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1
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Rodrigues MA, Gomes DA, Cosme AL, Sanches MD, Resende V, Cassali GD. Inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) is overexpressed in cholangiocarcinoma and its expression correlates with S100 calcium-binding protein A4 (S100A4). Biomed Pharmacother 2022; 145:112403. [PMID: 34798470 PMCID: PMC8678364 DOI: 10.1016/j.biopha.2021.112403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/31/2021] [Accepted: 11/03/2021] [Indexed: 01/03/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most malignant neoplasm in the liver that arises from the biliary tree. CCA is associated with a poor prognosis, and the key players involved in its pathogenesis are still not well understood. Receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), can mediate intracellular calcium (Ca2+) signaling pathways via inositol 1,4,5-trisphosphate (InsP3), activating inositol 1,4,5-trisphosphate receptors (ITPRs) and regulating tumor growth. ITPR isoform 3 (ITPR3) is the main intracellular Ca2+ release channel in cholangiocytes. The effects of intracellular Ca2+ are mediated by calcium-binding proteins such as Calmodulin and S100 calcium-binding protein A4 (S100A4). However, the clinicopathological and biological significance of EGFR, ITPR3 and S100A4 in CCA remains unclear. Thus, the present work investigates the immunoexpression of these three proteins in 59 CCAs from patients who underwent curative surgical treatment and correlates the data with clinicopathological features and survival. High ITPR3 expression was correlated with CA 19-9 levels, TNM stage and lymph node metastasis (N). Furthermore, ITPR3 expression was increased in distal CCA compared to control bile ducts and intrahepatic and perihilar CCAs. These observations were confirmed by proteomic analysis. ITPR3 and S100A4 clinical scores were significantly correlated. Furthermore, it was demonstrated that EGF induces calcium signaling in a cholangiocarcinoma cell line and ITPR3 colocalizes with nonmuscle myosin IIA (NMIIA). In summary, ITPR3 overexpression could contribute to CCA progression and it may represent a potential therapeutic target.
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Affiliation(s)
- Michele A. Rodrigues
- Department of General Pathology, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, Minas Gerais, CEP: 31270-901, Brazil
| | - Dawidson A. Gomes
- Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, Minas Gerais, CEP: 31270-901, Brazil
| | - Ana Luiza Cosme
- School of Medicine, Department of Surgery, Universidade Federal de Minas Gerais, Av. Prof. Alfredo Balena 190, Belo Horizonte, Minas Gerais, CEP: 30130-100, Brazil
| | - Marcelo Dias Sanches
- School of Medicine, Department of Surgery, Universidade Federal de Minas Gerais, Av. Prof. Alfredo Balena 190, Belo Horizonte, Minas Gerais, CEP: 30130-100, Brazil.,Hepatopancreatobiliary Division, Clinical Hospital, Universidade Federal de Minas Gerais, Av. Prof. Alfredo Balena 110, Belo Horizonte, Minas Gerais, CEP: 30130-100, Brazil
| | - Vivian Resende
- School of Medicine, Department of Surgery, Universidade Federal de Minas Gerais, Av. Prof. Alfredo Balena 190, Belo Horizonte, Minas Gerais, CEP: 30130-100, Brazil.,Hepatopancreatobiliary Division, Clinical Hospital, Universidade Federal de Minas Gerais, Av. Prof. Alfredo Balena 110, Belo Horizonte, Minas Gerais, CEP: 30130-100, Brazil
| | - Geovanni D. Cassali
- Department of General Pathology, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, Minas Gerais, CEP: 31270-901, Brazil.,Corresponding author: Department of General Pathology, Instituto de Ciências Biológicas, Bloco C3, Sala 102, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627 Belo Horizonte–MG, Brazil 31270-901. Tel: +55 31 34092891.
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Wijetunga I, McVeigh LE, Charalambous A, Antanaviciute A, Carr IM, Nair A, Prasad KR, Ingram N, Coletta PL. Translating Biomarkers of Cholangiocarcinoma for Theranosis: A Systematic Review. Cancers (Basel) 2020; 12:E2817. [PMID: 33007872 PMCID: PMC7601719 DOI: 10.3390/cancers12102817] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 09/22/2020] [Accepted: 09/29/2020] [Indexed: 12/16/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a rare disease with poor outcomes and limited research efforts into novel treatment options. A systematic review of CCA biomarkers was undertaken to identify promising biomarkers that may be used for theranosis (therapy and diagnosis). MEDLINE/EMBASE databases (1996-2019) were systematically searched using two strategies to identify biomarker studies of CCA. The PANTHER Go-Slim classification system and STRING network version 11.0 were used to interrogate the identified biomarkers. The TArget Selection Criteria for Theranosis (TASC-T) score was used to rank identified proteins as potential targetable biomarkers for theranosis. The following proteins scored the highest, CA9, CLDN18, TNC, MMP9, and EGFR, and they were evaluated in detail. None of these biomarkers had high sensitivity or specificity for CCA but have potential for theranosis. This review is unique in that it describes the process of selecting suitable markers for theranosis, which is also applicable to other diseases. This has highlighted existing validated markers of CCA that can be used for active tumor targeting for the future development of targeted theranostic delivery systems. It also emphasizes the relevance of bioinformatics in aiding the search for validated biomarkers that could be repurposed for theranosis.
