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Li F, Zhang Y, Li C, Li F, Gan B, Yu H, Li J, Feng X, Hu W. Clonorchis sinensis infection induces pathological changes in feline bile duct epithelium and alters biliary microbiota composition. Parasite 2024; 31:53. [PMID: 39240136 PMCID: PMC11378715 DOI: 10.1051/parasite/2024053] [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: 01/31/2024] [Accepted: 08/06/2024] [Indexed: 09/07/2024] Open
Abstract
BACKGROUND Clonorchis sinensis is a zoonotic liver fluke that inhabits the bile ducts of the human liver for prolonged periods, leading to cholangiocarcinoma. Recent research indicates associations between altered biliary microbiota and bile duct disorders. However, the impacts of C. sinensis infection on bile duct epithelium and subsequent effects on biliary microbiota remain unknown. METHODS Feline bile duct samples were collected from both uninfected and C. sinensis-infected cats. Histopathological examination was performed to assess epithelial changes, fibrosis, mucin and cell proliferation using hematoxylin-eosin staining and immunohistochemistry. Additionally, biliary microbiota composition was analyzed through 16S rRNA gene sequencing. Statistical analyses were conducted to compare the microbial diversity and relative abundance between infected and uninfected samples. RESULTS Histopathological analysis of infected feline bile ducts revealed prominent epithelial hyperplasia characterized by increased cell proliferation. Moreover, periductal fibrosis and collagen fibrosis were observed in infected samples compared to uninfected controls. Biliary microbial richness decreased with disease progression compared to uninfected controls. Streptococcus abundance positively correlated with disease severity, dominating communities in cancer samples. Predictive functional analysis suggested that C. sinensis may promote bile duct lesions by increasing microbial genes for carbohydrate metabolism, replication, and repair. CONCLUSIONS This study provides comprehensive insights into the pathological effects of C. sinensis infection on feline bile duct epithelium and its influence on biliary microbiota composition. These novel findings provide insight into C. sinensis pathogenesis and could inform therapeutic development against human clonorchiasis. Further research is warranted to elucidate the underlying mechanisms driving these changes and their implications for host-parasite interactions.
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Affiliation(s)
- Feng Li
- College of Life Sciences, Inner Mongolia University, Hohhot 010070, PR China - Department of Pathology, Inner Mongolia People's Hospital, Hohhot 010011, PR China
| | - Yanli Zhang
- College of Life Sciences, Inner Mongolia University, Hohhot 010070, PR China
| | - Chunfu Li
- College of Life Sciences, Inner Mongolia University, Hohhot 010070, PR China
| | - Fenqi Li
- College of Life Sciences, Inner Mongolia University, Hohhot 010070, PR China
| | - Baojiang Gan
- College of Life Sciences, Inner Mongolia University, Hohhot 010070, PR China
| | - Hong Yu
- Department of Pathology, Inner Mongolia People's Hospital, Hohhot 010011, PR China
| | - Jian Li
- College of Life Sciences, Inner Mongolia University, Hohhot 010070, PR China - Basic Medicine College, Guangxi Traditional Chinese Medical University, Nanning 530005, Guangxi, PR China
| | - Xinyu Feng
- One Health Center, Shanghai Jiao Tong University-The University of Edinburgh, Shanghai 20025, PR China - School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai 20025, PR China
| | - Wei Hu
- College of Life Sciences, Inner Mongolia University, Hohhot 010070, PR China - Department of Infectious Diseases, Huashan Hospital, State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory for Biodiversity Science and Ecological Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200438, PR China
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Yi J, Jeong JH, Won J, Chung S, Pak JH. The crosstalk between cholangiocytes and hepatic stellate cells promotes the progression of epithelial-mesenchymal transition and periductal fibrosis during Clonorchis sinensis infection. Parasit Vectors 2024; 17:151. [PMID: 38519993 PMCID: PMC10958959 DOI: 10.1186/s13071-024-06236-2] [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: 10/27/2023] [Accepted: 03/05/2024] [Indexed: 03/25/2024] Open
Abstract
UNLABELLED ABSTRACT: BACKGROUND: Clonorchis sinensis infection is one of the risk factors that provokes chronic inflammation, epithelial hyperplasia, periductal fibrosis and even cholangiocarcinoma (CCA). Disrupted or aberrant intercellular communication among liver-constituting cells leads to pathological states that cause various hepatic diseases. This study was designed to investigate the pathological changes caused by C. sinensis excretory-secretory products (ESPs) in non-cancerous human cell lines (cholangiocytes [H69 cell line] and human hepatic stellate cells [LX2 cell line]) and their intercellular crosstalk, as well the pathological changes in infected mouse liver tissues. METHODS The cells were treated with ESPs, following which transforming growth factor beta 1 (TGF-β1) and interleukin-6 (IL-6) secretion levels and epithelial-mesenchymal transition (EMT)- and fibrosis-related protein expression were measured. The ESP-mediated cellular motility (migration/invasion) between two cells was assessed using the Transwell and three-dimensional microfluidic assay models. The livers of C. sinensis-infected mice were stained using EMT and fibrotic marker proteins. RESULTS Treatment of cells with ESPs increased TGF-β1 and IL-6 secretion and the expression of EMT- and fibrosis-related proteins. The ESP-mediated mutual cell interaction further affected the cytokine secretion and protein expression levels and promoted cellular motility. N-cadherin overexpression and collagen fiber deposition were observed in the livers of C. sinensis-infected mice. CONCLUSIONS These findings suggest that EMT and biliary fibrosis occur through intercellular communication between cholangiocytes and hepatic stellate cells during C. sinensis infection, promoting malignant transformation and advanced hepatobiliary abnormalities.
