palliative therapeutic approach. MicroRNAs are small noncoding RNAs well known to regulate various cellular functions and pathologic events including the formation and progression of cancer. Over the last years, several studies have shed light on the role of microRNAs in BTC, making them potentially attractive therapeutic targets and candidates as biomarkers. In this review, we will focus on the role of oncogenic and tumor suppressor microRNAs and their direct targets in BTC. Furthermore, we summarize and discuss data that evaluate the diagnostic power of deregulated microRNAs as possible future biomarkers for BTC.
Collapse
|
|
38
|
Zhang C, Wang H, Ning Z, Xu L, Zhuang L, Wang P, Meng Z. Prognostic nutritional index serves as a predictive marker of survival and associates with systemic inflammatory response in metastatic intrahepatic cholangiocarcinoma. Onco Targets Ther 2016; 9:6417-6423. [PMID: 27799789 PMCID: PMC5077274 DOI: 10.2147/ott.s112501] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE The significance of the prognostic nutritional index (PNI) has been widely reported and confirmed in many types of cancers. However, few studies are available indicating its prognostic power in patients with intrahepatic cholangiocarcinoma (ICC). Thus, we investigated its relationship with overall survival (OS) to evaluate its role in predicting survival in patients with ICC. PATIENTS AND METHODS Between October 2011 and October 2015, 173 consecutive patients with pathologically confirmed locally advanced or metastatic ICC were enrolled. First, the correlations between PNI and clinical factors were analyzed among these patients. Next, univariate and multivariate analyses were conducted to evaluate the association between PNI and OS among these patients with ICC. In addition, the relationships between PNI and three typical systemic inflammatory response (SIR) markers - the neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR), and the lymphocyte/monocyte ratio (LMR) - were also assessed. RESULTS A lower PNI was linked with a shorter OS in patients with ICC, as reflected obviously in the Kaplan-Meier analyses. The patients with ICC were divided into the locally advanced group and the metastatic group. Further analyses revealed that PNI is not associated with OS in the locally advanced group. However, in the subgroup of patients with metastatic ICC, a lower PNI significantly correlated with a worsened OS. The OS for patients with a low PNI is 5 months, whereas the OS is 10.17 months for patients with a high PNI. Multivariate analyses revealed that PNI is independently correlated with OS. We finally proved that PNI is negatively proportional to NLR and PLR and positively proportional to LMR. CONCLUSION Our results demonstrate that decreased PNI signifies a poor OS and is associated with SIR in patients with metastatic ICC. Therefore, it may serve as a valuable predictive marker in patients with metastatic ICC.
Collapse
Affiliation(s)
- Chenyue Zhang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai
| | - Haiyong Wang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, People’s Republic of China
| | - Zhouyu Ning
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai
| | - Litao Xu
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai
| | - Liping Zhuang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai
| | - Peng Wang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai
| | - Zhiqiang Meng
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai
| |
Collapse
|
|
39
|
Lin ZY, Liang ZX, Zhuang PL, Chen JW, Cao Y, Yan LX, Yun JP, Xie D, Cai MY. Intrahepatic cholangiocarcinoma prognostic determination using pre-operative serum C-reactive protein levels. BMC Cancer 2016; 16:792. [PMID: 27733196 PMCID: PMC5059936 DOI: 10.1186/s12885-016-2827-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 09/30/2016] [Indexed: 02/08/2023] Open
Abstract
Background Serum C-reactive protein (CRP), an acute inflammatory response biomarker, has been recognized as an indicator of malignant disease progression. However, the prognostic significance of CRP levels collected before tumor removal in intrahepatic cholangiocarcinoma requires further investigation. Methods We sampled the CRP levels in 140 patients with intrahepatic cholangiocarcinoma who underwent hepatectomies with regional lymphadenectomies between 2006 and 2013. A retrospective analysis of the clinicopathological data was performed. We focused on the impact of serum CRP on the patients’ cancer-specific survival and recurrence-free survival rates. Results High levels of preoperative serum CRP were significantly associated with well-established clinicopathologic features, including gender, advanced tumor stage, and elevated carcinoembryonic antigen and carbohydrate antigen 19-9 levels (P < 0.05). Univariate analysis demonstrated a significant association between high levels of serum CRP and adverse cancer-specific survival (P = 0.001) and recurrence-free survival (P < 0.001). In patients with stage I/II intrahepatic cholangiocarcinoma, the serum CRP level was a prognostic indicator for cancer-specific survival. In patients with stage I/II or stage III/IV, the serum CRP level was a prognostic indicator for recurrence-free survival (P < 0.05). Additionally, multivariate analysis identified serum CRP level in intrahepatic cholangiocarcinoma as an independent prognostic factor (P < 0.05). Conclusions We confirmed a significant association of elevated pre-operative CRP levels with poor clinical outcomes for the tested patients with intrahepatic cholangiocarcinoma. Our results indicate that the serum CRP level may represent a useful factor for patient stratification in intrahepatic cholangiocarcinoma management.