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Affiliation(s)
- Imeshi Wijetunga
- Leeds Institute of Medical Research, Wellcome Trust Brenner Building, St James’s University Hospital, Leeds LS9 7TF, UK; (I.W.); (L.E.M.); (A.C.); (A.A.); (I.M.C.); (A.N.); (N.I.)
| | - Laura E. McVeigh
- Leeds Institute of Medical Research, Wellcome Trust Brenner Building, St James’s University Hospital, Leeds LS9 7TF, UK; (I.W.); (L.E.M.); (A.C.); (A.A.); (I.M.C.); (A.N.); (N.I.)
| | - Antonia Charalambous
- Leeds Institute of Medical Research, Wellcome Trust Brenner Building, St James’s University Hospital, Leeds LS9 7TF, UK; (I.W.); (L.E.M.); (A.C.); (A.A.); (I.M.C.); (A.N.); (N.I.)
| | - Agne Antanaviciute
- Leeds Institute of Medical Research, Wellcome Trust Brenner Building, St James’s University Hospital, Leeds LS9 7TF, UK; (I.W.); (L.E.M.); (A.C.); (A.A.); (I.M.C.); (A.N.); (N.I.)
| | - Ian M. Carr
- Leeds Institute of Medical Research, Wellcome Trust Brenner Building, St James’s University Hospital, Leeds LS9 7TF, UK; (I.W.); (L.E.M.); (A.C.); (A.A.); (I.M.C.); (A.N.); (N.I.)
| | - Amit Nair
- Leeds Institute of Medical Research, Wellcome Trust Brenner Building, St James’s University Hospital, Leeds LS9 7TF, UK; (I.W.); (L.E.M.); (A.C.); (A.A.); (I.M.C.); (A.N.); (N.I.)
| | - K. Raj Prasad
- Department of Hepatobiliary and Transplant Surgery, St. James’s University Hospital, Leeds LS9 7TF, UK;
| | - Nicola Ingram
- Leeds Institute of Medical Research, Wellcome Trust Brenner Building, St James’s University Hospital, Leeds LS9 7TF, UK; (I.W.); (L.E.M.); (A.C.); (A.A.); (I.M.C.); (A.N.); (N.I.)
| | - P. Louise Coletta
- Leeds Institute of Medical Research, Wellcome Trust Brenner Building, St James’s University Hospital, Leeds LS9 7TF, UK; (I.W.); (L.E.M.); (A.C.); (A.A.); (I.M.C.); (A.N.); (N.I.)
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3
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Tian X, Cao Z, Ding Q, Li Z, Zhang C. Prognostic value of multiple epithelial mesenchymal transition-associated proteins in intrahepatic cholangiocarcinoma. Oncol Lett 2019; 18:2059-2065. [PMID: 31423278 DOI: 10.3892/ol.2019.10522] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 04/05/2019] [Indexed: 02/06/2023] Open
Abstract
The aim of the present study was to investigate the expression of epithelial mesenchymal transition (EMT)-associated proteins and their prognostic value in intrahepatic cholangiocarcinoma (ICC). The expression of six EMT-associated proteins, including E-cadherin, N-cadherin, Vimentin, Snail family transcriptional repressor 1 (Snail), Snail family transcriptional repressor 2 (Slug) and S100 calcium binding protein A4 (S100A4) was determined by immunohistochemistry in 109 patients with ICC who had received surgery. Survival analysis showed that patients with low E-cadherin expression (P<0.001) or high S100A4 (P<0.001) or Snail (P<0.001) expression had a reduced survival time. Based on the numbers of alterations in the expression of EMT-associated proteins as determined by immunohistochemical analysis, the patients were categorized as low (score, 0-3; n=75) or high (score, ≥4; n=34) EMT expression groups. The high EMT expression group was significantly associated with positive lymph node metastasis (P=0.023) and late Tumor-Node-Metastasis (TNM) stage (P<0.001). Furthermore, patients in the high EMT expression group had a significantly poorer overall survival time than those in the low EMT expression group (P<0.001). Multivariate analysis indicated that EMT status was a significant independent predictor for overall survival time (P=0.004), and was linked to surgical margin (P=0.013) and TNM stage (P<0.001). In conclusion, the reduced expression of E-cadherin and high expression of Snail and S100A4 were significantly associated with the poor survival of patients with ICC after surgery. The EMT protein expression status was associated with ICC progression, and may be considered as an independent prognostic indicator for patients with ICC.