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Affiliation(s)
- Junyeong Yi
- Department of Biochemistry, Asan Medical Institute of Convergence Science and Technology (AMIST), University of Ulsan College of Medicine and Asan Medical Center (AMC), 88 Olympic-Ro 43-Gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Ji Hoon Jeong
- Department of Biochemistry, Asan Medical Institute of Convergence Science and Technology (AMIST), University of Ulsan College of Medicine and Asan Medical Center (AMC), 88 Olympic-Ro 43-Gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Jihee Won
- School of Mechanical Engineering, Korea University, 145 Anam-Ro, Seongbuk-gu, Seoul, 02841, Republic of Korea
| | - Seok Chung
- School of Mechanical Engineering, Korea University, 145 Anam-Ro, Seongbuk-gu, Seoul, 02841, Republic of Korea
| | - Jhang Ho Pak
- Department of Biochemistry, Asan Medical Institute of Convergence Science and Technology (AMIST), University of Ulsan College of Medicine and Asan Medical Center (AMC), 88 Olympic-Ro 43-Gil, Songpa-gu, Seoul, 05505, Republic of Korea.
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Capuozzo M, Santorsola M, Ferrara F, Cinque C, Farace S, Patrone R, Granata V, Zovi A, Nasti G, Ottaiano A. Intrahepatic cholangiocarcinoma biomarkers: Towards early detection and personalized pharmacological treatments. Mol Cell Probes 2024; 73:101951. [PMID: 38244704 DOI: 10.1016/j.mcp.2024.101951] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/17/2024] [Accepted: 01/17/2024] [Indexed: 01/22/2024]
Abstract
Cholangiocarcinoma (CCA) is a rare malignancy originating from the biliary tree and is anatomically categorized as intrahepatic (iCCA), perihilar, and extrahepatic or distal. iCCA, the second most prevalent hepatobiliary cancer following hepatocellular carcinoma (HCC), constitutes 5-20 % of all liver malignancies, with an increasing incidence. The challenging nature of iCCA, combined with nonspecific symptoms, often leads to late diagnoses, resulting in unfavorable outcomes. The advanced phase of this neoplasm is difficult to treat with dismal results. Early diagnosis could significantly reduce mortality attributed to iCCA but remains an elusive goal. The identification of biomarkers specific to iCCA and their translation into clinical practice could facilitate diagnosis, monitor therapy response, and potentially reveal novel interventions and personalized medicine. In this review, we present the current landscape of biomarkers in each of these contexts. In addition to CA19.9, a widely recognized biomarker for iCCA, others such as A1BG, CYFRA 21-1, FAM19A5, MMP-7, RBAK, SSP411, TuM2-PK, WFA, etc., as well as circulating tumor DNA, RNA, cells, and exosomes, are under investigation. Advancing our knowledge and monitoring of biomarkers may enable us to improve diagnosis, prognostication, and apply treatments dynamically and in a more personalized manner.
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Affiliation(s)
| | - Mariachiara Santorsola
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via Mariano Semmola, 80131, Napoli, Italy
| | | | - Claudia Cinque
- Pharmaceutical Department, ASL-Naples-3, 80056, Ercolano, Italy
| | - Stefania Farace
- Pharmaceutical Department, ASL-Naples-3, 80056, Ercolano, Italy
| | - Renato Patrone
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via Mariano Semmola, 80131, Napoli, Italy
| | - Vincenza Granata
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via Mariano Semmola, 80131, Napoli, Italy
| | - Andrea Zovi
- Hospital Pharmacist, Ministry of Health, 00144, Roma, Italy
| | - Guglielmo Nasti
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via Mariano Semmola, 80131, Napoli, Italy
| | - Alessandro Ottaiano
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via Mariano Semmola, 80131, Napoli, Italy.
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Sun Z, Zhang Y, Xia Y, Ba X, Zheng Q, Liu J, Kuang X, Xie H, Gong P, Shi Y, Mao N, Wang Y, Liu M, Ran C, Wang C, Wang X, Li M, Zhang W, Fang Z, Liu W, Guo H, Ma H, Song Y. Association between CT-based adipose variables, preoperative blood biochemical indicators and pathological T stage of clear cell renal cell carcinoma. Heliyon 2024; 10:e24456. [PMID: 38268833 PMCID: PMC10803934 DOI: 10.1016/j.heliyon.2024.e24456] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 01/02/2024] [Accepted: 01/09/2024] [Indexed: 01/26/2024] Open
Abstract
Background Clear cell renal cell carcinoma (ccRCC) is corelated with tumor-associated material (TAM), coagulation system and adipocyte tissue, but the relationships between them have been inconsistent. Our study aimed to explore the cut-off intervals of variables that are non-linearly related to ccRCC pathological T stage for providing clues to understand these discrepancies, and to effectively preoperative risk stratification. Methods This retrospective analysis included 218 ccRCC patients with a clear pathological T stage between January 1st, 2014, and November 30th, 2021. The patients were categorized into two cohorts based on their pathological T stage: low T stage (T1 and T2) and high T stage (T3 and T4). Abdominal and perirenal fat variables were measured based on preoperative CT images. Blood biochemical indexes from the last time before surgery were also collected. The generalized sum model was used to identify cut-off intervals for nonlinear variables. Results In specific intervals, fibrinogen levels (FIB) (2.63-4.06 g/L) and platelet (PLT) counts (>200.34 × 109/L) were significantly positively correlated with T stage, while PLT counts (<200.34 × 109/L) were significantly negatively correlated with T stage. Additionally, tumor-associated material exhibited varying degrees of positive correlation with T stage at different cut-off intervals (cut-off value: 90.556 U/mL). Conclusion Preoperative PLT, FIB and TAM are nonlinearly related to pathological T stage. This study is the first to provide specific cut-off intervals for preoperative variables that are nonlinearly related to ccRCC T stage. These intervals can aid in the risk stratification of ccRCC patients before surgery, allowing for developing a more personalized treatment planning.