Collapse
Affiliation(s)
- Zi-Ying Lin
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, No. 651, Dongfeng Road East, 510060, Guangzhou, China
| | - Zhen-Xing Liang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, No. 651, Dongfeng Road East, 510060, Guangzhou, China
| | - Pei-Lin Zhuang
- Department of Prosthodontics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jie-Wei Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, No. 651, Dongfeng Road East, 510060, Guangzhou, China
| | - Yun Cao
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, No. 651, Dongfeng Road East, 510060, Guangzhou, China
| | - Li-Xu Yan
- Department of Pathology and Laboratory Medicine, Guangdong General Hospital, Guangzhou, China
| | - Jing-Ping Yun
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, No. 651, Dongfeng Road East, 510060, Guangzhou, China
| | - Dan Xie
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, No. 651, Dongfeng Road East, 510060, Guangzhou, China
| | - Mu-Yan Cai
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. .,Department of Pathology, Sun Yat-sen University Cancer Center, No. 651, Dongfeng Road East, 510060, Guangzhou, China.
| |
Collapse
|
|
40
|
Hahn MA, Dheilly NM. Experimental Models to Study the Role of Microbes in Host-Parasite Interactions. Front Microbiol 2016; 7:1300. [PMID: 27602023 PMCID: PMC4993751 DOI: 10.3389/fmicb.2016.01300] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 08/08/2016] [Indexed: 01/09/2023] Open
Abstract
Until recently, parasitic infections have been primarily studied as interactions between the parasite and the host, leaving out crucial players: microbes. The recent realization that microbes play key roles in the biology of all living organisms is not only challenging our understanding of host-parasite evolution, but it also provides new clues to develop new therapies and remediation strategies. In this paper we provide a review of promising and advanced experimental organismal systems to examine the dynamic of host-parasite-microbe interactions. We address the benefits of developing new experimental models appropriate to this new research area and identify systems that offer the best promises considering the nature of the interactions among hosts, parasites, and microbes. Based on these systems, we identify key criteria for selecting experimental models to elucidate the fundamental principles of these complex webs of interactions. It appears that no model is ideal and that complementary studies should be performed on different systems in order to understand the driving roles of microbes in host and parasite evolution.
