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Mukherjee A, Sen R, Al Hoque A, Giri TK, Mukherjee B. H-ras-targeted genetic therapy remarkably surpassed docetaxel treatment in inhibiting chemically induced hepatic tumors in rats. Life Sci 2024; 348:122680. [PMID: 38697280 DOI: 10.1016/j.lfs.2024.122680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 04/19/2024] [Accepted: 04/27/2024] [Indexed: 05/04/2024]
Abstract
AIMS Hepatocellular carcinoma (HCC) is still a leading cause of cancer-related death worldwide. But its chemotherapeutic options are far from expectation. We here compared H-ras targeted genetic therapy to a commercial docetaxel formulation (DXT) in inhibiting HCC in rats. MAIN METHODS After the physicochemical characterization of phosphorothioate-antisense oligomer (PS-ASO) against H-ras mutated gene, the PS-ASO-mediated in vitro hemolysis, in vivo hepatic uptake, its pharmacokinetic profile, tissue distribution in some highly perfused organs, its effect in normal rats, antineoplastic efficacy in carcinogen-induced HCC in rats were evaluated and compared against DXT treatment. Mutated H-ras expression by in situ hybridization, hep-par-I, CK-7, CD-15, p53 expression patterns by immunohistochemical methods, scanning electron microscopic evaluation of hepatic architecture, various hepatic marker enzyme levels and caspase-3/9 apoptotic enzyme activities were also carried out in the experimental rats. KEY FINDINGS PS-ASO showed low in vitro hemolysis (<3 %), and had a sustained PS-ASO blood residence time in vivo compared to DTX, with a time-dependent hepatic uptake. It showed no toxic manifestations in normal rats. PS-ASO distribution was although initially less in the lung than liver and kidney, but at 8 h it accumulated more in lung than kidney. Antineoplastic potential of PS-ASO (treated for 6 weeks) excelled in inhibiting chemically induced tumorigenesis compared to DTX in rats, by inhibiting H-ras gene expression, some immonohistochemical modulations, and inducing caspase-3/9-mediated apoptosis. It prevented HCC-mediated lung metastatic tumor in the experimental rats. SIGNIFICANCE PS-ASO genetic therapy showed potential to inhibit HCC far more effectively than DXT in rats.
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Affiliation(s)
- Alankar Mukherjee
- Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Ramkrishna Sen
- Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India; Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa city, IA 52242, USA
| | - Ashique Al Hoque
- Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Tapan Kumar Giri
- Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Biswajit Mukherjee
- Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India.
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Wen KW, Kakar S. Hepatic Precancerous Lesions and Early Hepatocellular Carcinoma. Gastroenterol Clin North Am 2024; 53:109-132. [PMID: 38280744 DOI: 10.1016/j.gtc.2023.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2024]
Abstract
This review discusses the diagnostic challenges of diagnosing and treating precursor lesions of hepatocellular carcinoma (HCC) in both cirrhotic and non-cirrhotic livers. The distinction of high-grade dysplastic nodule (the primary precursor lesion in cirrhotic liver) from early HCC is emphasized based on morphologic, immunohistochemical, and genomic features. The risk factors associated with HCC in hepatocellular adenomas (precursor lesion in non-cirrhotic liver) are delineated, and the risk in different subtypes is discussed with emphasis on terminology, diagnosis, and genomic features.
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Affiliation(s)
- Kwun Wah Wen
- 505 Parnassus Avenue, M545, Box #0102, San Francisco, CA 94143, USA.
| | - Sanjay Kakar
- 505 Parnassus Avenue, M545, Box #0102, San Francisco, CA 94143, USA
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Shen C, Cao Y, Qi GQ, Huang J, Liu ZP. Discovering pathway biomarkers of hepatocellular carcinoma occurrence and development by dynamic network entropy analysis. Gene 2023; 873:147467. [PMID: 37164125 DOI: 10.1016/j.gene.2023.147467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/26/2023] [Accepted: 05/03/2023] [Indexed: 05/12/2023]
Abstract
OBJECTIVE Gene expression profiling techniques measure the transcription of thousands of genes in a parallel manner. With more and more hepatocellular carcinoma (HCC) transcriptomic data becoming available, the high-throughput data provides an unprecedented opportunity to discover HCC diagnostic biomarkers. In this work, we propose a bioinformatics method based on dynamic network entropy analysis, called DNEA, to identify potential pathway biomarkers for HCC occurrence and development by integrating transcriptome and interactome. METHODS We firstly collect the pathways documented in different knowledge-bases and then impose the genome-wide human transcriptomic data of multistage cancerous tissues during the development and progression of HCC. After linking the gene sets of pathways into individual connected networks, we map the corresponding gene expression information onto these pathways. The dynamic network entropy of individual pathways is calculated to evaluate its activities and dysfunctionalities during the disease occurrence and development. We use the overall significant difference in the entropic dynamics during the time course to prioritize distinctive pathways during disease progression. Then machine learning classification methods are employed to screen out pathway biomarkers with the classification ability to distinguish different-stage samples of HCC progression. RESULTS Pathway biomarkers discovered based on DNEA demonstrate good classification performance in measuring HCC progression. The classification accuracy is as follows: DNA replication pathway (mean AUC= 0.82, 20 genes) from KEGG, FMLP pathway (mean AUC=0.84, 14 genes) from BioCarta, and downstream signaling of activated FGFR pathway (mean AUC =0.80, 15 genes) from Reactome. At the same time, previous studies have shown that these genes and pathways screened are closely related to the occurrence and development of HCC in terms of oncogenesis dysfunctions. CONCLUSIONS Our method for cancer biomarker discovery based on dynamic network entropy analysis is effective and efficient in identifying pathway biomarkers related to the progression of complex diseases.
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Affiliation(s)
- Chen Shen
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong 250061, China; Department of Data and Information, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310052, China; Sino-Finland Joint AI Laboratory for Child Health of Zhejiang Province, Hangzhou, Zhejiang 310052, China
| | - Yi Cao
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong 250061, China; Center for Biomedical Engineering, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Guo-Qiang Qi
- Department of Data and Information, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310052, China; Sino-Finland Joint AI Laboratory for Child Health of Zhejiang Province, Hangzhou, Zhejiang 310052, China
| | - Jian Huang
- Department of Data and Information, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310052, China; Sino-Finland Joint AI Laboratory for Child Health of Zhejiang Province, Hangzhou, Zhejiang 310052, China
| | - Zhi-Ping Liu
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong 250061, China.
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Chen TY, Mai JY, Zhang P, Xue JH, He SL, Xi J, Chen JJ, Cheng Y. Efficacy of erzhu jiedu recipe on hepatitis B cirrhosis with hyperalphafetoproteinemia: A randomized, double-blind, placebo-controlled clinical trial. Medicine (Baltimore) 2021; 100:e27231. [PMID: 34559118 PMCID: PMC10545361 DOI: 10.1097/md.0000000000027231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 08/02/2021] [Accepted: 08/22/2021] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND Hepatitis B cirrhosis with hyperalphafetoproteinemia is the intermediate stage of liver cirrhosis progressing to hepatocellular carcinoma (HCC), there is no effective way to treat precancerous lesions of liver in modern medicine. In recent decades, clinical and experimental evidence shows that Chinese medicine (CM) has a certain beneficial effect on Hepatitis B Cirrhosis. Therefore, this trial aims to evaluate the efficacy and safety of a CM erzhu jiedu recipe (EZJDR) for the treatment of Hepatitis B Cirrhosis with Hyperalphafetoproteinemia. METHODS We designed a randomized, double blind, placebo-controlled clinical trial. A total of 72 patients of Hepatitis B Cirrhosis with hyperalphafetoproteinemia were randomized in 2 parallel groups. Patients in the control group received placebo granules similar to the EZJDR. In the EZJDR group, patients received EZJDR twice a day, after meals, for 48 weeks. The primary efficacy measures were changes in serum alpha-fetoprotein (AFP) and alpha-fetoprotein alloplasm (AFP-L3); The secondary indicators of efficacy are changes in liver function indicators, HBV-DNA level; Liver stiffness measurement (LSM); Hepatic portal vein diameter; T lymphocyte subgroup indexes during treatment. All data will be recorded in case report forms and analyzed by Statistical Analysis System software. Adverse events will also be evaluated. RESULTS The results showed that EZJDR can significantly inhibit the levels of AFP and AFP-L3 in patients with hepatitis B cirrhosis and hyperalphafetoproteinemia and have good security. ETHICS AND DISSEMINATION The study protocol was approved by the Medical Ethics Committee of Shuguang Hospital, affiliated with University of Traditional Chinese Medicine, Shanghai (NO.2018-579-08-01). TRIAL REGISTRATION This trial was registered on Chinese Clinical Trial Center (NO.ChiCTR1800017165).