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Affiliation(s)
- Zehua Sun
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
| | - Yumei Zhang
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
| | - Yuanhao Xia
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
- Department of Radiology, Binzhou Medical University, Yantai, 264000, Shandong, China
| | - Xinru Ba
- Department of Radiology, Yantaishan Hospital, Yantai, 264000, Shandong, China
| | - Qingyin Zheng
- Department of Otolaryngology-Head & Neck Surgery, Case Western Reserve University, Cleveland, OH, 44106, United States
| | - Jing Liu
- Department of Pediatrics, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
| | - Xiaojing Kuang
- School of Basic Medicine, Qingdao University, Qingdao, 266021, Shandong, China
| | - Haizhu Xie
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
| | - Peiyou Gong
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
| | - Yinghong Shi
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
| | - Ning Mao
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
| | - Yongtao Wang
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
| | - Ming Liu
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
| | - Chao Ran
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
| | - Chenchen Wang
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
| | - Xiaoni Wang
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
| | - Min Li
- Department of Radiology, Yantai Traditional Chinese Medicine Hospital, Yantai, 264000, Shandong, China
| | - Wei Zhang
- Department of Radiology, Yantai Penglai People's Hospital, Yantai, 265600, Shandong, China
| | - Zishuo Fang
- School of Electronic Science and Engineering, University of Electronic Science and Technology of China, Chengdu, 610000, China
| | - Wanchen Liu
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
| | - Hao Guo
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
| | - Heng Ma
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, Shandong, China
| | - Yang Song
- Department of Nutrition and Food Hygiene, School of Public Health, College of Medicine, Qingdao University, Qingdao, 266021, Shandong, China
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Loilome W, Namwat N, Jusakul A, Techasen A, Klanrit P, Phetcharaburanin J, Wangwiwatsin A. The Hallmarks of Liver Fluke Related Cholangiocarcinoma: Insight into Drug Target Possibility. Recent Results Cancer Res 2023; 219:53-90. [PMID: 37660331 DOI: 10.1007/978-3-031-35166-2_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Cholangiocarcinoma (CCA) is a malignant tumor of the biliary tree that is classified into three groups based on its anatomic location: intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA). Perihilar CCA is the most common type and accounts for 50-60% of CCA cases. It is followed by distal CCA and then intrahepatic CCA that account for 20-30% and 10-20% of cases, respectively. This chapter discusses the hallmarks of liver fluke related CCA and explores insights into drug target possibilities.
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Affiliation(s)
- Watcharin Loilome
- Department of System Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.
| | - Nisana Namwat
- Department of System Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Apinya Jusakul
- Faculty of Associated Medical Science, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Anchalee Techasen
- Faculty of Associated Medical Science, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Poramate Klanrit
- Department of System Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Jutarop Phetcharaburanin
- Department of System Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Arporn Wangwiwatsin
- Department of System Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
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Kimawaha P, Thanan R, Jusakul A, Jamnongkan W, Silsirivanit A, Sa-Ngaimwibool P, Titapun A, Khuntikeo N, Sithithaworn P, Worasith C, Janthamala S, Lebrilla CB, Techasen A. Serum α2,6-sialylated glycoform of serotransferrin as a glycobiomarker for diagnosis and prediction of clinical severity in cholangiocarcinoma. Clin Chim Acta 2022; 536:142-154. [PMID: 36174722 DOI: 10.1016/j.cca.2022.09.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 08/26/2022] [Accepted: 09/11/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND Glycoprotein sialylation changes are associated with severe development of various cancers. We previously discovered the sialylation of serotransferrin (TF) in cholangiocarcinoma (CCA) using glycoproteomics approach. However, a simple and reliable method for validating sialylation of a specific glycobiomarker is urgently needed. METHODS We identified the altered glycosylation in CCA tissues by glycoproteomics approach using mass spectrometry. An enzyme-linked lectin assay (ELLA) was developed for determining the serum levels of sialylated TF in CCA, hepatocellular carcinoma (HCC) and healthy controls in training and validation cohorts. RESULTS The nine highly sialylated glycoforms of TF were markedly abundant in CCA tumor tissues than in control. Serum SNA-TF and MAL1-TF were significantly higher in CCA patients. Under receiver operating characteristic curve, serum SNA-TF concentrations significantly differentiated CCA from healthy control. Higher SNA-TF were significantly correlated with severe tumor stages and lymph node metastasis. The combined SNA-TF, MAL1-TF, and CA19-9 as a novel glycobiomarkers panel demonstrated the highest specificity (96.2%) for distinguishing CCA from HCC patients. In CCA patients with low CA19-9 levels, SNA-TF in combination with CA19-9 achieved in 97% diagnostic accuracy. CONCLUSIONS Sialylated serotransferrin glycoforms could be used as a novel glycobiomarker for diagnosis and prediction of clinical severity in CCA patients.