Collapse
Affiliation(s)
- Megan A Hahn
- School of Marine and Atmospheric Sciences, Stony Brook University Stony Brook, NY, USA
| | - Nolwenn M Dheilly
- School of Marine and Atmospheric Sciences, Stony Brook University Stony Brook, NY, USA
| |
Collapse
|
|
41
|
Sombattheera S, Proungvitaya T, Limpaiboon T, Wongkham S, Wongkham C, Luvira V, Proungvitaya S. Total serum bile acid as a potential marker for the diagnosis of cholangiocarcinoma without jaundice. Asian Pac J Cancer Prev 2015; 16:1367-70. [PMID: 25743800 DOI: 10.7314/apjcp.2015.16.4.1367] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Diagnosis of cholangiocarcinoma (CCA) is difficult when patients do not show jaundice. The aim of this study was to examine the feasibility of using the total serum bile acid (TSBA) level as an aid for the diagnosis of CCA in patients without jaundice. For this purpose, TSBA of the following groups were measured using a Beckman Synchron CX4 clinical chemistry analyzer: 60 cases of CCA with total serum bilirubin ≤2 mg/dL (low total bilirubin group, LTB); 32 cases of CCA with total serum bilirubin >2 mg/dL (high total bilirubin group, HTB); and 115 healthy controls. Liver function parameters such as serum cholesterol, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were also examined. The results showed that the TSBA of both LTB and HTB groups of the CCA patients were significantly higher than that of the healthy controls. Also, significant correlation was observed between TSBA and total bilirubin levels in the HTB group of CCA patients. However, no such correlation was seen in the LTB group. The cut-off value of TSBA was determined for the LTB group of CCA patients using the receiver operating characteristic curve analysis, and it was 6.05 μmol/L with the sensitivity and specificity of 46.7% and 84.4%, respectively. In addition, the ALP level was correlated well with the TSBA level and ALP in HTB group was significantly higher than that of LTB group. Moreover, the combination of high TSBA and high ALP levels gave higher specificity up to 97.4%. TSBA might be useful for the diagnosis of CCA patients without jaundice.
Collapse
Affiliation(s)
- Sutthikan Sombattheera
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand E-mail :
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Zhang JW, Chu YM, Lan ZM, Tang XL, Chen YT, Wang CF, Che X. Correlation between metastatic lymph node ratio and prognosis in patients with extrahepatic cholangiocarcinoma. World J Gastroenterol 2015; 21:4255-4260. [PMID: 25892876 PMCID: PMC4394087 DOI: 10.3748/wjg.v21.i14.4255] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 01/16/2015] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the prognostic value of metastatic lymph node ratio (MLNR) in extrahepatic cholangiocarcinoma (ECC) patients undergoing radical resection.
METHODS: Seventy-eight patients with ECC were enrolled. Associations between various clinicopathologic factors and prognosis were investigated by Kaplan-Meier analyses. The Cox proportional-hazards model was used for multivariate survival analysis.
RESULTS: The overall three- and five-year survival rates were 47.26% and 23.99%, respectively. MLNR of 0, 0-0.2, 0.2-0.5, and > 0.5 corresponded to five-year survival rates of 28.59%, 21.60%, 18.84%, and 10.03%, respectively. Univariate analysis showed that degree of tumor differentiation, lymph node metastasis, MLNR, tumor-node-metastasis (TNM) stage, and margin status were closely associated with postoperative survival in ECC patients (P < 0.05). Multivariate analysis showed that MLNR and TNM stage were independent prognostic factors after pancreaticoduodenectomy (HR = 2.13, 95%CI: 1.45-3.11; P < 0.01; and HR = 1.97, 95%CI: 1.17-3.31; P = 0.01, respectively). The median survival time for MLNR > 0.5, 0.2-0.5, 0-0.2, and 0 was 15 mo, 24 mo, 23 mo, and 35.5 mo, respectively. There were statistical differences in survival time between patients with different MLNR (χ2 = 15.38; P < 0.01).
CONCLUSION: MLNR is an independent prognostic factor for ECC patients after radical resection and is useful for predicting postoperative survival.