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Affiliation(s)
- Tian-Yang Chen
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Pudong District, Shanghai, China
| | - Jing-Yin Mai
- Shanghai Guanghua Integrated Traditional Chinese and Western Medicine Hospital, No.40 Xinhua Road, Changning District, Shanghai, China
| | - Ping Zhang
- Foreign Language Center of Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Pudong District, Shanghai, China
| | - Jian-Hua Xue
- Department of Liver Disease, Hospital for Infectious Diseases of Pudong District, No.46 East Huaxia Road, Shanghai, China
| | - Sheng-Li He
- Minhang Branch of Tumor Hospital Affiliated to Fudan University, No.106 Ruili Road, Minhang District, Shanghai, China
| | - Jun Xi
- Department of Liver Disease, Hospital for Infectious Diseases of Pudong District, No.46 East Huaxia Road, Shanghai, China
| | - Jian-Jie Chen
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Pudong District, Shanghai, China
- Department of Liver Disease, Hospital for Infectious Diseases of Pudong District, No.46 East Huaxia Road, Shanghai, China
| | - Yang Cheng
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Pudong District, Shanghai, China
- Department of Liver Disease, Hospital for Infectious Diseases of Pudong District, No.46 East Huaxia Road, Shanghai, China
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Effects of C60 Fullerene on Thioacetamide-Induced Rat Liver Toxicity and Gut Microbiome Changes. Antioxidants (Basel) 2021; 10:antiox10060911. [PMID: 34199786 PMCID: PMC8226855 DOI: 10.3390/antiox10060911] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/24/2021] [Accepted: 05/25/2021] [Indexed: 12/30/2022] Open
Abstract
Thioacetamide (TAA) is widely used to study liver toxicity accompanied by oxidative stress, inflammation, cell necrosis, fibrosis, cholestasis, and hepatocellular carcinoma. As an efficient free radical's scavenger, C60 fullerene is considered a potential liver-protective agent in chemically-induced liver injury. In the present work, we examined the hepatoprotective effects of two C60 doses dissolved in virgin olive oil against TAA-induced hepatotoxicity in rats. We showed that TAA-induced increase in liver oxidative stress, judged by the changes in the activities of SOD, CAT, GPx, GR, GST, the content of GSH and 4-HNE, and expression of HO-1, MnSOD, and CuZnSOD, was more effectively ameliorated with a lower C60 dose. Improvement in liver antioxidative status caused by C60 was accompanied by a decrease in liver HMGB1 expression and an increase in nuclear Nrf2/NF-κB p65 ratio, suggesting a reduction in inflammation, necrosis and fibrosis. These results were in accordance with liver histology analysis, liver comet assay, and changes in serum levels of ALT, AST, and AP. The changes observed in gut microbiome support detrimental effects of TAA and hepatoprotective effects of low C60 dose. Less protective effects of a higher C60 dose could be a consequence of its enhanced aggregation and related pro-oxidant role.
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Abstract
Hepatocellular carcinoma (HCC) is a morphologically heterogeneous tumor with variable architectural growth patterns and several distinct histologic subtypes. Large-scale attempts have been made over the past decade to identify targetable genomic alterations in HCC; however, its translation into clinical personalized care remains a challenge to precision oncology. The role of pathology is no longer limited to confirmation of diagnosis when radiologic features are atypical. Pathology is now in a position to predict the underlying molecular alteration, prognosis, and behavior of HCC. This review outlines various aspects of histopathologic diagnosis and role of pathology in cutting-edge diagnostics of HCC.
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Affiliation(s)
- Monika Vyas
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 303 Brookline Avenue, Boston, MA 02215, USA
| | - Xuchen Zhang
- Department of Pathology, Yale School of Medicine, 310 Cedar Street, PO Box 208023, New Haven, CT 06520-8023, USA.
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Fan PL, Ding H, Mao F, Chen LL, Dong Y, Wang WP. Enhancement patterns of small hepatocellular carcinoma (≤ 30 mm) on contrast-enhanced ultrasound: Correlation with clinicopathologic characteristics. Eur J Radiol 2020; 132:109341. [PMID: 33069987 DOI: 10.1016/j.ejrad.2020.109341] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 08/10/2020] [Accepted: 10/03/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE To analyze the correlation between enhancement patterns of small hepatic carcinomas (HCCs; ≤ 30 mm) on contrast-enhanced ultrasound (CEUS) and the clinicopathologic characteristics. METHODS The retrospective study included 346 inpatients (288 males and 58 females) with 372 pathologically confirmed small HCCs between January 2017 and December 2018. All patients underwent CEUS examination before pathological examination. Statistical analysis was used to determine the correlation between enhancement patterns of small HCCs on CEUS and clinicopathologic characteristics including serum alpha-feto-protein level, protein induced by vitamin K absence or antagonist-II (PIVKA-II) level, primary or recurrent HCC condition, tumor number, tumor differentiation, tumor size, liver background and microvascular invasion (MVI). RESULTS Three hundred forty-seven out of 372 (93.3 %) HCCs manifested arterial phase hyper-enhancement (APHE). The arterial enhancement patterns were correlated with the tumor differentiation (odds ratio = 10.336, P = 0.000). Moderately- or poorly-differentiated HCCs were more likely to display APHE than well-differentiated HCCs (96.2 % vs 58.6 %, P < 0.001). Two hundred ninety-five of 372 (79.3 %) HCCs showed washout in the portal venous/late phase. Washout was correlated with serum PIVKA-II level, tumor size, tumor differentiation, and MVI on univariate analysis (P < 0.05). Logistic regression analysis revealed that only tumor size was significantly associated with washout of small HCCs (odds ratio = 2.335, P = 0.006). Large HCCs (20-30 mm) displayed a higher proportion of washout compared with that of HCCs ≤ 20 mm. CONCLUSIONS Enhancement patterns of small HCCs on CEUS were significantly correlated with tumor size and tumor differentiation among all clinicopathologic characteristics.
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Affiliation(s)
- Pei Li Fan
- Department of Ultrasound, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, 200032, Shanghai, China; Shanghai Institute of Medical Imaging, No.180 Fenglin Road, 200032, Shanghai, China
| | - Hong Ding
- Department of Ultrasound, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, 200032, Shanghai, China; Shanghai Institute of Medical Imaging, No.180 Fenglin Road, 200032, Shanghai, China
| | - Feng Mao
- Department of Ultrasound, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, 200032, Shanghai, China; Shanghai Institute of Medical Imaging, No.180 Fenglin Road, 200032, Shanghai, China
| | - Ling Li Chen
- Department of Pathology, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, 200032, Shanghai, China
| | - Yi Dong
- Department of Ultrasound, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, 200032, Shanghai, China; Shanghai Institute of Medical Imaging, No.180 Fenglin Road, 200032, Shanghai, China
| | - Wen Ping Wang
- Department of Ultrasound, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, 200032, Shanghai, China; Shanghai Institute of Medical Imaging, No.180 Fenglin Road, 200032, Shanghai, China.
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Cheng Y, Chen T, Chen J. Erzhu Jiedu decoction ameliorates liver precancerous lesions in a rat model of liver cancer. J Cancer 2020; 11:7302-7311. [PMID: 33193894 PMCID: PMC7646158 DOI: 10.7150/jca.49554] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 09/24/2020] [Indexed: 12/13/2022] Open
Abstract
Precancerous lesions are the intermediate stage in the development of liver cancer from cirrhosis. Early intervention measures can effectively prevent the occurrence of liver cancer and prolong the lives of patients, resulting in greater economic effects. Erzhu Jiedu decoction (EJD) is a semiempirical formula that is used in the treatment of cirrhosis and liver cancer according to the academic philosophy of "Preventive treatment of disease" and has achieved good curative effects in clinical practice. The purpose of this study was to investigate the effect of EJD on liver precancerous lesions induced by diethylnitrosamine (DEN) in rats. The results showed that EJD improved the general conditions (body weight, ALT, AST, and GGT) and reduced the number of precancerous lesions in the rat model. Notably, the medium dose of EJD (1.05 g/kg) had better treatment effects than the low dose of EJD, and the high dose of EJD did not further improve the liver lesions compared to the medium dose of EJD. Moreover, EJD effectively reduced the DEN-induced GST-Pi, AFP, CK19, c-Myc, and Ki67 protein expression in liver precancerous tissues. Interestingly, EJD significantly reduced YAP and TAZ mRNA expression in the liver precancerous lesions. Collectively, EJD protects against in the initiation of liver cancer and the regulation of c-Myc and Hippo signaling pathways may be the underlying mechanism.