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Affiliation(s)
- Phongsaran Kimawaha
- Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Raynoo Thanan
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Apinya Jusakul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Clinical Immunology and Transfusion Sciences, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Wassana Jamnongkan
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Atit Silsirivanit
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Prakasit Sa-Ngaimwibool
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Attapol Titapun
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Narong Khuntikeo
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Paiboon Sithithaworn
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Chanika Worasith
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Sutthiwan Janthamala
- Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | | | - Anchalee Techasen
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Clinical Microbiology, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.
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Detection of Human Cholangiocarcinoma Markers in Serum Using Infrared Spectroscopy. Cancers (Basel) 2021; 13:cancers13205109. [PMID: 34680259 PMCID: PMC8534168 DOI: 10.3390/cancers13205109] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/07/2021] [Accepted: 10/08/2021] [Indexed: 12/21/2022] Open
Abstract
Simple Summary Cholangiocarcinoma is a form of liver cancer that is found, predominantly, in Thailand. Due to the non-specific symptoms and laboratory investigation, it is difficult to rule out cholangiocarcinoma from other liver conditions. Here, we demonstrate the development of a diagnostic tool for cholangiocarcinoma, based on the ATR-FTIR analyses of sera, coupled with multivariate analyses and machine learning tools to obtain a better specificity. The innovative approach that shows highly promising results for this otherwise difficult to diagnose cancer. Abstract Cholangiocarcinoma (CCA) is a malignancy of the bile duct epithelium. Opisthorchis viverrini infection is a known high-risk factor for CCA and in found, predominantly, in Northeast Thailand. The silent disease development and ineffective diagnosis have led to late-stage detection and reduction in the survival rate. Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) is currently being explored as a diagnostic tool in medicine. In this study, we apply ATR-FTIR to discriminate CCA sera from hepatocellular carcinoma (HCC), biliary disease (BD) and healthy donors using a multivariate analysis. Spectral markers differing from healthy ones are observed in the collagen band at 1284, 1339 and 1035 cm−1, the phosphate band (vsPO2−) at 1073 cm−1, the polysaccharides band at 1152 cm−1 and 1747 cm−1 of lipid ester carbonyl. A Principal Component Analysis (PCA) shows discrimination between CCA and healthy sera using the 1400–1000 cm−1 region and the combined 1800—1700 + 1400–1000 cm−1 region. Partial Least Square-Discriminant Analysis (PLS-DA) scores plots in four of five regions investigated, namely, the 1400–1000 cm−1, 1800–1000 cm−1, 3000–2800 + 1800–1000 cm−1 and 1800–1700 + 1400–1000 cm−1 regions, show discrimination between sera from CCA and healthy volunteers. It was not possible to separate CCA from HCC and BD by PCA and PLS-DA. CCA spectral modelling is established using the PLS-DA, Support Vector Machine (SVM), Random Forest (RF) and Neural Network (NN). The best model is the NN, which achieved a sensitivity of 80–100% and a specificity between 83 and 100% for CCA, depending on the spectral window used to model the spectra. This study demonstrates the potential of ATR-FTIR spectroscopy and spectral modelling as an additional tool to discriminate CCA from other conditions.
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Chatchawal P, Wongwattanakul M, Tippayawat P, Jearanaikoon N, Jumniansong A, Boonmars T, Jearanaikoon P, Wood BR. Monitoring the Progression of Liver Fluke-Induced Cholangiocarcinoma in a Hamster Model Using Synchrotron FTIR Microspectroscopy and Focal Plane Array Infrared Imaging. Anal Chem 2020; 92:15361-15369. [PMID: 33170647 DOI: 10.1021/acs.analchem.0c02656] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cholangiocarcinoma (CCA) is a bile duct cancer that originates in the bile duct epithelium. Northeastern Thailand has the highest incidence of CCA, and there is a direct correlation with liver fluke (Opisthorchis viverrini) infection. The high mortality rate of CCA is a consequence of delayed diagnosis. Fourier transform infrared (FTIR) spectroscopy is a powerful technique that detects the absorbance of molecular vibrations and is perfectly suited for the interrogation of biological samples. In this study, we applied synchrotron radiation-FTIR (SR-FTIR) microspectroscopy and focal plane array (FPA-FTIR) microspectroscopy to characterize periductal fibrosis and bile duct cells progressing to CCA induced by inoculating O. viverrini metacercariae into hamsters. SR-FTIR and FPA-FTIR measurements were performed in liver sections harvested from 1-, 2-, 3-, and 6-month post-infected hamsters compared to uninfected liver tissues. Principal component analysis (PCA) of the tissue samples showed a clear discrimination among uninfected and early-stage (1 and 2 months) and cancerous-stage (3 and 6 months) tissues. The discrimination is based on intensity changes in the phosphodiester band (1081 cm-1), amino acid residue (∼1396 cm-1), and C═O stretching carboxylic esters (1745 cm-1). Infected tissues also show definitive bands at ∼1280, 1234, and 1201 cm-1 characteristic of the collagen triplet and indicative of fibrosis. Hierarchical cluster analysis (HCA) was performed on the FPA data and showed a classification into specific cell types. Hepatocyte, fibrotic lesion, and bile duct (cancer) were classified and HCA mapping showed similar cellular distribution pattern compared to Sirius red staining. This study was also extended to less invasive sample analysis using attenuated total reflectance-FTIR (ATR-FTIR) spectroscopy. Sera from O. viverrini-infected and uninfected hamsters were analyzed using multivariate analysis, including principal component analysis (PCA), and partial least squares-discriminant analysis (PLS-DA). PCA was able to classify spectra of normal, early-stage CCA, and CCA, while the PLS-DA gave 100% accuracy for the validation. The model was established from 17 samples (11 normal, 6 cancer) in the calibration set and 9 samples in the validation set (4 normal, 2 cancer, 3 precancerous). These results indicate that FTIR-based technology is a potential tool to detect the progression of CCA, especially in the early stages of the disease.