Collapse
|
|
43
|
Mayr C, Neureiter D, Pichler M, Berr F, Wagner A, Kiesslich T, Namberger K. Cytotoxic effects of chemokine receptor 4 inhibition by AMD3100 in biliary tract cancer cells: Potential drug synergism with gemcitabine. Mol Med Rep 2015; 12:2247-52. [PMID: 25846744 DOI: 10.3892/mmr.2015.3589] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 02/27/2015] [Indexed: 12/21/2022] Open
Abstract
Biliary tract cancer (BTC) remains one of the most life-threatening types of cancer due to the lack of efficient therapies. Advanced tumour stages at the point of diagnosis and high chemoresistance are two of the predominant reasons for a 5-year survival rate of only ~5%. The present study investigated the effect of the chemokine receptor 4 (CXCR4) inhibitor AMD3100 (Plerixafor), alone and in combination with standard gemcitabine chemotherapy, on the proliferation of BTC cells. The expression of CXCR4 was analysed by reverse transcription-quantitative polymerase chain reaction in eight heterogeneously differentiated BTC cell lines. The effects of treatment with the CXCR4 antagonist, AMD3100, on cell viability and anchorage-independent growth, and the possible synergistic cytotoxic effects of AMD3100 with standard chemotherapeutics were assessed. The expression of CXCR4 was observed to a variable extent in all eight BTC cell lines, with SkChA-1 cells exhibiting the highest expression levels. Treatment with AMD3100 led to a marginal decrease in cell viability in the cell lines, with the exception of the CCSW-1 cells, and a significant reduction in the GBC, MzChA-1, SkChA.-1 and TFK-1 cell lines. The combined treatment of the SkChA-1 cells with varying concentrations of AMD3100 and standard gemcitabine chemotherapy revealed a more marked overall cytotoxicity, indicating a potential synergistic effect. In addition, AMD3100 significantly reduced anchorage-independent growth in the SkChA-1 cells. Overall, the results of the present study suggest that the inhibition of CXCR4 by AMD3100, in combination with gemcitabine, may be a suitable strategy for the future therapy of BTC.
Collapse
Affiliation(s)
- Christian Mayr
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg A‑5020, Austria
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg A‑5020, Austria
| | - Martin Pichler
- Department of Experimental Therapeutics, UT MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Frieder Berr
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg A‑5020, Austria
| | - Andrej Wagner
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg A‑5020, Austria
| | - Tobias Kiesslich
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg A‑5020, Austria
| | - Konrad Namberger
- Department of Hematology and Oncology, Klinikum Braunschweig, Braunschweig D‑38118, Germany
| |
Collapse
|
|
44
|
The MUTYH hotspot mutations p.G396D and p.Y179C do not cause substantial genetic susceptibility to biliary cancer. Fam Cancer 2015; 13:243-7. [PMID: 24420788 DOI: 10.1007/s10689-014-9699-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Inflammation-associated oxidative stress and DNA damage are involved in malignant transformation of cholangiocytes. Defective DNA repair mechanisms may predispose to cholangiocarcinoma (CCA) formation, and an elevated CCA risk for MutY human homologue (MUTYH) germline mutation carriers has been proposed previously. The aim of this study was to re-evaluate the MUTYH hotspot mutations p.Y179C (rs34612342) and p.G396D (rs36053993) as genetic susceptibility factors in a large CCA cohort. The study population consisted of 219 Caucasian CCA patients (66.2 ± 11.9 years, 130 males, 89 females; 43 intrahepatic and 176 extrahepatic tumours; tissue diagnosis in 77.6 %) and 355 healthy controls (61.0 ± 11.0 years; 158 males, 197 females). MUTYH hotspot variants were genotyped using TaqMan assays. Four CCA patients were monoallelic mutation carriers (3 p.G396D; 1 p.Y179C) whereas 6 control subjects were heterozygotes (5 p.G396D; 1 p.Y179C). None of the patients carried a biallelic hotspot mutation. The observed allele frequencies did not differ significantly between cases and controls (p > 0.05) and association tests did not provide evidence for an involvement of p.Y179C (OR 1.6 [95 % CI 0.1-26.0]) or p.G396D (OR 1.0 [95 % CI 0.2-4.1]) in the susceptibility to CCA. Power analysis identified a sufficient power only for large effect sizes (>90 % for OR > 5.8 for p.G396D and OR > 18.5 for p.Y179C). Monoallelic MUTYH hotspot mutations do not act as major genetic susceptibility factors causing a substantial CCA risk in the Caucasian population. Due to the low statistical power for the identification of small effect sizes, much larger studies will be needed to detect such effects of minor clinical significance.