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Affiliation(s)
- Yang Cheng
- Department of liver disease, Hospital for Infectious Diseases of Pudong District, Shanghai 201299, P.R. China.,Institute of liver disease, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Tianyang Chen
- Institute of liver disease, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Jianjie Chen
- Department of liver disease, Hospital for Infectious Diseases of Pudong District, Shanghai 201299, P.R. China.,Institute of liver disease, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
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Liver stiffness measured by MR elastography is a predictor of early HCC recurrence after treatment. Eur Radiol 2020; 30:4182-4192. [PMID: 32189053 DOI: 10.1007/s00330-020-06792-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 02/26/2020] [Accepted: 03/05/2020] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Magnetic resonance elastography (MRE) is a non-invasive tool for measuring liver stiffness (LS) with high diagnostic accuracy. This study investigated whether quantified LS by MRE could predict early recurrence of patients with hepatocellular carcinoma (HCC) within the Milan criteria. METHODS A prospectively collected cohort, which included the HCC patients who underwent MRE before treatment (an HCC-MRE cohort), was analyzed. In the HCC-MRE cohort, only patients under the Milan criteria, who underwent hepatic resection, radiofrequency ablation (RFA), or transarterial chemoembolization (TACE), were reviewed. We investigated whether LS assessed by MRE was an independent predictor of early recurrence using Cox regressions and Kaplan-Meier analyses. RESULTS A total of 192 HCC patients under the Milan criteria who underwent hepatic resection (n = 96), RFA (n = 23), or TACE (n = 73) were included. Higher LS ratings (kPa; hazard ratio [HR] = 1.12; 95% confidence interval [CI] = 1.01-1.25; p = 0.040) emerged as an independent risk factor for early tumor recurrence. In the subgroup analysis, higher LS ratings were associated with higher risks of early HCC recurrence in both the resection/RFA group (> 4.5 kPa; HR = 2.95; 95% CI = 1.26-6.94; p = 0.013) and the TACE group (> 6 kPa; HR = 2.94; 95% CI = 1.27-6.83; p = 0.012). CONCLUSION LS assessed by MRE was an independent predictor of early recurrence among HCC patients under the Milan criteria after achieving a complete response. KEY POINTS • Liver parenchymal stiffness measured by MRE predicts early recurrence of treated HCC under Milan criteria. • A liver stiffness > 5.5 kPa was associated with worse recurrence-free survival. • Patients with high pre-treatment LS may benefit from stringent follow-up.
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Jak-Stat Signaling Induced by Interleukin-6 Family Cytokines in Hepatocellular Carcinoma. Cancers (Basel) 2019; 11:cancers11111704. [PMID: 31683891 PMCID: PMC6896168 DOI: 10.3390/cancers11111704] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 10/29/2019] [Accepted: 10/30/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. It can be caused by chronic liver cell injury with resulting sustained inflammation, e.g., triggered by infections with hepatitis viruses B (HBV) and C (HCV). Death of hepatocytes leads to the activation of compensatory mechanisms, which can ultimately result in liver fibrosis and cirrhosis. Another common feature is the infiltration of the liver with inflammatory cells, which secrete cytokines and chemokines that act directly on the hepatocytes. Among several secreted proteins, members of the interleukin-6 (IL-6) family of cytokines have emerged as important regulatory proteins that might constitute an attractive target for therapeutic intervention. The IL-6-type cytokines activate multiple intracellular signaling pathways, and especially the Jak/STAT cascade has been shown to be crucial for HCC development. In this review, we give an overview about HCC pathogenesis with respect to IL-6-type cytokines and the Jak/STAT pathway. We highlight the role of mutations in genes encoding several proteins involved in the cytokine/Jak/STAT axis and summarize current knowledge about IL-6 family cytokines in this context. We further discuss possible anti-cytokine therapies for HCC patients in comparison to already established therapies.
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The Evaluation of Angiogenesis Markers in Hepatocellular Carcinoma and Precursor Lesions in Liver Explants From a Single Institution. Appl Immunohistochem Mol Morphol 2019; 26:330-336. [PMID: 27556821 DOI: 10.1097/pai.0000000000000426] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Hepatocellular carcinoma (HCC) is a global health problem associated with chronic liver disease. Precursor lesions are described, and the correct diagnosis of liver nodules is paramount when considering liver transplantation. We evaluated the immunohistochemical expression of vascular endothelial growth factor (VEGF) and angiopoietin-2 in HCC and precursors lesion in a single institution series of whole liver explants between 2013 and 2015, evaluating morphologic and clinical variables. The study comprised 67 patients (32.8% female) and 107 nodules. The mean age of the patients was 52.7 years (29 to 70 y). There were no significant epidemiologic differences among malignant lesions, dysplastic nodules, and regenerative nodules. Angiopoietin-2 expression was significantly more expressed in carcinoma when compared with regenerative lesions (P<0.0001). A statistically significant relationship was noted between the expression of VEGF in hepatocytes and Ang-2 expression in the small vasculature (P=0.006). VEGF expression also correlated significantly with the number of nonpaired arteries (P=0.03), although it was not useful in separating benign from malignant cases. We identified a sensitivity of 54% and a specificity of 96% using angiopoietin-2, and a sensitivity of 68.7% and a specificity of 31.2% when using VEGF for the diagnosis of HCC. There was no significant correlation between the immunohistochemical parameters and the clinical staging, the number of gross lesions, and the histologic grade in cases of HCC. Angiopoietin-2 may be a candidate biomarker in assessing liver nodules in transplant patients, and may assist in the diagnosis of difficult lesions and in small biopsies pretransplant.
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Abstract
The differential diagnosis of hepatic mass lesions is broad and arriving at the right diagnosis can be challenging, especially on needle biopsies. The differential diagnosis of liver tumors in children is different from adults and is beyond the scope of this review. In adults, the approach varies depending on the age, gender, and presence of background liver disease. The lesions can be divided broadly into primary and metastatic (secondary), and the primary lesions can be further divided into those of hepatocellular origin and nonhepatocellular origin. The first category consists of benign and malignant lesions arising from hepatocytes, while the second category includes biliary, mesenchymal, hematopoietic, and vascular tumors. Discussion of nonepithelial neoplasms is beyond the scope of this review. The hepatocytic lesions comprise dysplastic nodules, focal nodular hyperplasia, hepatic adenoma, and hepatocellular carcinoma, and the differential diagnosis can be challenging requiring clinicopathological correlation and application of immunohistochemical (IHC) markers. Liver is a common site for metastasis, sometimes presenting with an unknown primary site, and proper workup is the key to arriving at the correct diagnosis. The correct diagnosis in this setting requires a systematic approach with attention to histologic features, imaging findings, clinical presentation, and judicious use of IHC markers. The list of antibodies that can be used for this purpose keeps on growing continually. It is important for pathologists to be up to date with the sensitivity and specificity of these markers and their diagnostic role and clinical implications. The purpose of this review is to outline the differential diagnosis of hepatic masses in adults and discuss an algorithmic approach to make a right diagnosis.
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Affiliation(s)
- Monika Vyas
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Dhanpat Jain
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
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Inchingolo R, Faletti R, Grazioli L, Tricarico E, Gatti M, Pecorelli A, Ippolito D. MR with Gd-EOB-DTPA in assessment of liver nodules in cirrhotic patients. World J Hepatol 2018; 10:462-473. [PMID: 30079132 PMCID: PMC6068846 DOI: 10.4254/wjh.v10.i7.462] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 04/25/2018] [Accepted: 05/30/2018] [Indexed: 02/06/2023] Open
Abstract
To date the imaging diagnosis of liver lesions is based mainly on the identification of vascular features, which are typical of overt hepatocellular carcinoma (HCC), but the hepatocarcinogenesis is a complex and multistep event during which, a spectrum of nodules develop within the liver parenchyma, including benign small and large regenerative nodule (RN), low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC, and well differentiated HCC. These nodules may be characterised not only on the basis of their respective different blood supplies, but also on their different hepatocyte function. Recently, in liver imaging the introduction of hepatobiliary magnetic resonance imaging contrast agent offered the clinicians the possibility to obtain, at once, information not only related to the vascular changes of liver nodules but also information on hepatocyte function. For this reasons this new approach becomes the most relevant diagnostic clue for differentiating low-risk nodules (LGDN-RN) from high-risk nodules (HGDN/early HCC or overt HCC) and consequently new diagnostic algorithms for HCC have been proposed. The use of hepatobiliary contrast agents is constantly increasing and gradually changing the standard of diagnosis of HCC. The main purpose of this review is to underline the added value of Gd-EOB-DTPA in early-stage diagnoses of HCC. We also analyse the guidelines for the diagnosis and management of HCC, the key concepts of HCC development, growth and spread and the imaging appearance of precursor nodules that eventually may transform into overt HCC.