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Affiliation(s)
- Xiangguo Tian
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Zhixin Cao
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Qian Ding
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Zhen Li
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Chunqing Zhang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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Zhang MX, Gan W, Jing CY, Zheng SS, Yi Y, Zhang J, Xu X, Lin JJ, Zhang BH, Qiu SJ. S100A11 promotes cell proliferation via P38/MAPK signaling pathway in intrahepatic cholangiocarcinoma. Mol Carcinog 2018; 58:19-30. [PMID: 30182496 PMCID: PMC6587853 DOI: 10.1002/mc.22903] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 08/20/2018] [Accepted: 09/03/2018] [Indexed: 12/23/2022]
Abstract
S100A11 is reported to associate with progression and poor prognosis in several tumors. We previously reported that S100A11 was highly expressed in intrahepatic cholangiocarcinoma (ICC) cells and promoted TGF-β1-induced EMT through SMAD2/3 signaling pathway. Here, we explored the prognostic role of S100A11 on ICC patients and preliminary molecular mechanisms how S100A11 regulated ICC cell proliferation. Our results showed that S100A11 was obviously increased in ICC tumor tissues. High expression of S100A11 was closely correlated with lymph node metastasis (LNM) and TNM stage and was an independent risk factor for patients' overall survival (OS) and recurrence-free survival (RFS). The nomograms comprising LNM and S100A11 achieved better predictive accuracy compared with TNM staging system for OS and RFS prediction. Silencing S100A11 significantly suppressed RBE cells and HCCC9810 cells proliferation, colony formation, and activation of P38/mitogen-activated protein kinase (MAPK) signaling pathway in vitro and inhibited tumor growth in vivo. In contrast, the overexpression of S100A11 in RBE cells and HCCC9810 cells achieved the opposite results. S100A11-induced proliferation was abolished after treatment with P38 inhibitor. Our findings suggest S100A11/P38/MAPK signaling pathway may be a potential therapeutic target for ICC patients.
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Affiliation(s)
- Mei-Xia Zhang
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Shanghai, P.R. China.,Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Wei Gan
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Shanghai, P.R. China.,Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Chu-Yu Jing
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Shanghai, P.R. China.,Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Su-Su Zheng
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Shanghai, P.R. China.,Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Yong Yi
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Shanghai, P.R. China.,Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Juan Zhang
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Shanghai, P.R. China.,Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Xin Xu
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Shanghai, P.R. China.,Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Jia-Jia Lin
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Shanghai, P.R. China.,Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Bo-Heng Zhang
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Shanghai, P.R. China.,Center for Evidence-Based Medicine, Fudan University, Shanghai, P.R. China
| | - Shuang-Jian Qiu
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Shanghai, P.R. China.,Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
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5
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Xu D, Miao Y, Gu X, Wang J, Yu G. Pyrophosphatase 1 expression is associated with future recurrence and overall survival in Chinese patients with intrahepatic cholangiocarcinoma. Oncol Lett 2018; 15:8095-8101. [PMID: 29740496 DOI: 10.3892/ol.2018.8278] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 12/22/2017] [Indexed: 01/07/2023] Open
Abstract
The inorganic pyrophosphatase gene (PPA1) encodes inorganic pyrophosphatase, an enzyme that catalyzes the hydrolysis of inorganic pyrophosphate to orthophosphate, and has been revealed to be dysregulated in several types of human cancer. However, the role of PPA1 in intrahepatic cholangiocarcinoma (ICC) has not yet been determined. The present study detected PPA1 expression and investigated its clinical significance in ICC. Tissue microarray blocks containing 93 ICC specimens were constructed. The protein expression of PPA1 in these specimens was detected by immunohistochemistry. PPA1 was overexpressed in 49.5% of the ICC specimens and was significantly associated with large tumor size, positive margins, T stage, lymph nodal metastases, poorly differentiated tumors and advanced disease stage. Furthermore, PPA1 expression was an indicator of future recurrence and poor survival in patients with ICC. Increased expression of PPA1 is a common event in human ICC and is significantly associated with a poor outcome in patients with ICC, suggesting a potential role for PPA1 in the development and progression of ICC.