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Affiliation(s)
- Patutong Chatchawal
- Biomedical Sciences, Graduate School, Khon Kaen University, Khon Kaen 40002, Thailand.,Center for Research and Development of Medical Diagnosis Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen40002, Thailand
| | - Molin Wongwattanakul
- Center for Research and Development of Medical Diagnosis Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen40002, Thailand
| | - Patcharaporn Tippayawat
- Center for Research and Development of Medical Diagnosis Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | | | - Amonrat Jumniansong
- Center for Research and Development of Medical Diagnosis Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Thidarat Boonmars
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen40002, Thailand.,Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Patcharee Jearanaikoon
- Center for Research and Development of Medical Diagnosis Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen40002, Thailand
| | - Bayden R Wood
- Center for Biospectroscopy, School of Chemistry, Faculty of Science, Monash University, Victoria 3800, Australia
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9
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Mohanty SK, Lobeck I, Donnelly B, Dupree P, Walther A, Mowery S, Coots A, Bondoc A, Sheridan RM, Poling HM, Temple H, McNeal M, Sestak K, Bansal R, Tiao G. Rotavirus Reassortant-Induced Murine Model of Liver Fibrosis Parallels Human Biliary Atresia. Hepatology 2020; 71:1316-1330. [PMID: 31442322 PMCID: PMC7384231 DOI: 10.1002/hep.30907] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Accepted: 08/15/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS Biliary atresia (BA) is a devastating neonatal cholangiopathy that progresses to fibrosis and end-stage liver disease by 2 years of age. Portoenterostomy may reestablish biliary drainage, but, despite drainage, virtually all afflicted patients develop fibrosis and progress to end-stage liver disease requiring liver transplantation for survival. APPROACH AND RESULTS In the murine model of BA, rhesus rotavirus (RRV) infection of newborn pups results in a cholangiopathy paralleling human BA and has been used to study mechanistic aspects of the disease. Unfortunately, nearly all RRV-infected pups succumb by day of life 14. Thus, in this study we generated an RRV-TUCH rotavirus reassortant (designated as TR(VP2,VP4) ) that when injected into newborn mice causes an obstructive jaundice phenotype with lower mortality rates. Of the mice that survived, 63% developed Ishak stage 3-5 fibrosis with histopathological signs of inflammation/fibrosis and bile duct obstruction. CONCLUSIONS This model of rotavirus-induced neonatal fibrosis will provide an opportunity to study disease pathogenesis and has potential to be used in preclinical studies with an objective to identify therapeutic targets that may alter the course of BA.
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Affiliation(s)
- Sujit K. Mohanty
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Inna Lobeck
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Bryan Donnelly
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Phylicia Dupree
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Ashley Walther
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Sarah Mowery
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Abigail Coots
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Alexander Bondoc
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Rachel M. Sheridan
- Division of Pathology and Laboratory MedicineCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Holly M. Poling
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Haley Temple
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Monica McNeal
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOH,Division of Infectious DiseasesCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Karol Sestak
- Tulane National Primate Research CenterCovingtonLA
| | - Ruchi Bansal
- Department of Biomaterials Science and Technology, Technical Medical CentreUniversity of TwenteEnschedethe Netherlands
| | - Greg Tiao
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
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10
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Xu S, Xu H, Wang W, Li S, Li H, Li T, Zhang W, Yu X, Liu L. The role of collagen in cancer: from bench to bedside. J Transl Med 2019; 17:309. [PMID: 31521169 PMCID: PMC6744664 DOI: 10.1186/s12967-019-2058-1] [Citation(s) in RCA: 474] [Impact Index Per Article: 79.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 09/06/2019] [Indexed: 02/06/2023] Open
Abstract
Collagen is the major component of the tumor microenvironment and participates in cancer fibrosis. Collagen biosynthesis can be regulated by cancer cells through mutated genes, transcription factors, signaling pathways and receptors; furthermore, collagen can influence tumor cell behavior through integrins, discoidin domain receptors, tyrosine kinase receptors, and some signaling pathways. Exosomes and microRNAs are closely associated with collagen in cancer. Hypoxia, which is common in collagen-rich conditions, intensifies cancer progression, and other substances in the extracellular matrix, such as fibronectin, hyaluronic acid, laminin, and matrix metalloproteinases, interact with collagen to influence cancer cell activity. Macrophages, lymphocytes, and fibroblasts play a role with collagen in cancer immunity and progression. Microscopic changes in collagen content within cancer cells and matrix cells and in other molecules ultimately contribute to the mutual feedback loop that influences prognosis, recurrence, and resistance in cancer. Nanoparticles, nanoplatforms, and nanoenzymes exhibit the expected gratifying properties. The pathophysiological functions of collagen in diverse cancers illustrate the dual roles of collagen and provide promising therapeutic options that can be readily translated from bench to bedside. The emerging understanding of the structural properties and functions of collagen in cancer will guide the development of new strategies for anticancer therapy.