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Affiliation(s)
- Riccardo Inchingolo
- Division of Interventional Radiology, Department of Radiology, Madonna delle Grazie Hospital, Matera 75100, Italy.
| | - Riccardo Faletti
- Department of Surgical Sciences, Radiology Unit, University of Turin, Turin 10126, Italy
| | - Luigi Grazioli
- Department of Radiology, University of Brescia "Spedali Civili", Brescia 25123, Italy
| | - Eleonora Tricarico
- Division of Interventional Radiology, Department of Radiology, Madonna delle Grazie Hospital, Matera 75100, Italy
| | - Marco Gatti
- Department of Surgical Sciences, Radiology Unit, University of Turin, Turin 10126, Italy
| | - Anna Pecorelli
- Department of Diagnostic Radiology, School of Medicine, University of Milano-Bicocca, Monza 20900, Italy
| | - Davide Ippolito
- Department of Diagnostic Radiology, School of Medicine, University of Milano-Bicocca, Monza 20900, Italy
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14
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Lee M, Kim K, Kim SY, Jung SH, Yoon J, Kim MS, Park HC, Jung ES, Chung YJ, Lee SH. Genomic structures of dysplastic nodule and concurrent hepatocellular carcinoma. Hum Pathol 2018; 81:37-46. [PMID: 29949741 DOI: 10.1016/j.humpath.2018.06.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 05/28/2018] [Accepted: 06/09/2018] [Indexed: 12/19/2022]
Abstract
Although high-grade dysplastic nodule (HGDN) is a preneoplastic lesion that precedes hepatocellular carcinoma (HCC), the genomic structures of HGDN in conjunction with HCC remain elusive. The objective of this study was to identify genomic alterations of HGDN and its difference from HCC that may drive HGDN progression to HCC. We analyzed 16 regions of paired HGDN and HCC from 6 patients using whole-exome sequencing to find somatic mutation and copy number alteration (CNA) profiles of HGDN and HCC. The numbers of mutations, driver mutations, and CNAs of HGDNs were not significantly different from those of HCCs. We identified that the CNA gain of 1q25.3-1q42.13 was predominant in the HCCs compared with that in the HGDNs. Two cases (one nodule-in-nodule case and another case with closely attached HCC and HGDN) showed several overlapped driver mutations (CTNNB1 and CEBPA) and CNAs (losses of CDKN2A, RB1, and TP53) between HGDNs and HCCs, suggesting their roles in the early HCC development. The other 4 cases with spatially separated HCCs and HGDNs showed few overlapped alterations between the paired HCCs and HGDNs. Mutations in ERBB2 and CCND1, and CNAs (gains of CTNNB1, MET, and SMO and losses of PTEN, TP53, and SETD2) were identified as "HCC predominant," suggesting their roles in the progression of HGDN to HCC. Our data show that HCCs are direct descendants of HGDNs in some cases, but there is no direct evidence of such relationship in spatially separated cases. Genomic features of HGDN identified in this study provide a useful resource for dissecting clues for the genetic diagnosis of HGDN and HCC.
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Affiliation(s)
- Minho Lee
- Catholic Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Kyung Kim
- Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Shinn Young Kim
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Seung-Hyun Jung
- Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jonghwan Yoon
- Catholic Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Min Sung Kim
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Hyeon-Chun Park
- Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Eun Sun Jung
- Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Yeun-Jun Chung
- Catholic Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
| | - Sug Hyung Lee
- Catholic Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
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15
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Chen Q, Wang M, Wang M, Jin S, Xiao SY, Tian S. Expansile invasive growth pattern is definite evidence for the diagnosis of small hepatocellular carcinomas: a comparative study of 37 cases. Hum Pathol 2018; 80:130-137. [PMID: 29936057 DOI: 10.1016/j.humpath.2018.06.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Revised: 05/26/2018] [Accepted: 06/09/2018] [Indexed: 12/11/2022]
Abstract
Small HCCs, including seHCC and spHCC, are rarely encountered in daily practice. Definite diagnosis is difficult for general pathologists. In this study, we reviewed 1025 cases of HCC and examined the histologic characteristics of small HCCs to facilitate more accurate diagnosis. Slides of archived HCC cases were reviewed by 2 senior pathologists, and small HCCs were identified according to the canonical criteria. Additional immunohistochemical stains were performed. Thirty-seven cases of small HCC were identified, including 22 cases of seHCC and 15 cases of spHCC. We found 2 types of invasive growth patterns in these lesions. The first is the expansile invasive growth pattern, with monomorphic tumor cells penetrating through the incomplete fibrous capsules and expanding into the adjacent noncancerous liver with a spherical, hemispheric, or mushroom shape. The second is the classic stromal invasion pattern. At least one type of invasive pattern was observed in all of the 37 cases of small HCC, and the seHCCs exhibit the expansile invasive growth pattern more frequently than the classic stromal invasion pattern. On the contrary, stromal invasive pattern was more common in spHCC nodules. In conclusion, with the background of chronic hepatitis and cirrhosis, histologic features including crowdedness of hepatocytic trabeculae and the expansile invasive growth pattern are strong evidence for the diagnoses of small HCC.
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Affiliation(s)
- Qiongrong Chen
- Department of Pathology, Wuhan University Zhongnan Hospital, and Wuhan University Pathology Center, Wuhan 430071, Hubei Province, China
| | - Manxiang Wang
- Department of Pathology, Hubei Cancer Hospital, Wuhan 430079, Hubei Province, China
| | - Mingwei Wang
- Department of Pathology, Hubei Cancer Hospital, Wuhan 430079, Hubei Province, China
| | - Su Jin
- Department of Pathology, Hubei Cancer Hospital, Wuhan 430079, Hubei Province, China
| | - Shu-Yuan Xiao
- Department of Pathology, Wuhan University Zhongnan Hospital, and Wuhan University Pathology Center, Wuhan 430071, Hubei Province, China
| | - Sufang Tian
- Department of Pathology, Wuhan University Zhongnan Hospital, and Wuhan University Pathology Center, Wuhan 430071, Hubei Province, China.
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16
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Hassan S, Mansy SS, Tabak SA, AbdelFattah AS, Abdel-Aziz AM, Hamam O, Seleem MI, Abdelaal A. Immunohistochemical and electron microscopic morphometric image analysis of hepatocellular carcinoma in association of HCV infection. Ultrastruct Pathol 2018; 42:97-107. [PMID: 29424576 DOI: 10.1080/01913123.2017.1422065] [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] [Indexed: 02/06/2023]
Abstract
Early detection of hepatocellular carcinoma (HCC) is crucial for successful therapy. The present work examined the value of ultrastructural morphometric image analysis of hepatocyte nuclei in patients with chronic hepatitis C virus (HCV) versus HCC cases with chronic HCV and the corresponding surgical tumor-free safe margins (TFMs), to highlight any early predictive signs of neoplastic cellular transformation. This work also performed an immunohistochemical assessment of cytokeratin 19 (CK19) and Ki-67-positive cells to visualize any associated proliferative activity in the examined groups. The results showed significant decrease in the hepatocyte nuclear surface areas in the HCC and TFMs versus those in the HCV cases. The hepatocyte nucleolar surface area was significantly increased in the HCC cases versus that in the HCV cases. This increase was associated with a significant increase in Ki-67-positive cells in the HCC cases compared to those in the other groups. Conversely, the mean number of CK 19-positive cells was significantly reduced in the HCC cases compared to the cell numbers in TFMs and HCV cases with severe hepatic fibrosis. Liver progenitor cells (LPCs) were discerned in the reactive ductules and canaliculo-ductular junctions that characterized TFMs. LPCs were sporadically distributed in the liver lobules and reactive bile ductules in the HCC samples. In conclusion, CK 19 represents an important marker for distinguishing between dysplastic and malignant liver nodules. Electron microscopic morphometric image analysis may be considered as adjunct factor for assessing hepatocyte malignant transformation. Wider scale studies are needed to authenticate these results.