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Affiliation(s)
- Dongyun Xu
- Department of Oncology, Huaihai Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu 221003, P.R. China.,Department of Oncology, No. 97 Hospital of The People's Liberation Army, Xuzhou, Jiangsu 221003, P.R. China
| | - Yuqing Miao
- Department of Oncology, Changzheng Hospital, Shanghai 200070, P.R. China
| | - Xiaoqiang Gu
- Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Jiejun Wang
- Department of Oncology, Changzheng Hospital, Shanghai 200070, P.R. China
| | - Guanzhen Yu
- Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
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Onsurathum S, Haonon O, Pinlaor P, Pairojkul C, Khuntikeo N, Thanan R, Roytrakul S, Pinlaor S. Proteomics detection of S100A6 in tumor tissue interstitial fluid and evaluation of its potential as a biomarker of cholangiocarcinoma. Tumour Biol 2018; 40:1010428318767195. [DOI: 10.1177/1010428318767195] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Tumor interstitial fluid contains tumor-specific proteins that may be useful biomarkers for cancers. In this study, we identified proteins present in cholangiocarcinoma interstitial fluid. Proteins derived from three samples of tumor interstitial fluid and paired samples of adjacent normal interstitial fluid from cholangiocarcinoma patients were subjected to two-dimensional liquid chromatography with tandem mass spectrometry. Candidate proteins were selected based on a greater than twofold change in expression levels between tumor interstitial fluid and normal interstitial fluid. Upregulation of six proteins in tumor interstitial fluid, including S100 calcium binding protein A6 (S100A6), S100 calcium binding protein A9, aldo-keto reductase family 1 member C4, neuropilin-1, 14-3-3 zeta/delta, and triosephosphate isomerase was assessed by western blot and immunohistochemistry. Their potential as markers was evaluated in human cholangiocarcinoma tissue arrays, and in serum using enzyme-linked immunosorbent assay. Expression of S100A6 was higher in tumor interstitial fluid than in normal interstitial fluid and showed the highest positive rate (98.96%) in cholangiocarcinoma tissues. Serum levels of S100A6 did not differ between cholangitis and cholangiocarcinoma patients, but were significantly higher than in healthy individuals ( p < 0.0001). In cholangiocarcinoma cases, S100A6 level was associated with vascular invasion ( p = 0.007) and could distinguish cholangiocarcinoma patients from healthy individuals as effectively as the carbohydrate antigen 19-9. In addition, potential for drug treatment targeting S100A6 and other candidate proteins was also demonstrated using STITCH analysis. In conclusion, proteomics analysis of tumor interstitial fluid could be a new approach for biomarker discovery, and S100A6 is a potential risk marker for screening of cholangiocarcinoma.
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Affiliation(s)
- Sudarat Onsurathum
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Ornuma Haonon
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Porntip Pinlaor
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Chawalit Pairojkul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Narong Khuntikeo
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Raynoo Thanan
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sittiruk Roytrakul
- Proteomics Research Laboratory, National Center for Genetic Engineering and Biotechnology, Pathumthani, Thailand
| | - Somchai Pinlaor
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
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7
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Zhang M, Zheng S, Jing C, Zhang J, Shen H, Xu X, Lin J, Zhang B. S100A11 promotes TGF-β1-induced epithelial-mesenchymal transition through SMAD2/3 signaling pathway in intrahepatic cholangiocarcinoma. Future Oncol 2018; 14:837-847. [PMID: 29569474 DOI: 10.2217/fon-2017-0534] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
AIM Our previous study found S100A11 was significantly raised in intrahepatic cholangiocarcinoma cells, but the relationship between S100A11 and intrahepatic cholangiocarcinoma remains unclear. METHODS We investigated the effect of silencing S100A11 on TGF-β1-induced epithelial-mesenchymal transition (EMT), cell migration and invasion. RESULTS Our results demonstrated silencing S100A11 inhibited TGF-β1-induced cell migration, invasion and EMT, expression of EMT markers E-cadherin, N-cadherin, β-catenin, vimentin, Slug and Snail was reversed. Furthermore, TGF-β1-induced p-SMAD2 and 3 were also inhibited due to low S100A11 expression. CONCLUSION Our present study indicated that S100A11 promotes EMT through accumulation of TGF-β1 expression, and TGF-β1-induced upregulation of p-SMAD2 and 3.