Collapse
|
|
45
|
Haga H, Yan IK, Takahashi K, Wood J, Zubair A, Patel T. Tumour cell-derived extracellular vesicles interact with mesenchymal stem cells to modulate the microenvironment and enhance cholangiocarcinoma growth. J Extracell Vesicles 2015; 4:24900. [PMID: 25557794 PMCID: PMC4283029 DOI: 10.3402/jev.v4.24900] [Citation(s) in RCA: 116] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2014] [Revised: 10/31/2014] [Accepted: 11/28/2014] [Indexed: 12/15/2022] Open
Abstract
The contributions of mesenchymal stem cells (MSCs) to tumour growth and stroma formation are poorly understood. Tumour cells can transfer genetic information and modulate cell signalling in other cells through the release of extracellular vesicles (EVs). We examined the contribution of EV-mediated inter-cellular signalling between bone marrow MSCs and tumour cells in human cholangiocarcinoma, highly desmoplastic cancers that are characterized by tumour cells closely intertwined within a dense fibrous stroma. Exposure of MSCs to tumour cell–derived EVs enhanced MSC migratory capability and expression of alpha-smooth muscle actin mRNA, in addition to mRNA expression and release of CXCL-1, CCL2 and IL-6. Conditioned media from MSCs exposed to tumour cell–derived EVs increased STAT-3 phosphorylation and proliferation in tumour cells. These effects were completely blocked by anti-IL-6R antibody. In conclusion, tumour cell–derived EVs can contribute to the generation of tumour stroma through fibroblastic differentiation of MSCs, and can also selectively modulate the cellular release of soluble factors such as IL-6 by MSCs that can, in turn, alter tumour cell proliferation. Thus, malignant cells can “educate” MSCs to induce local microenvironmental changes that enhance tumour cell growth.
Collapse
Affiliation(s)
- Hiroaki Haga
- Department of Cancer Biology, Mayo Clinic Jacksonville, FL, USA
| | - Irene K Yan
- Department of Cancer Biology, Mayo Clinic Jacksonville, FL, USA
| | - Kenji Takahashi
- Department of Cancer Biology, Mayo Clinic Jacksonville, FL, USA
| | - Joseph Wood
- Department of Cancer Biology, Mayo Clinic Jacksonville, FL, USA
| | - Abba Zubair
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, USA
| | - Tushar Patel
- Department of Cancer Biology, Mayo Clinic Jacksonville, FL, USA; Department of Transplantation, Mayo Clinic Jacksonville, FL, USA;
| |
Collapse
|
|
46
|
Mayr C, Neureiter D, Wagner A, Pichler M, Kiesslich T. The role of polycomb repressive complexes in biliary tract cancer. Expert Opin Ther Targets 2014; 19:363-75. [PMID: 25424424 DOI: 10.1517/14728222.2014.986460] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Polycomb group proteins are major epigenetic regulators that modify histone tails. They are organized in two multi-protein complexes called polycomb repressive complex (PRC) 1 and 2. Aberrant PRC activity is known to contribute to the development and aggressiveness of many cancers. Biliary tract cancer (BTC) is a rare malignancy associated with high chemoresistance and poor clinical outcome. Here we review the role of the PRC complexes and the effects of RNAi and drug-mediated inhibition of PRC1 and PRC2 in BTC. AREAS COVERED This review gives a short overview of the composition, biochemical functions and oncogenic role of PRC complexes. We then focus on and summarize the results of current studies that address the role of PRC in BTC. Finally, we discuss options and results of therapeutic targeting of PRC in BTC. EXPERT OPINION Pharmacological inhibition of the two PRC complexes seems to be a promising strategy for treatment of BTC. To date, only few studies have addressed the therapeutic effect of PRC inhibition in BTC. Therefore, it will be important to test established PRC inhibitors, such as DZNep, as well as newly developed drugs, for example, PTC209, to gain more insight into the role of the PRC complexes in BTC and potentially to develop new therapeutic strategies.