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Affiliation(s)
- Sarah Hassan
- a Electron Microscopy Research Department (Pathology) , Theodor Bilharz Research Institute , Cairo , Egypt
| | - Soheir S Mansy
- a Electron Microscopy Research Department (Pathology) , Theodor Bilharz Research Institute , Cairo , Egypt
| | - Sahar A Tabak
- b Pathology Department, Faculty of Medicine , Cairo University , Egypt
| | - Ahmed S AbdelFattah
- c Hepatogastroenterology Department , Theodor Bilharz Research Institute , Cairo , Egypt
| | | | - Olfat Hamam
- d Pathology Department , Theodor Bilharz Research Institute , Cairo , Egypt
| | - Mohammed I Seleem
- e Hepatobiliary Surgery and Liver Transplantation , National Hepatology and Tropical Medicine Research Institute , Cairo , Egypt
| | - Amr Abdelaal
- f Surgery Department, Faculty of Medicine , Ain Shams University , Cairo , Egypt
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17
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Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma. J Hepatol 2017; 67:1222-1231. [PMID: 28843658 DOI: 10.1016/j.jhep.2017.08.013] [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: 04/25/2017] [Revised: 08/10/2017] [Accepted: 08/15/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS According to the clonal model of tumor evolution, trunk alterations arise at early stages and are ubiquitous. Through the characterization of early stages of hepatocarcinogenesis, we aimed to identify trunk alterations in hepatocellular carcinoma (HCC) and study their intra- and inter-tumor distribution in advanced lesions. METHODS A total of 151 samples representing the multistep process of hepatocarcinogenesis were analyzed by targeted-sequencing and a single nucleotide polymorphism array. Genes altered in early lesions (31 dysplastic nodules [DNs] and 38 small HCCs [sHCC]) were defined as trunk. Their distribution was explored in: a) different regions of large tumors (43 regions, 21 tumors), and b) different nodules of the same patient (39 tumors, 17 patients). Multinodular lesions were classified as intrahepatic metastases (IMs) or synchronous tumors based on chromosomal aberrations. RESULTS TERT promoter mutations (10.5%) and broad copy-number aberrations in chromosomes 1 and 8 (3-7%) were identified as trunk gatekeepers in DNs and were maintained in sHCCs. Trunk drivers identified in sHCCs included TP53 (23%) and CTNNB1 (11%) mutations, and focal amplifications or deletions in known drivers (6%). Overall, TERT, TP53 and CTNNB1 mutations were the most frequent trunk events and at least one was present in 51% of sHCCs. Around 90% of mutations in these genes were ubiquitous among different regions of large tumors. In multinodular HCCs, 35% of patients harbored IMs; 85% of mutations in TERT, TP53 and/or CTNNB1 were retained in primary and metastatic tumors. CONCLUSIONS Trunk events in early stages (TERT, TP53, CTNNB1 mutations) were ubiquitous across different regions of the same tumor and between primary and metastatic nodules in >85% of cases. This concept supports the knowledge that single biopsies would suffice to capture trunk mutations in HCC. LAY SUMMARY Trunk alterations arise at early stages of cancer and are shared among all malignant cells of the tumor. In order to identify trunk alterations in HCC, we characterized early stages of hepatocarcinogenesis represented by dysplastic nodules and small lesions. Mutations in TERT, TP53 and CTNNB1 genes were the most frequent. Analyses in more advanced lesions showed that mutations in these same genes were shared between different regions of the same tumor and between primary and metastatic tumors, suggesting their trunk role in this disease.
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18
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Mansy SS, El-Ahwany E, Mahmoud S, Hassan S, Seleem MI, Abdelaal A, Helmy AH, Zoheiry MK, AbdelFattah AS, Hassanein MH. Potential ultrastructure predicting factors for hepatocellular carcinoma in HCV infected patients. Ultrastruct Pathol 2017; 41:209-226. [PMID: 28494215 DOI: 10.1080/01913123.2017.1316330] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus represents one of the rising causes of hepatocellular carcinoma (HCC). Although the early diagnosis of HCC is vital for successful curative treatment, the majority of lesions are diagnosed in an irredeemable phase. This work deals with a comparative ultrastructural study of experimentally gradually induced HCC, surgically resected HCC, and potential premalignant lesions from HCV-infected patients, with the prospect to detect cellular criteria denoting premalignant transformation. Among the main detected pathological changes which are postulated to precede frank HCC: failure of normal hepatocyte regeneration with star shape clonal fragmentation, frequent elucidation of hepatic progenitor cells and Hering canals, hepatocytes of different electron density loaded with small sized rounded monotonous mitochondria, increase junctional complexes bordering bile canaliculi and in between hepatocyte membranes, abundant cellular proteinaceous material with hypertrophied or vesiculated rough endoplasmic reticulum (RER), sequestrated nucleus with proteinaceous granular material or hypertrophied RER, formation of lipolysosomes, large autophagosomes, and micro-vesicular fat deposition. In conclusion, the present work has visualized new hepatocytic division or regenerative process that mimic splitting or clonal fragmentation that occurs in primitive creature. Also, new observations that may be of value or assist in predicting HCC and identifying the appropriate patient for surveillance have been reported. Moreover, it has pointed to the possible malignant potentiality of liver stem/progenitor cells. For reliability, the results can be subjected to cohort longitudinal study.
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Affiliation(s)
- Soheir S Mansy
- a Electron Microscopy Research Department (Pathology) , Theodor Bilharz Research Institute , Giza , Egypt
| | - Eman El-Ahwany
- b Immunology Department , Theodor Bilharz Research Institute , Giza , Egypt
| | - Soheir Mahmoud
- c Parasitology Department , Theodor Bilharz Research Institute , Giza , Egypt
| | - Sara Hassan
- a Electron Microscopy Research Department (Pathology) , Theodor Bilharz Research Institute , Giza , Egypt
| | - Mohammed I Seleem
- d Hepatobiliary Surgery and Liver Transplantation , National Hepatology and Tropical Medicine Research Institute , Cairo , Egypt
| | - Amr Abdelaal
- e Surgery Department , Faculty of Medicine, Ain Shams University , Cairo , Egypt
| | - Ahmed H Helmy
- f Surgery Department , Theodor Bilharz Research Institute , Giza , Egypt
| | - Mona K Zoheiry
- b Immunology Department , Theodor Bilharz Research Institute , Giza , Egypt
| | - Ahmed S AbdelFattah
- g Hepatogastroenterology Department , Theodor Bilharz Research Institute , Giza , Egypt
| | - Moataz H Hassanein
- g Hepatogastroenterology Department , Theodor Bilharz Research Institute , Giza , Egypt
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19
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Kowalik MA, Sulas P, Ledda-Columbano GM, Giordano S, Columbano A, Perra A. Cytokeratin-19 positivity is acquired along cancer progression and does not predict cell origin in rat hepatocarcinogenesis. Oncotarget 2016; 6:38749-63. [PMID: 26452031 PMCID: PMC4770734 DOI: 10.18632/oncotarget.5501] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Accepted: 09/21/2015] [Indexed: 02/06/2023] Open
Abstract
Although the expression of the stem/progenitor cell marker cytokeratin-19 (CK-19) has been associated with the worst clinical prognosis among all HCC subclasses, it is yet unknown whether its presence in HCC is the result of clonal expansion of hepatic progenitor cells (HPCs) or of de-differentiation of mature hepatocytes towards a progenitor-like cell phenotype. We addressed this question by using two rat models of hepatocarcinogenesis: the Resistant-Hepatocyte (R-H) and the Choline-methionine deficient (CMD) models. Our data indicate that the expression of CK-19 is not the result of a clonal expansion of HPCs (oval cells in rodents), but rather of a further step of preneoplastic hepatocytes towards a less differentiated phenotype and a more aggressive behavior. Indeed, although HCCs were positive for CK-19, very early preneoplastic foci (EPFs) were completely negative for this marker. While a few weeks later the vast majority of preneoplastic nodules remained CK-19 negative, a minority became positive, suggesting that CK-19 expression is the result of de-differentiation of a subset of EPFs, rather than a marker of stem/progenitor cells. Moreover, the gene expression profile of CK-19-negative EPFs clustered together with CK-19-positive nodules, but was clearly distinct from CK-19 negative nodules and oval cells.
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Affiliation(s)
- Marta Anna Kowalik
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Pia Sulas
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | | | - Silvia Giordano
- University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS Candiolo, Torino, Italy
| | - Amedeo Columbano
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Andrea Perra
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
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20
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Yang Y, Lin X, Lu X, Luo G, Zeng T, Tang J, Jiang F, Li L, Cui X, Huang W, Hou G, Chen X, Ouyang Q, Tang S, Sun H, Chen L, Gonzalez FJ, Wu M, Cong W, Chen L, Wang H. Interferon-microRNA signalling drives liver precancerous lesion formation and hepatocarcinogenesis. Gut 2016; 65:1186-201. [PMID: 26860770 PMCID: PMC6624432 DOI: 10.1136/gutjnl-2015-310318] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 01/12/2016] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Precancerous lesion, a well-established histopathologically premalignant tissue with the highest risk for tumourigenesis, develops preferentially from activation of DNA damage checkpoint and persistent inflammation. However, little is known about the mechanisms by which precancerous lesions are initiated and their physiological significance. DESIGN Laser capture microdissection was used to acquire matched normal liver, precancerous lesion and tumour tissues. miR-484(-/-), Ifnar1(-/-) and Tgfbr2(△hep) mice were employed to determine the critical role of the interferon (IFN)-microRNA pathway in precancerous lesion formation and tumourigenesis. RNA immunoprecipitation (RIP), pull-down and chromatin immunoprecipitation (ChIP) assays were applied to explore the underlying mechanisms. RESULTS miR-484 is highly expressed in over 88% liver samples clinically. DEN-induced precancerous lesions and hepatocellular carcinoma were dramatically impaired in miR-484(-/-) mice. Mechanistically, ectopic expression of miR-484 initiates tumourigenesis and cell malignant transformation through synergistic activation of the transforming growth factor-β/Gli and nuclear factor-κB/type I IFN pathways. Specific acetylation of H3K27 is indispensable for basal IFN-induced continuous transcription of miR-484 and cell transformation. Convincingly, formation of precancerous lesions were significantly attenuated in both Tgfbr2(△hep) and Ifnar1(-/-) mice. CONCLUSIONS These findings demonstrate a new protumourigenic axis involving type I IFN-microRNA signalling, providing a potential therapeutic strategy to manipulate or reverse liver precancerous lesions and tumourigenesis.