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Affiliation(s)
- Meixia Zhang
- Liver Cancer Institute & Zhongshan Hospital of Fudan University, Shanghai 200032, PR China
| | - Susu Zheng
- Liver Cancer Institute & Zhongshan Hospital of Fudan University, Shanghai 200032, PR China
| | - Chuyu Jing
- Liver Cancer Institute & Zhongshan Hospital of Fudan University, Shanghai 200032, PR China
| | - Juan Zhang
- Liver Cancer Institute & Zhongshan Hospital of Fudan University, Shanghai 200032, PR China
| | - Hujia Shen
- Liver Cancer Institute & Zhongshan Hospital of Fudan University, Shanghai 200032, PR China
| | - Xin Xu
- Liver Cancer Institute & Zhongshan Hospital of Fudan University, Shanghai 200032, PR China
| | - Jiajia Lin
- Liver Cancer Institute & Zhongshan Hospital of Fudan University, Shanghai 200032, PR China
| | - Boheng Zhang
- Liver Cancer Institute & Zhongshan Hospital of Fudan University, Shanghai 200032, PR China.,Center for Evidence-Based Medicine, Fudan University, Shanghai 200032, PR China
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Jiao J, González Á, Stevenson HL, Gagea M, Sugimoto H, Kalluri R, Beretta L. Depletion of S100A4 + stromal cells does not prevent HCC development but reduces the stem cell-like phenotype of the tumors. Exp Mol Med 2018; 50:e422. [PMID: 29303514 PMCID: PMC5992984 DOI: 10.1038/emm.2017.175] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 05/11/2017] [Indexed: 02/06/2023] Open
Abstract
There is a pressing need for the development of novel approaches to treat and prevent hepatocellular carcinoma (HCC). The S100 calcium-binding protein S100A4 is associated with poor prognosis and metastasis in several human cancers. In addition, a role for S100A4 in modulating cancer-initiating cells stemness properties was recently proposed in head and neck and gastric cancers. Whether S100A4+ stromal cells contribute to tumor onset remains, however, an unanswered question. To address that question, we generated a new mouse model allowing for the depletion of S100A4+ cells in a mouse model of HCC with stemness properties, by crossing mice with hepatic deletion of phosphatase and tensin homolog (PTEN) with mice expressing viral thymidine kinase under the control of S100A4 promoter. Depletion of S100A4+ cells by ganciclovir injection did not prevent the development of HCC but reduced the stemness phenotype of the tumor as measured by the expression of progenitor cell, biliary cell and hepatocyte markers. The results were further confirmed by histology analysis showing reduction of cholangiolar tumor components and degree of oval cell hyperplasia in the adjacent liver. Depletion of S100A4+ cells had also some beneficial effect on the underlying liver disease with a reduction of NAS score, largely due to the reduction of inflammation. In conclusion, this study demonstrated that S100A4+ cells do not contribute to HCC onset but maintain the stemness phenotype of the tumor. This study also suggests for the first time a crosstalk between inflammation and stemness.
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Affiliation(s)
- Jingjing Jiao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Álvaro González
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Heather L Stevenson
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA
| | - Mihai Gagea
- Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hikaru Sugimoto
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Raghu Kalluri
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Martínez AK, Jensen K, Hall C, O'Brien A, Ehrlich L, White T, Meng F, Zhou T, Greene J, Bernuzzi F, Invernizzi P, Dostal DE, Lairmore T, Alpini G, Glaser SS. Nicotine Promotes Cholangiocarcinoma Growth in Xenograft Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:1093-1105. [PMID: 28315314 DOI: 10.1016/j.ajpath.2017.01.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 12/29/2016] [Accepted: 01/17/2017] [Indexed: 12/20/2022]
Abstract
Nicotine, the main addictive substance in tobacco, is known to play a role in the development and/or progression of a number of malignant tumors. However, nicotine's involvement in the pathogenesis of cholangiocarcinoma is controversial. Therefore, we studied the effects of nicotine on the growth of cholangiocarcinoma cells in vitro and the progression of cholangiocarcinoma in a mouse xenograft model. The predominant subunit responsible for nicotine-mediated proliferation in normal and cancer cells, the α7 nicotinic acetylcholine receptor (α7-nAChR), was more highly expressed in human cholangiocarcinoma cell lines compared with normal human cholangiocytes. Nicotine also stimulated the proliferation of cholangiocarcinoma cell lines and promoted α7-nAChR-dependent activation of proliferation and phosphorylation of extracellular-regulated kinase in Mz-ChA-1 cells. In addition, nicotine and PNU282987 (α7-nAChR agonist) accelerated the growth of the cholangiocarcinoma tumors in our xenograft mouse model and increased fibrosis, proliferation of the tumor cells, and phosphorylation of extracellular-regulated kinase activation. Finally, α7-nAChR was expressed at significantly higher levels in human cholangiocarcinoma compared with normal human control liver samples. Taken together, results of this study suggest that nicotine acts through α7-nAChR and plays a novel role in the pathogenesis of cholangiocarcinoma. Furthermore, nicotine may act as a mitogen in cholestatic liver disease processes, thereby facilitating malignant transformation.