Collapse
Affiliation(s)
- Christian Mayr
- Department of Internal Medicine I, Paracelsus Medical University / Salzburger Landeskliniken and Laboratory for Tumor Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University , Salzburg , Austria +43 662 4482 2795 ;
| | | | | | | | | |
Collapse
|
|
47
|
Ma J, Shi J, Zhao D, Cheng L, Wang W, Li F, Jiang X, Jiang H. Raf kinase inhibitor protein inhibits cholangiocarcinoma cell metastasis by downregulating matrix metalloproteinase 9 and upregulating tissue inhibitor of metalloproteinase 4 expression. Oncol Lett 2014; 9:15-24. [PMID: 25435928 PMCID: PMC4246646 DOI: 10.3892/ol.2014.2637] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 08/15/2014] [Indexed: 12/26/2022] Open
Abstract
Cholangiocarcinoma cells originate in the biliary epithelium. The cells easily metastasize and cause relapse. The effect of Raf kinase inhibitor protein (RKIP) on the biological behavior of cholangiocarcinoma cells is not yet clear. In the present study, RKIP and cytokeratin 19 expression was detected in the extrahepatic tissues of cholangiocarcinoma patients by immunohistochemistry. RKIP small interfering (si)RNA or an RKIP-overexpressing adenoviral vector were used to infect the human cholangiocarcinoma RBE cell line. RKIP protein or gene expression was analyzed by western blotting or reverse transcription-quantitative polymerase chain reaction (RT-qPCR), respectively. The cells were assayed for proliferation, apoptosis, invasion and migration. Matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 4 (TIMP-4) mRNA was assayed by RT-qPCR. RKIP expression was reduced in the extrahepatic cholangiocarcinoma tumor compared with the adjacent uninvolved peritumoral tissues. The current study revealed that RKIP expression was positively correlated with cell differentiation, but negatively correlated with lymph node or distant metastasis (P<0.05). RKIP siRNA treatment promoted RBE cell invasion, but RKIP overexpression prevented cell invasion. In the pDC316-siRNA recombinant vector group, the cells migrated more quickly compared with the siRNA-negative control group, and in the RKIP-expressing adenoviral vector group, the cells migrated more slowly compared with the adenoviral negative control group. RKIP inhibited the invasive and metastatic ability of the cholangiocarcinoma cell line, RBE, by downregulating MMP-9 and upregulating TIMP-4 mRNA expression. RKIP is negatively associated with cholangiocarcinoma distant metastasis and prevents cholangiocarcinoma cell metastasis through downregulating MMP-9 expression and upregulating TIMP-4 expression.
Collapse
Affiliation(s)
- Junji Ma
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei 050000, P.R. China
| | - Junli Shi
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei 050000, P.R. China
| | - Dongqiang Zhao
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei 050000, P.R. China
| | - Lijuan Cheng
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei 050000, P.R. China
| | - Wenbin Wang
- Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Fangfang Li
- Department of Biochemistry and Molecular Biology, Basic Medical College of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Xiaoyu Jiang
- Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Huiqing Jiang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei 050000, P.R. China
| |
Collapse
|
|
48
|
Imaging bile duct tumors: pathologic concepts, classification, and early tumor detection. ACTA ACUST UNITED AC 2014; 38:1334-50. [PMID: 23925840 DOI: 10.1007/s00261-013-0027-3] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cholangiocarcinoma is the most common primary malignancy of the bile ducts which has several predisposing factors such as hepatolithiasis and primary sclerosing cholangitis, and can develop from precancerous conditions such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. As surgical resection of early stage cholangiocarcinoma or precancerous lesions may provide better prognosis, early detection of those lesions is very important. Imaging studies play important roles in the diagnosis of bile duct tumors followed by appropriate management. Indeed, not only diagnosis of cholangiocarcinoma but also appropriate categorization of bile duct tumors based on their morphologic features and location on cross-sectional imaging studies, including computed tomography and magnetic resonance imaging, is important to predict their biologic behaviors, and choose relevant treatment strategies. We herein review the classification system of the bile duct tumors with their radiologic and pathologic findings as well as role of imaging in the early detection of bile duct tumors.