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Affiliation(s)
- Yingcheng Yang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China,Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Ximeng Lin
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China,Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Xinyuan Lu
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Guijuan Luo
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China,National Center for Liver Cancer, Shanghai, China
| | - Tao Zeng
- Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Jing Tang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China,National Center for Liver Cancer, Shanghai, China
| | - Feng Jiang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Liang Li
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China,National Center for Liver Cancer, Shanghai, China
| | - Xiuliang Cui
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China,National Center for Liver Cancer, Shanghai, China
| | - Wentao Huang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Guojun Hou
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Xin Chen
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Qing Ouyang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Shanhua Tang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Huanlin Sun
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Luonan Chen
- Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Mengchao Wu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Wenming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lei Chen
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China,National Center for Liver Cancer, Shanghai, China,Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Hongyang Wang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China,National Center for Liver Cancer, Shanghai, China,State Key Laboratory for Oncogenes and Related Genes, Cancer Institute of RenJi Hospital, Shanghai JiaoTong University, Shanghai, China
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21
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Niu ZS, Niu XJ, Wang WH, Zhao J. Latest developments in precancerous lesions of hepatocellular carcinoma. World J Gastroenterol 2016; 22:3305-3314. [PMID: 27022212 PMCID: PMC4806188 DOI: 10.3748/wjg.v22.i12.3305] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Revised: 11/16/2015] [Accepted: 12/08/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocarcinogenesis in human chronic liver diseases is a multi-step process in which hepatic precancerous lesions progress into early hepatocellular carcinoma (HCC) and progressed HCC, and the close surveillance and treatment of these lesions will help improve the survival rates of patients with HCC. The rapid development and extensive application of imaging technology have facilitated the discovery of nodular lesions of ambiguous significance, such as dysplastic nodules. Further investigations showed that these nodules may be hepatic precancerous lesions, and they often appear in patients with liver cirrhosis. Although the morphology of these nodules is not sufficient to support a diagnosis of malignant tumor, these nodules are closely correlated with the occurrence of HCC, as indicated by long-term follow-up studies. In recent years, the rapid development and wide application of pathology, molecular genetics and imaging technology have elucidated the characteristics of precancerous lesions. Based on our extensive review of the relevant literature, this article focuses on evidence indicating that high-grade dysplastic nodules are more likely to transform into HCC than low-grade dysplastic nodules based on clinical, pathological, molecular genetic and radiological assessments. In addition, evidence supporting the precancerous nature of large cell change in hepatitis B virus-related HCC is discussed.
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22
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Xu MY, Chen R, Yu JX, Liu T, Qu Y, Lu LG. AZGP1 suppresses epithelial-to-mesenchymal transition and hepatic carcinogenesis by blocking TGFβ1-ERK2 pathways. Cancer Lett 2016; 374:241-9. [PMID: 26902423 DOI: 10.1016/j.canlet.2016.02.025] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 01/31/2016] [Accepted: 02/14/2016] [Indexed: 01/10/2023]
Abstract
Zinc-α2-glycoprotein 1 (AZGP1) has been found to play important roles in TGF-β1 induced epithelial-to-mesenchymal transition (EMT). However, the mechanisms of AZGP1 inhibiting EMT and its therapeutic potential remain unknown in hepatocellular carcinoma (HCC). AZGP1, TGF-β1 or ERK2 expressions were examined in liver tissues of HCC patients and rat model. The effect of AZGP1 on EMT and crosstalking of TGFβ1-ERK2 signaling in human hepatic cancer cell was tested in vitro and in vivo. Hepatic expression of AZGP1 was nearly deficient in HCC patients and rats. It was proved that AZGP1 has the ability of down-regulating mesenchymal markers, up-regulating epithelial marker, inhibiting cell invasion and suppressing EMT in human HCC cells. The results clarified that AZGP1 has the effect on blocking TGF-β1 mediated ERK2 phosphorylation leading to depressing EMT and invasive potential in vitro. Local injection of AZGP1 mimic in vivo could significantly withhold lung metastasis in HCC. In conclusion, loss of AZGP1 could trigger EMT induced by TGFβ1-ERK2 signaling, confuse in energy metabolism, reduce cell proliferation and apoptosis, activate survival signals and promote invasion. Up-regulation of AZGP1 should be proposed to reverse EMT and might be a new promising therapy for HCC.
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Affiliation(s)
- Ming-Yi Xu
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Rong Chen
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Jing-Xia Yu
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Ting Liu
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Ying Qu
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Lun-Gen Lu
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
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23
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Peng C, Kaščáková S, Chiappini F, Olaya N, Sandt C, Yousef I, Samuel D, Dumas P, Guettier C, Le Naour F. Discrimination of cirrhotic nodules, dysplastic lesions and hepatocellular carcinoma by their vibrational signature. J Transl Med 2016; 14:9. [PMID: 26754490 PMCID: PMC4710034 DOI: 10.1186/s12967-016-0763-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 01/02/2016] [Indexed: 01/14/2023] Open
Abstract
Background Hepatocarcinogenesis is a multistep process characterized in patients with chronic liver diseases by a spectrum of hepatic nodules that mark the progression from regenerative nodules to dysplastic lesions followed by hepatocellular carcinoma (HCC). The differential diagnosis between precancerous dysplastic nodules and early HCC still represents a challenge for both radiologists and pathologists. We addressed the potential of Fourier transform-infrared (FTIR) microspectroscopy for grading cirrhotic nodules on frozen tissue sections. Methods The study was focused on 39 surgical specimens including normal livers (n = 11), dysplastic nodules (n = 6), early HCC (n = 1), progressed HCC on alcoholic cirrhosis (n = 10) or hepatitis C virus cirrhosis (n = 11). The use of the bright infrared source emitted by the synchrotron radiation allowed investigating the biochemical composition at the cellular level. Chemical mapping on whole tissue sections was further performed using a FTIR microscope equipped with a laboratory-based infrared source. The variance was addressed by principal component analysis. Results Profound alterations of the biochemical composition of the pathological liver were demonstrated by FTIR microspectroscopy. Indeed, dramatic changes were observed in lipids, proteins and sugars highlighting the metabolic reprogramming in carcinogenesis. Quantifiable spectral markers were characterized by calculating ratios of areas under specific bands along the infrared spectrum. These markers allowed the discrimination of cirrhotic nodules, dysplastic lesions and HCC. Finally, the spectral markers can be measured using a laboratory FTIR microscope that may be easily implemented at the hospital. Conclusion Metabolic reprogramming in liver carcinogenesis can constitute a signature easily detectable using FTIR microspectroscopy for the diagnosis of precancerous and cancerous lesions. Electronic supplementary material The online version of this article (doi:10.1186/s12967-016-0763-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Chengyuan Peng
- Inserm, Unité 1193, 94800, Villejuif, France. .,Univ Paris-Sud, UMR-S1193, 94800, Villejuif, France.
| | - Slávka Kaščáková
- Inserm, Unité 1193, 94800, Villejuif, France. .,Univ Paris-Sud, UMR-S1193, 94800, Villejuif, France.
| | - Franck Chiappini
- Inserm, Unité 1193, 94800, Villejuif, France. .,Univ Paris-Sud, UMR-S1193, 94800, Villejuif, France.
| | - Natalia Olaya
- Instituto Nacional de Cancerologia, Bogota, Colombia.
| | | | | | - Didier Samuel
- Inserm, Unité 1193, 94800, Villejuif, France. .,Univ Paris-Sud, UMR-S1193, 94800, Villejuif, France. .,Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, 94800, Villejuif, France.
| | - Paul Dumas
- SOLEIL Synchrotron, 91192, Gif sur Yvette, France.
| | - Catherine Guettier
- Inserm, Unité 1193, 94800, Villejuif, France. .,Univ Paris-Sud, UMR-S1193, 94800, Villejuif, France. .,Service d'Anatomopathologie, AP-HP Hôpital Bicêtre, 94275, Le Kremlin-Bicêtre, France.
| | - François Le Naour
- Inserm, Unité 1193, 94800, Villejuif, France. .,Univ Paris-Sud, UMR-S1193, 94800, Villejuif, France.