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Affiliation(s)
- Allyson K Martínez
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Kendal Jensen
- Department of Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Chad Hall
- Department of Surgery, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - April O'Brien
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Laurent Ehrlich
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Tori White
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Fanyin Meng
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas; Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas
| | - Tianhao Zhou
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - John Greene
- Department of Pathology, Baylor Scott & White Health, Temple, Texas
| | - Francesca Bernuzzi
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Pietro Invernizzi
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - David E Dostal
- Department of Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas
| | - Terry Lairmore
- Department of Surgery, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Gianfranco Alpini
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Department of Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas; Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas
| | - Shannon S Glaser
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas; Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas.
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10
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Mathema VB, Na-Bangchang K. Regulatory roles of brain-specific angiogenesis inhibitor 1(BAI1) protein in inflammation, tumorigenesis and phagocytosis: A brief review. Crit Rev Oncol Hematol 2017; 111:81-86. [DOI: 10.1016/j.critrevonc.2017.01.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 08/26/2016] [Accepted: 01/10/2017] [Indexed: 02/06/2023] Open
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11
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Vaquero J, Guedj N, Clapéron A, Nguyen Ho-Bouldoires TH, Paradis V, Fouassier L. Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks. J Hepatol 2017; 66:424-441. [PMID: 27686679 DOI: 10.1016/j.jhep.2016.09.010] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Revised: 08/26/2016] [Accepted: 09/17/2016] [Indexed: 02/06/2023]
Abstract
Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a centre of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analysed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT.
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Affiliation(s)
- Javier Vaquero
- INSERM, Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche Saint-Antoine (CRSA), F-75012 Paris, France; FONDATION ARC, F-94803 Villejuif, France
| | - Nathalie Guedj
- Service d'Anatomie Pathologique Hôpital Beaujon, F-92110 Clichy, France; INSERM, UMR 1149, Centre de Recherche sur l'Inflammation, F-75018 Paris, France
| | - Audrey Clapéron
- INSERM, Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche Saint-Antoine (CRSA), F-75012 Paris, France
| | | | - Valérie Paradis
- Service d'Anatomie Pathologique Hôpital Beaujon, F-92110 Clichy, France; INSERM, UMR 1149, Centre de Recherche sur l'Inflammation, F-75018 Paris, France
| | - Laura Fouassier
- INSERM, Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche Saint-Antoine (CRSA), F-75012 Paris, France.
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12
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Jin GZ, Dong W, Dong H, Yu H, Chen J, Yu WL, Li AJ, Cong WM, Wu MC. The diagnostic and prognostic value of MRP8/MRP14 in intrahepatic cholangiocarcinoma. Oncotarget 2016; 6:39357-64. [PMID: 26472105 PMCID: PMC4770777 DOI: 10.18632/oncotarget.5329] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 10/02/2015] [Indexed: 12/14/2022] Open
Abstract
Myeloid-related protein 8 (MRP8) and 14 (MRP14) are abundantly expressed in several kinds of benign and malignant tumors. However, little is known about their clinicopathological significance in intrahepatic cholangiocarcinoma (ICC), biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of bile duct (IPNB), or inflammatory hepatic biliary ducts epithelium (IHBD). This study aimed to investigate the diagnostic and prognostic values of MRP8 and MRP14 as new biomarkers for ICC. We examined MRP8 and MRP14 expression levels by immunohistochemistry in IHBD (n = 15), BilIN (BilIN1 = 24, BilIN2 = 9, BilIN3 = 5), IPNB (n = 18) and ICC (n = 416). The differential diagnostic and prognosis values were also evaluated. The results showed that the ratio of tumor-infiltrating MRP8 and MRP14 positive immune cells, relative to biliary epithelial cells, was significantly increased in ICC tissues compared with nonmalignant tissues, including IHBD, BilIN1, BilIN2, BilIN3, and IPNB (P value < 0.05). In addition, over-expression levels of MRP8 and MRP14 were correlated with overall survival (OS) and time to recurrence (TTR) by univariate analysis; MRP8/MRP14 combination was an independent prognostic factor for OS and TTR. MRP8 and MRP14 expression might help to identify the benign bile duct diseases from ICC, as high expression of MRP8 and MRP14 suggests a poor prognosis after surgical resection.