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Affiliation(s)
- Shuaishuai Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Huaxiang Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Wenquan Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Shuo Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Hao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Tianjiao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Wuhu Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China.
| | - Liang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China.
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11
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Edwards SW, Spofford EM, Price C, Wright HL, Salao K, Suttiprapa S, Sripa B. Opisthorchiasis-Induced Cholangiocarcinoma: How Innate Immunity May Cause Cancer. ADVANCES IN PARASITOLOGY 2018; 101:149-176. [PMID: 29907253 DOI: 10.1016/bs.apar.2018.05.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Innate, inflammatory responses towards persistent Opisthorchis viverrini (OV) infection are likely to contribute to the development of cholangiocarcinoma (CCA), a liver cancer that is rare in the West but prevalent in Greater Mekong Subregion countries in Southeast Asia. Infection results in the infiltration of innate immune cells into the bile ducts and subsequent activation of inflammatory immune responses that fail to clear OV but instead may damage local tissues within the bile ducts. Not all patients infected with OV develop CCA, and so tumourigenesis may be dependent on multiple factors including the magnitude of the inflammatory response that is activated in infected individuals. The purpose of this review is to summarize how innate immune responses may promote tumourigenesis following OV infection and if such responses can be used to predict CCA onset in OV-infected individuals. It also hypothesizes on the role that Helicobacterspp., which are associated with liver fluke infections, may play in activation of the innate the immune system to promote tissue damage and persistent inflammation leading to CCA.
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Affiliation(s)
- Steven W Edwards
- Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Edward M Spofford
- Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Charlotte Price
- Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Helen L Wright
- Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Kanin Salao
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sutas Suttiprapa
- Tropical Medicine Graduate Program, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Banchob Sripa
- Tropical Medicine Graduate Program, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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12
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Gabr SA, Alghadir AH, Sherif YE, Ghfar AA. Hydroxyproline as a Biomarker in Liver Disease. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/978-94-007-7675-3_26] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2023]
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13
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Elmahdy NA, Sokar SS, Salem ML, Sarhan NI, Abou-Elela SH. Anti-fibrotic potential of human umbilical cord mononuclear cells and mouse bone marrow cells in CCl 4- induced liver fibrosis in mice. Biomed Pharmacother 2017; 89:1378-1386. [PMID: 28320105 DOI: 10.1016/j.biopha.2017.03.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2016] [Revised: 02/17/2017] [Accepted: 03/03/2017] [Indexed: 02/07/2023] Open
Abstract
Liver fibrosis is the consequence of hepatocyte injury that leads to the activation of hepatic stellate cells (HSC). The treatment of choice is Liver transplantation; however, it has many problems such as surgery-related complications, immunological rejection and high costs associated with the procedure. Stem cell-based therapy would be a potential alternative, so the aim of this study is to investigate the therapeutic potential of human umbilical cord mononuclear cells (MNC) and mouse bone marrow cells (BMC) against carbon tetrachloride (CCl4) induced liver fibrosis in mice and compare it with that of silymarin. In the present study, male albino mice (N=60) were divided into six groups (10 mice each), the first group served as the normal control group while the remaining five groups were rendered fibrotic by intraperitoneal injections of CCl4 and being left for 6 weeks to develop hepatic fibrosis. Thereafter, the mice were divided into CCl4 group, CCl4 group receiving MNC or BMC or silymarin or MNC and silymarin combination. After the specified treatment period, animals were then euthanized, blood and tissue samples were collected for measurement of alanine aminotransferase(ALT), aspartate aminotransferase(AST), malondialdehyde(MDA), reduced glutathione(GSH), collagen, Laminin, transforming growth factor β1(TGFβ1), tumor necrosis factor alpha(TNFα). MNC, BMC, and the combination therapy showed a significant decrease in ALT, AST, MDA, collagen, Laminin, TGFβ1, and TNFα and a significant increase in GSH. The data displayed a similar regression of fibrosis with the histological and immunohistological parameters. In conclusion, MNC, BMC and the combination therapy showed a potential therapeutic effect against liver fibrosis via reducing oxidative stress, inflammatory mediators, and fibrogenic markers.