Collapse
|
|
49
|
Zhang GW, Lin JH, Qian JP, Zhou J. Identification of risk and prognostic factors for patients with clonorchiasis-associated intrahepatic cholangiocarcinoma. Ann Surg Oncol 2014; 21:3628-37. [PMID: 24781504 DOI: 10.1245/s10434-014-3710-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Indexed: 12/28/2022]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma caused by clonorchiasis (CICC) has a poor prognosis, and there have been insufficient studies regarding risk and prognostic factors. We aimed to identify CICC-associated factors. METHODS A retrospective analysis of 127 eligible patients with CICC was performed with 254 clonorchiasis cases used as matched controls to identify risk factors for CICC. The main outcomes analyzed included overall survival (OS) and disease-free survival (DFS). RESULTS Out of 127 surgeries, R0 resection was performed in 61 patients, R1 in 32 patients, and R2 in 22 patients; nonresection surgery was performed in 12 patients. Median OS for the entire cohort was 29.5 months. Median OS and DFS for 61 patients with R0 resection were 52.4 months and 41.5 months, respectively. We found independent risk factors for CICC were duration of raw fish consumption of ≥28 years (p < 0.001) and hepatitis B virus infection (p = 0.040). R0 resection (p < 0.001), well or moderately differentiated tumor (p = 0.019), and stage I to II tumor (p < 0.001) predicted improved OS for CICC. Serum carcinoembryonic antigen level of ≤5 ng/ml (p = 0.029) and stage I to II tumor (p < 0.001) predicted improved DFS. CONCLUSIONS Duration of raw fish consumption ≥28 years and hepatitis B virus infection were significant risk factors for CICC in patients with clonorchiasis. For patients with CICC, curative resection is an effective treatment. Higher tumor differentiation and earlier American Joint Committee on Cancer stage predicted good prognosis. Serum carcinoembryonic antigen level was found to predict the possibility of recurrence after curative resection.
Collapse
Affiliation(s)
- Guo-Wei Zhang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China,
| | | | | | | |
Collapse
|
|
50
|
New insights into the molecular pathogenesis of intrahepatic cholangiocarcinoma. J Gastroenterol 2014; 49:165-72. [PMID: 24145988 PMCID: PMC3944910 DOI: 10.1007/s00535-013-0894-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Accepted: 09/24/2013] [Indexed: 02/04/2023]
Abstract
Intrahepatic cholangiocarcinoma is an aggressive malignancy and is one of the most devastating cancers of the gastrointestinal tract. The molecular mechanisms contributing to the pathogenesis of these cancers are not well understood. The recognition and distinction of these cancers from other tumors such as perihilar or extrahepatic distal cholangiocarcinoma and hepatocellular carcinoma are important in defining the pathogenesis. New insights into molecular mechanisms contributing to disease pathogenesis are emerging from recent epidemiological, genome-wide profiling and laboratory based studies. These have contributed to an improved understanding of risk factors, genetic mutations and pathophysiological mechanisms that are associated with these tumors. The contribution of well-established risk factors such as biliary tract inflammation and key signaling pathways involved in intrahepatic cholangiocarcinoma are being further defined. These new insights have several important implications for both molecular diagnosis and therapy of these cancers.
Collapse
|