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24
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Sciarra A, Di Tommaso L, Nakano M, Destro A, Torzilli G, Donadon M, Maggioni M, Bosari S, Bulfamante G, Matsuda M, Fujii H, Ichikawa T, Morisaka H, Sano K, Ichikawa S, Roncalli M. Morphophenotypic changes in human multistep hepatocarcinogenesis with translational implications. J Hepatol 2016; 64:87-93. [PMID: 26343958 DOI: 10.1016/j.jhep.2015.08.031] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 08/11/2015] [Accepted: 08/25/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Human hepatocarcinogenesis in cirrhosis is thought to be multistep and characterized by a spectrum of nodular lesions, ranging from low to high grade dysplastic nodules (LGDN and HGDN) to early and progressed hepatocellular carcinoma (eHCC and pHCC). The aim of this study was to investigate the morphophenotypical changes of this sequence and their potential translational significance. METHODS We scored the vascular profile, ductular reaction/stromal invasion and overexpression of five biomarkers (GPC3, HSP70, GS, CHC, and EZH2), in a series of 100 resected nodules (13 LGDN, 16 HGDN, 42 eHCC and 29 small pHCC). RESULTS The score separated the four groups of nodules as individual entities (p<0.01). In the sequence, biomarker's overexpression progressively increased with parallel decrease of ductular reaction; the vascular remodeling started very early (LGDN) but did not further develop in a proportion of HCC. eHCC was the most heterogeneous entity, with marginal overlap with HGDN and pHCC. Liver environment (fibrosis, etiology) did not impact on the phenotype of the different nodules. A subclass of eHCC (16/42) without evidence of stromal invasion was identified, suggesting a "preinvasive stage" (p<0.05). For diagnosis, the application of four and five biomarkers (rather than the usual three) improved the sensitivity of the assay for the detection of eHCC (76% and 93% vs. 52%); biomarkers in alternative combinations, and also increased the sensitivity of the assay (GS+CHC+EZH2: 76%; GS+CHC+EZH2+HSP70: 90%). CONCLUSIONS This study supports the multistep nature of human hepatocarcinogenesis, and suggests that eHCC is more heterogeneous than previously thought. This provides further information of the potential translational significance into clinical practice.
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Affiliation(s)
- Amedeo Sciarra
- Pathology Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, School of Medicine, Milan, Italy
| | - Luca Di Tommaso
- Pathology Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, School of Medicine, Milan, Italy
| | - Masayuki Nakano
- Pathology Department, Shonan Fujisawa Tokushukai Hospital, Fujisawa, Kanagawa, Japan
| | - Annarita Destro
- Pathology Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Guido Torzilli
- Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, School of Medicine, Milan, Italy; Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Matteo Donadon
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Marco Maggioni
- Pathology, Fondazione IRCCS Ca' Granda Ospedale Policlinico and University of Milan, School of Medicine, Milan, Italy
| | - Silvano Bosari
- Pathology, Fondazione IRCCS Ca' Granda Ospedale Policlinico and University of Milan, School of Medicine, Milan, Italy
| | - Gaetano Bulfamante
- Department of Health Sciences, San Paolo Hospital Medical School, Milan, Italy
| | - Masanori Matsuda
- First Department of Surgery, University of Yamanashi, Yamanashi, Japan
| | - Hideki Fujii
- First Department of Surgery, University of Yamanashi, Yamanashi, Japan
| | - Tomoaki Ichikawa
- Department of Radiology, University of Yamanashi, Yamanashi, Japan
| | | | - Katsuhiro Sano
- Department of Radiology, University of Yamanashi, Yamanashi, Japan
| | | | - Massimo Roncalli
- Pathology Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, School of Medicine, Milan, Italy.
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25
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Ieni A, Barresi V, Todaro P, Caruso RA, Tuccari G. Cell-block procedure in endoscopic ultrasound-guided-fine-needle-aspiration of gastrointestinal solid neoplastic lesions. World J Gastrointest Endosc 2015; 7:1014-1022. [PMID: 26322154 PMCID: PMC4549658 DOI: 10.4253/wjge.v7.i11.1014] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2015] [Revised: 07/01/2015] [Accepted: 08/03/2015] [Indexed: 02/05/2023] Open
Abstract
In the present review we have analyzed the clinical applications of endoscopic ultrasound-guided-fine-needle-aspiration (EUS-FNA) and the methodological aspects obtained by cell-block procedure (CBP) in the diagnostic approach to the gastrointestinal neoplastic pathology. CBP showed numerous advantages in comparison to the cytologic routine smears; in particular, better preservation of cell architecture, achievement of routine haematoxylin-eosin staining equivalent to histological slides and possibility to perform immunohistochemistry or molecular analyses represented the most evident reasons to choose this method. Moreover, by this approach, the differential diagnosis of solid gastrointestinal neoplasias may be more easily achieved and the background of contaminant non-neoplastic gastrointestinal avoided. Finally, biological samples collected by EUS-FNA CBP-assisted should be investigated in order to identify and quantify further potential molecular markers.
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26
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Mustafa GM, Larry D, Petersen JR, Elferink CJ. Targeted proteomics for biomarker discovery and validation of hepatocellular carcinoma in hepatitis C infected patients. World J Hepatol 2015; 7:1312-1324. [PMID: 26052377 PMCID: PMC4450195 DOI: 10.4254/wjh.v7.i10.1312] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Revised: 10/24/2014] [Accepted: 03/09/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC)-related mortality is high because early detection modalities are hampered by inaccuracy, expense and inherent procedural risks. Thus there is an urgent need for minimally invasive, highly specific and sensitive biomarkers that enable early disease detection when therapeutic intervention remains practical. Successful therapeutic intervention is predicated on the ability to detect the cancer early. Similar unmet medical needs abound in most fields of medicine and require novel methodological approaches. Proteomic profiling of body fluids presents a sensitive diagnostic tool for early cancer detection. Here we describe such a strategy of comparative proteomics to identify potential serum-based biomarkers to distinguish high-risk chronic hepatitis C virus infected patients from HCC patients. In order to compensate for the extraordinary dynamic range in serum proteins, enrichment methods that compress the dynamic range without surrendering proteome complexity can help minimize the problems associated with many depletion methods. The enriched serum can be resolved using 2D-difference in-gel electrophoresis and the spots showing statistically significant changes selected for identification by liquid chromatography-tandem mass spectrometry. Subsequent quantitative verification and validation of these candidate biomarkers represent an obligatory and rate-limiting process that is greatly enabled by selected reaction monitoring (SRM). SRM is a tandem mass spectrometry method suitable for identification and quantitation of target peptides within complex mixtures independent on peptide-specific antibodies. Ultimately, multiplexed SRM and dynamic multiple reaction monitoring can be utilized for the simultaneous analysis of a biomarker panel derived from support vector machine learning approaches, which allows monitoring a specific disease state such as early HCC. Overall, this approach yields high probability biomarkers for clinical validation in large patient cohorts and represents a strategy extensible to many diseases.
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27
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Huh J, Kim KW, Kim J, Yu E. Pathology-MRI Correlation of Hepatocarcinogenesis: Recent Update. J Pathol Transl Med 2015; 49:218-29. [PMID: 26018513 PMCID: PMC4440933 DOI: 10.4132/jptm.2015.04.15] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 04/14/2015] [Indexed: 02/07/2023] Open
Abstract
Understanding the important alterations during hepatocarcinogenesis as well as the characteristic magnetic resonance imaging (MRI) and histopathological features will be helpful for managing patients with chronic liver disease and hepatocellular carcinoma. Recent advances in MRI techniques, such as fat/iron quantification, diffusion-weighted images, and gadoxetic acid-enhanced MRI, have greatly enhanced our understanding of hepatocarcinogenesis.
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Affiliation(s)
- Jimi Huh
- Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Won Kim
- Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea ; Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jihun Kim
- Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea ; Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eunsil Yu
- Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea ; Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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28
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Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet 2015; 47:505-511. [PMID: 25822088 PMCID: PMC4587544 DOI: 10.1038/ng.3252] [Citation(s) in RCA: 1324] [Impact Index Per Article: 132.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 02/24/2015] [Indexed: 11/08/2022]
Abstract
Genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. Analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereas FGF3, FGF4, FGF19 or CCND1 amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)-approved drugs. In conclusion, we identified risk factor-specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.