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Affiliation(s)
- Nageh Ahmed Elmahdy
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Samia Salem Sokar
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Mohamed Labib Salem
- Zoology Department, Faculty of Science, Immunology and Biotechnology Unit, Immunology and Biotechnology Division, Center of Excellence in Cancer Research, Tanta University, Tanta, Egypt
| | | | - Sherin Hamed Abou-Elela
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
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14
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Rahnemai-Azar AA, Weisbrod A, Dillhoff M, Schmidt C, Pawlik TM. Intrahepatic cholangiocarcinoma: Molecular markers for diagnosis and prognosis. Surg Oncol 2017; 26:125-137. [PMID: 28577718 DOI: 10.1016/j.suronc.2016.12.009] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 12/24/2016] [Accepted: 12/29/2016] [Indexed: 02/08/2023]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver tumor with increasing incidence worldwide. The outcome of patients with iCCA is dismal owing to tumor's aggressiveness, late diagnosis and lack of effective treatment options. Detection of the tumor at early stages may make surgical resection, as only potential curative treatment, more feasible. Unfortunately, despite recent developments in imaging modalities and laboratory tests, the diagnosis of iCCA remains challenging and patients often present in advanced stages when surgery cannot be offered. Moreover, accurate assessment of disease burden is critical to optimize management strategy, including the use of adjuvant therapies and clinical trials. Identifying iCCA specific diagnostic and prognostic biomarkers has been a focus of interest among many investigators with a progressive increase in data on iCCA related to advances in "omics" technologies. We herein summarize iCCA biomarkers and define the molecular mechanisms underlying iCCA carcinogenesis, as well as highlight potential diagnostic and prognostic application of molecular biomarkers.
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Affiliation(s)
- Amir A Rahnemai-Azar
- Department of Surgery, University of Washington Medical Center, Seattle, WA, USA
| | - Allison Weisbrod
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Mary Dillhoff
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Carl Schmidt
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.
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15
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Viterbo D, Gausman V, Gonda T. Diagnostic and therapeutic biomarkers in pancreaticobiliary malignancy. World J Gastrointest Endosc 2016; 8:128-142. [PMID: 26862363 PMCID: PMC4734972 DOI: 10.4253/wjge.v8.i3.128] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 10/17/2015] [Accepted: 12/08/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) are two malignancies that carry significant morbidity and mortality. The poor prognoses of these cancers are strongly related to lack of effective screening modalities as well as few therapeutic options. In this review, we highlight novel biomarkers that have the potential to be used as diagnostic, prognostic and predictive markers. The focus of this review is biomarkers that can be evaluated on endoscopically-obtained biopsies or brush specimens in the pre-operative setting. We also provide an overview of novel serum based markers in the early diagnosis of both PDAC and CCA. In pancreatic cancer, the emphasis is placed on prognostic and theranostic markers, whereas in CCA the utility of molecular markers in diagnosis and prognosis are highlighted.
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16
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Uddin MH, Choi MH, Kim WH, Jang JJ, Hong ST. Involvement of PSMD10, CDK4, and Tumor Suppressors in Development of Intrahepatic Cholangiocarcinoma of Syrian Golden Hamsters Induced by Clonorchis sinensis and N-Nitrosodimethylamine. PLoS Negl Trop Dis 2015; 9:e0004008. [PMID: 26313366 PMCID: PMC4551803 DOI: 10.1371/journal.pntd.0004008] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 07/24/2015] [Indexed: 12/28/2022] Open
Abstract
Background Clonorchis sinensis is a group-I bio-carcinogen for cholangiocarcinoma (CCA). Although the epidemiological evidence links clonorchiasis and CCA, the underlying molecular mechanism involved in this process is poorly understood. In the present study, we investigated expression of oncogenes and tumor suppressors, including PSMD10, CDK4, p53 and RB in C. sinensis induced hamster CCA model. Methods Different histochemical/immunohistochemical techniques were performed to detect CCA in 4 groups of hamsters: uninfected control (Ctrl.), infected with C. sinensis (Cs), ingested N-nitrosodimethylamine (NDMA), and both Cs infected and NDMA introduced (Cs+NDMA). The liver tissues from all groups were analyzed for gene/protein expressions by quantitative PCR (qPCR) and western blotting. Principal Findings CCA was observed in all hamsters of Cs+NDMA group with well, moderate, and poorly differentiated types measured in 21.8% ± 1.5%, 13.3% ± 1.3%, and 10.8% ± 1.3% of total tissue section areas respectively. All CCA differentiations progressed in a time dependent manner, starting from the 8th week of infection. CCA stroma was characterized with increased collagen type I, mucin, and proliferative cell nuclear antigen (PCNA). The qPCR analysis showed PSMD10, CDK4 and p16INK4 were over-expressed, whereas p53 was under-expressed in the Cs+NDMA group. We observed no change in RB1 at mRNA level but found significant down-regulation of RB protein. The apoptosis related genes, BAX and caspase 9 were found downregulated in the CCA tissue. Gene/protein expressions were matched well with the pathological changes of different groups except the NDMA group. Though the hamsters in the NDMA group showed no marked pathological lesions, we observed over-expression of Akt/PKB and p53 genes proposing molecular interplay in this group which might be related to the CCA initiation in this animal model. Conclusions/Significance The present findings suggest that oncogenes, PSMD10 and CDK4, and tumor suppressors, p53 and RB, are involved in the carcinogenesis process of C. sinensis induced CCA in hamsters. Clonorchis sinensis is a helminth parasite and a carcinogenic agent for cholangiocarcinoma (CCA) or bile duct cancer in humans. Though a large and compelling body of evidence suggests an association between C. sinensis and CCA, the mechanism underlying at the genetic/proteomic level is little known. To explore the underlying molecular mechanism we investigated a number of genes/proteins in C. sinensis induced hamster CCA model. Here C. sinensis induced CCA successfully in all hamsters when introduced with N-nitrosodimethylamine. The histopathology confirmed the development of CCA and detected excessive collagen fibers, mucin and cell division related protein. The quantitative PCR analysis showed increased levels of oncogenes PSMD10, CDK4 and decreased level of tumor suppressor gene p53. The western blot analysis observed significant decrease of another tumor suppressor called RB protein. Genes/protein expressions were matched well with the pathological changes of CCA hamster. The present study suggests that oncogenes, PSMD10 and CDK4, and tumor suppressors gene p53 and protein RB, are involved in the carcinogenesis process of C. sinensis induced CCA in hamsters.