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Affiliation(s)
- Guang-Zhi Jin
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Wei Dong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Hui Dong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Hua Yu
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Jia Chen
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Wen-Long Yu
- Department II of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Ai-Jun Li
- Division of Special Treatment II, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Wen-Ming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Meng-Chao Wu
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
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13
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Loosen SH, Benz F, Niedeggen J, Schmeding M, Schüller F, Koch A, Vucur M, Tacke F, Trautwein C, Roderburg C, Neumann UP, Luedde T. Serum levels of S100A6 are unaltered in patients with resectable cholangiocarcinoma. Clin Transl Med 2016; 5:39. [PMID: 27709523 PMCID: PMC5052241 DOI: 10.1186/s40169-016-0120-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 09/10/2016] [Indexed: 02/12/2023] Open
Abstract
Background Elevated expression levels of S100A6, a calcium-binding low-molecular-weight protein, were demonstrated in various malignancies. Moreover, increased serum levels of S100A6 were suggested as a novel biomarker for various inflammatory and malignant diseases including lung and gastric cancer. However, up to now, serum concentrations of S100A6 have not been analyzed in patients with cholangiocarcinoma (CCA). Methods S100A6 mRNA expression levels were analyzed in human and murine CCA tumor samples, using semi-quantitative reverse transcriptase PCR. S100A6 serum concentrations were measured using an enzyme-linked immunosorbent assay in 112 patients with CCA referred to surgery for curative resection and were compared to those of 42 healthy controls. Results were correlated with clinical data. Results S100A6 mRNA expression levels were significantly up-regulated in tumor samples of CCA patients and in tumor tissue of a CCA mouse model. In contrast, serum levels of S100A6 were not significantly altered in patients with CCA compared to healthy controls. Whereas no differences became apparent within the different clinical subgroups of CCA, patients with primary sclerosing cholangitis (PSC)-based CCA displayed higher levels of S100A6 compared to the other patients. Nevertheless, patients with higher S100A6 serum concentrations showed a trend towards an impaired prognosis compared to patients with lower levels. Finally, within our cohort of patients both the diagnostic and prognostic potentials of S100A6 were similar to those of the clinically established biomarkers CEA and CA19-9. Conclusion Although S100A6 was expressed at significantly higher levels in human and murine CCA tumor samples, S100A6 serum levels were not regulated in patients with CCA and are thus not suitable for diagnosis of CCA. However, CCA-patients with elevated S100A6 displayed a trend toward an impaired prognosis compared to patients with lower S100A6 levels, supporting its further evaluation as a prognostic biomarker in CCA. Electronic supplementary material The online version of this article (doi:10.1186/s40169-016-0120-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sven H Loosen
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Fabian Benz
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Jennifer Niedeggen
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Maximilian Schmeding
- Department of Surgery, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Florian Schüller
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Alexander Koch
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Mihael Vucur
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Frank Tacke
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Christoph Roderburg
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Ulf P Neumann
- Department of Surgery, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Tom Luedde
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. .,Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.
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14
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Li Z, Shen J, Chan MTV, Wu WKK. The role of microRNAs in intrahepatic cholangiocarcinoma. J Cell Mol Med 2016; 21:177-184. [PMID: 27619971 PMCID: PMC5192883 DOI: 10.1111/jcmm.12951] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 07/14/2016] [Indexed: 12/14/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy with poor prognosis. Despite improvements in its diagnosis and therapy, the prognosis for ICC patients remains poor. An improved understanding of ICC pathogenesis and consequential identification of novel therapeutic targets would improve the prognosis of ICC patients. MicroRNAs (miRNAs) are a class of highly conserved, endogenous, small non‐coding RNA molecules of 18–23 nucleotides in length, which regulate gene expression through complementary base‐pairing with target messenger RNAs and subsequent gene silencing. Several studies have shown deregulated expression of miRNAs in ICC cell lines and tissues, in which these miRNAs play important roles in ICC apoptosis, cell proliferation, invasion, migration and metastasis. In this review, we illustrate the potential role of miRNA in the pathogenesis of ICC and explore the possibilities of using miRNAs as prognostic and diagnostic markers, as well as therapeutic targets in ICC.