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Affiliation(s)
- Md. Hafiz Uddin
- Department of Parasitology and Tropical Medicine, Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Min-Ho Choi
- Department of Parasitology and Tropical Medicine, Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ja-June Jang
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sung-Tae Hong
- Department of Parasitology and Tropical Medicine, Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Republic of Korea
- * E-mail:
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17
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Zeng X, Tao H. Diagnostic and prognostic serum marker of cholangiocarcinoma (Review). Oncol Lett 2014; 9:3-8. [PMID: 25435926 PMCID: PMC4247112 DOI: 10.3892/ol.2014.2696] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Accepted: 10/24/2014] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a fatal disease that is typically diagnosed late and treated ineffectively. As the morbidity and mortality rates for CCA rise markedly, patietns with CCA currently have a poor prognosis. However, if it were possible to diagnose CCA early while effective treat methods are available, CCA patients would achieve a better quality of life. Therefore, preventing the process of CCA in the early stages is an urgent problem to solve. An accurate, quick and safe method to diagnose early-stage CCA is required. The present review discusses the risk factors, status of research and certain serum markers of CCA. The sensitivity and specificity of these markers differ from each other. To explore the more accurate serum markers may be a novel direction and method for the diagnosis of CCA in laboratory medicine in the future.
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Affiliation(s)
- Xiaojun Zeng
- Department of Laboratory Medicine, Luzhou Medical College, Luzhou, Sichuan 646000, P.R. China
| | - Hualin Tao
- Department of Laboratory Medicine, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, P.R. China
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18
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Yongvanit P, Pinlaor S, Loilome W. Risk biomarkers for assessment and chemoprevention of liver fluke-associated cholangiocarcinoma. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2014; 21:309-15. [DOI: 10.1002/jhbp.63] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Puangrat Yongvanit
- Department of Biochemistry, Faculty of Medicine; Khon Kaen University; 123 Mitraparb Road Khon Kaen 40002 Thailand
- Liver Fluke and Cholangiocarcinoma Research Center; Faculty of Medicine; Khon Kaen University; Khon Kaen Thailand
| | - Somchai Pinlaor
- Department of Parasitology, Faculty of Medicine; Khon Kaen University; Khon Kaen Thailand
- Liver Fluke and Cholangiocarcinoma Research Center; Faculty of Medicine; Khon Kaen University; Khon Kaen Thailand
| | - Watcharin Loilome
- Department of Biochemistry, Faculty of Medicine; Khon Kaen University; 123 Mitraparb Road Khon Kaen 40002 Thailand
- Liver Fluke and Cholangiocarcinoma Research Center; Faculty of Medicine; Khon Kaen University; Khon Kaen Thailand
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19
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Tzeng JI, Chen MF, Chung HH, Cheng JT. Silymarin decreases connective tissue growth factor to improve liver fibrosis in rats treated with carbon tetrachloride. Phytother Res 2012; 27:1023-8. [PMID: 22933420 DOI: 10.1002/ptr.4829] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Revised: 07/29/2012] [Accepted: 08/01/2012] [Indexed: 12/21/2022]
Abstract
Silymarin is an herbal product showing potential as protection against hepatic disorders. In an attempt to develop the agent for the treatment of hepatic fibrosis, we screened the effects of silymarin on a rat model of hepatic fibrosis induced by carbon tetrachloride (CCl₄). Intraperitoneal administration of CCl₄ to rats for 8 weeks not only increased the plasma levels of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) but also induced a marked increase in the formation of hepatic fibrosis. Moreover, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were also reduced in the liver of rats treated with CCl₄. Oral administration of silymarin (200 mg/kg, three times daily), in parallel, decreased the plasma levels of GOT and GPT. Furthermore, in addition to the improvement of hepatic fibrosis, the hepatic levels of hydroxyproline and connective tissue growth factor (CTGF) were both markedly decreased by silymarin. Silymarin also elevated the activities of SOD and GPx in liver isolated from CCl₄-treated rats. The results suggest that oral administration of silymarin protects against CCl₄-induced hepatic fibrosis in rats, likely due to the decrease in fibrotic parameters such as CTGF.
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Affiliation(s)
- Jann-Inn Tzeng
- Department of Food Sciences and Technology, Chia Nan University of Pharmacy and Sciences, Jen-Te, Tainan City, Taiwan 71701
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