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Affiliation(s)
- Zheng Li
- Department of Orthopedics Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianxiong Shen
- Department of Orthopedics Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Matthew T V Chan
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China
| | - William Ka Kei Wu
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Digestive Daase, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
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15
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Atanasov G, Schierle K, Hau HM, Dietel C, Krenzien F, Brandl A, Wiltberger G, Englisch JP, Robson SC, Reutzel-Selke A, Pascher A, Jonas S, Pratschke J, Benzing C, Schmelzle M. Prognostic Significance of Tumor Necrosis in Hilar Cholangiocarcinoma. Ann Surg Oncol 2016; 24:518-525. [PMID: 27480355 DOI: 10.1245/s10434-016-5472-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Indexed: 12/26/2022]
Abstract
BACKGROUND Tumor necrosis and peritumoral fibrosis have both been suggested to have a prognostic value in selected solid tumors. However, little is known regarding their influence on tumor progression and prognosis in hilar cholangiocarcinoma (HC). METHODS Surgically resected tumor specimens of HC (n = 47) were analyzed for formation of necrosis and extent of peritumoral fibrosis. Tumor necrosis and grade of fibrosis were assessed histologically and correlated with clinicopathological characteristics, tumor recurrence, and patients' survival. Univariate Kaplan-Meier analysis and a stepwise multivariable Cox regression model were applied. RESULTS Mild peritumoral fibrosis was evident in 12 tumor samples, moderate peritumoral fibrosis in 20, and high-grade fibrosis in 15. Necrosis was evident in 19 of 47 tumor samples. Patients with tumors characterized by necrosis showed a significantly decreased 5-year recurrence-free survival (37.9 vs. 25.7 %; p < .05) and a significantly decreased 5-year overall survival (42.6 vs. 12.4 %; p < .05), when compared with patients with tumors showing no necrosis. R status, tumor recurrence, and tumor necrosis were of prognostic value in the univariate analysis (all p < .05). Multivariate survival analysis confirmed tumor necrosis (p = .038) as the only independent prognostic variable. CONCLUSIONS The assessment of tumor necrosis appears as a valuable additional prognostic tool in routine histopathological evaluation of HC. These observations might have implications for monitoring and more individualized multimodal therapeutic strategies.
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Affiliation(s)
- Georgi Atanasov
- Department of Surgery, Campus Virchow and Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany.
| | - Katrin Schierle
- Institute of Pathology, University Hospital Leipzig, Leipzig, Germany
| | - Hans-Michael Hau
- Department of Visceral-, Transplantation-, Thoracic- and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Corinna Dietel
- Department of Visceral-, Transplantation-, Thoracic- and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Felix Krenzien
- Department of Surgery, Campus Virchow and Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Andreas Brandl
- Department of Surgery, Campus Virchow and Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Georg Wiltberger
- Department of Visceral-, Transplantation-, Thoracic- and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Julianna Paulina Englisch
- Department of Surgery, Campus Virchow and Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Simon C Robson
- The Transplant Institute and Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA, USA
| | - Anja Reutzel-Selke
- Department of Surgery, Campus Virchow and Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Andreas Pascher
- Department of Surgery, Campus Virchow and Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Sven Jonas
- Department of Hepato-Pancreato-Biliary Surgery, 310Klinik Nürnberg, Nuremberg, Germany
| | - Johann Pratschke
- Department of Surgery, Campus Virchow and Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Christian Benzing
- Department of Surgery, Campus Virchow and Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Moritz Schmelzle
- Department of Surgery, Campus Virchow and Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
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16
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Li MX, Bi XY, Li ZY, Huang Z, Han Y, Zhao JJ, Zhao H, Cai JQ. Impaction of surgical margin status on the survival outcome after surgical resection of intrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Surg Res 2016; 203:163-73. [PMID: 27338547 DOI: 10.1016/j.jss.2016.02.012] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Revised: 02/03/2016] [Accepted: 02/11/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Conflicting results about the prognostic value of surgical margin status in patients with intrahepatic cholangiocarcinoma (ICC) have been reported. We aimed to assess the association between surgical margin status and prognosis in ICC through a meta-analysis. MATERIALS AND METHODS We conducted a literature search of the articles evaluating the prognostic value of surgical margin status in patients with ICC. The pooled estimation of the hazard ratio (HR) with the 95% confidence interval (CI) was performed to determine the influence of surgical margin status on the survival outcome. RESULTS A total of 21 studies involving 3201 patients were finally included into the meta-analysis. The percentage of patients with positive surgical margin ranged from 7.2% to 75.9% in the enrolled studies. The pooled estimates showed that patients with positive surgical margin had inferior overall survival (HR: 1.864; 95% CI: 1.542-2.252; P < 0.001) and progression-free survival (HR: 2.033; 95% CI: 1.030-4.011; P = 0.041) than patients with negative ones. The subgroup analyses and sensitivity analyses were consistent with the overall results. CONCLUSIONS Patients with negative surgical margin had significantly favorable overall survival and progression-free survival after surgical resection for ICC. The notion of achieving the R0 resection should be emphasized.
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Affiliation(s)
- Mu-Xing Li
- Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, P. R. China
| | - Xin-Yu Bi
- Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, P. R. China
| | - Zhi-Yu Li
- Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, P. R. China
| | - Zhen Huang
- Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, P. R. China
| | - Yue Han
- Department of Radiofrequency Ablation, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, P. R. China
| | - Jian-Jun Zhao
- Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, P. R. China
| | - Hong Zhao
- Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, P. R. China.
| | - Jian-Qiang Cai
- Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, P. R. China.
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17
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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.
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