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29
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Nault JC, Calderaro J, Di Tommaso L, Balabaud C, Zafrani ES, Bioulac-Sage P, Roncalli M, Zucman-Rossi J. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. Hepatology 2014; 60:1983-92. [PMID: 25123086 DOI: 10.1002/hep.27372] [Citation(s) in RCA: 254] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Accepted: 07/30/2014] [Indexed: 12/07/2022]
Abstract
UNLABELLED Genetic determinants of the early steps of carcinogenesis on cirrhosis are still poorly understood. We aimed to evaluate the occurrence of telomerase reverse transcriptase (TERT) promoter mutations in the transformation of cirrhotic nodules into hepatocellular carcinoma (HCC). We analyzed a series of 268 liver samples, including 96 nodules developed in 58 patients with cirrhosis and 114 additional cirrhosis. All samples were screened for TERT promoter mutations, and in 31 nodules, for 10 genes recurrently mutated in HCC. Immunohistochemistry (IHC) analyses were performed for glypican 3, glutamine synthase, and heat shock protein 70. Six liver pathologists reviewed all the samples. Among The 96 nodules, 88 were firmly diagnosed as low-grade dysplastic nodules (LGDNs; 32 cases), high-grade dysplastic nodules (HGDNs; 16 cases), early HCC (eHCC; 23 cases), or small and progressed HCC in 17 cases. The agreement between the initial diagnosis from pathological report and the final expert consensus report was moderate for the diagnosis of benign versus malignant nodules (weighted kappa = 0.530). TERT promoter mutations were highly related to the step-wise hepatocarcinogenesis because mutations were identified in 6% of LGDNs, 19% of HGDNs, 61% of eHCCs, and 42% of small and progressed HCC. TERT promoter mutation is the most frequent molecular alteration in eHCC given that the IHC criteria for diagnosis of malignancy were found in only 39% of the cases. TERT promoter mutation was also the earliest genetic alteration because mutations in 10 other genes were only identified in 28% of the small and progressed HCC. CONCLUSION Frequency of TERT promoter mutations rapidly increases during the different steps of the transformation of premalignant lesions into HCC on cirrhosis. Consequently, somatic TERT promoter mutation is a new biomarker predictive of transformation of premalignant lesions into HCC.
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Affiliation(s)
- Jean Charles Nault
- Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, IUH, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France; Université Paris Diderot, Paris, France; APHP, Hôpitaux Universitaires Paris-Seine Saint-Denis, Site Jean Verdier, Pôle d'Activité Cancérologique Spécialisée, Service d'Hépatologie, Bondy, France
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30
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Schlageter M, Terracciano LM, D’Angelo S, Sorrentino P. Histopathology of hepatocellular carcinoma. World J Gastroenterol 2014; 20:15955-15964. [PMID: 25473149 PMCID: PMC4239483 DOI: 10.3748/wjg.v20.i43.15955] [Citation(s) in RCA: 164] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 05/09/2014] [Accepted: 07/22/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is currently the sixth most common type of cancer with a high mortality rate and an increasing incidence worldwide. Its etiology is usually linked to environmental, dietary or life-style factors. HCC most commonly arises in a cirrhotic liver but interestingly an increasing proportion of HCCs develop in the non-fibrotic or minimal fibrotic liver and a shift in the underlying etiology can be observed. Although this process is yet to be completely understood, this changing scenario also has impact on the material seen by pathologists, presenting them with new diagnostic dilemmas. Histopathologic criteria for diagnosing classical, progressed HCC are well established and known, but with an increase in detection of small and early HCCs due to routine screening programs, the diagnosis of these small lesions in core needle biopsies poses a difficult challenge. These lesions can be far more difficult to distinguish from one another than progressed HCC, which is usually a clear cut hematoxylin and eosin diagnosis. Furthermore lesions thought to derive from progenitor cells have recently been reclassified in the WHO. This review summarizes recent developments and tries to put new HCC biomarkers in context with the WHOs reclassification. Furthermore it also addresses the group of tumors known as combined hepatocellular-cholangiocellular carcinomas.
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MESH Headings
- Animals
- Bile Duct Neoplasms/chemistry
- Bile Duct Neoplasms/classification
- Bile Duct Neoplasms/epidemiology
- Bile Duct Neoplasms/pathology
- Bile Ducts, Intrahepatic/chemistry
- Bile Ducts, Intrahepatic/pathology
- Biomarkers, Tumor/analysis
- Biopsy
- Carcinoma, Hepatocellular/chemistry
- Carcinoma, Hepatocellular/classification
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/pathology
- Cholangiocarcinoma/chemistry
- Cholangiocarcinoma/classification
- Cholangiocarcinoma/epidemiology
- Cholangiocarcinoma/pathology
- Diagnosis, Differential
- Humans
- Immunohistochemistry
- Liver Neoplasms/chemistry
- Liver Neoplasms/classification
- Liver Neoplasms/epidemiology
- Liver Neoplasms/pathology
- Neoplasm Grading
- Neoplasms, Complex and Mixed/chemistry
- Neoplasms, Complex and Mixed/classification
- Neoplasms, Complex and Mixed/epidemiology
- Neoplasms, Complex and Mixed/pathology
- Precancerous Conditions/chemistry
- Precancerous Conditions/classification
- Precancerous Conditions/epidemiology
- Precancerous Conditions/pathology
- Predictive Value of Tests
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31
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Luchini C, Capelli P, Fassan M, Simbolo M, Mafficini A, Pedica F, Ruzzenente A, Guglielmi A, Corbo V, Scarpa A. Next-generation histopathologic diagnosis: a lesson from a hepatic carcinosarcoma. J Clin Oncol 2014; 32:e63-e66. [PMID: 24493719 DOI: 10.1200/jco.2012.47.5855] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
- Claudio Luchini
- Miriam Cherubini Centre for Applied Research on Cancer, University of Verona, Verona, Italy
| | - Paola Capelli
- Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Matteo Fassan
- Miriam Cherubini Centre for Applied Research on Cancer, University of Verona, Verona, Italy
| | - Michele Simbolo
- Miriam Cherubini Centre for Applied Research on Cancer, University of Verona, Verona, Italy
| | - Andrea Mafficini
- Miriam Cherubini Centre for Applied Research on Cancer, University of Verona, Verona, Italy
| | - Federica Pedica
- Miriam Cherubini Centre for Applied Research on Cancer, University of Verona, Verona, Italy
| | - Andrea Ruzzenente
- Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Alfredo Guglielmi
- Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Vincenzo Corbo
- Miriam Cherubini Centre for Applied Research on Cancer, University of Verona, Verona, Italy
| | - Aldo Scarpa
- Azienda Ospedaliera Universitaria Integrata di Verona; Miriam Cherubini Centre for Applied Research on Cancer, University of Verona, Verona, Italy
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32
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El-Ashmawy NE, El-Bahrawy HA, Shamloula MM, El-Feky OA. Biochemical/metabolic changes associated with hepatocellular carcinoma development in mice. Tumour Biol 2014; 35:5459-66. [PMID: 24523022 DOI: 10.1007/s13277-014-1714-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Accepted: 01/29/2014] [Indexed: 01/20/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality after lung and stomach cancers. This work was undertaken to investigate some of the biochemical mediators/pathways associated with or implicated in the pathogenesis of HCC. Male albino mice were classified into two groups: normal control group and HCC group. Early stage HCC was induced by injection of diethylnitrosamine (DEN) i.p. 200 mg/kg as a single dose, and after 2 weeks, the mice were given i.p. injection of thioacetamide (TAA) 100 mg/kg twice per week for 4 weeks. Mice were left for further 2 weeks without any treatment, after which, mice were sacrificed; blood and liver samples were collected. Serum was used for determination of activities of glucose-6-phosphate dehydrogenase (G6PDH) and aldolase as well as levels of insulin-like growth factor-1 (IGF-1) and epithelial cadherin (E-cadherin). One portion of the liver was used for histopathological examination and immunohistochemical staining of the tumor suppressor p53 protein. Another portion of the liver was used for determination of citrate synthase activity. Induction of HCC in mice resulted in significant increase in G6PDH and aldolase activities, and E-cadherin level, but significant decrease in IGF-1. HCC mice group showed moderate expression of p53 protein. These results suggest that the molecular pathogenesis of HCC in mice involves reduction of serum level of IGF-1 and increased serum level of E-cadherin accompanied by dysregulation of p53 protein expression. HCC was also associated with reprogrammed metabolic profile shifted toward increased glycolysis and lipogenesis.
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Affiliation(s)
- Nahla E El-Ashmawy
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
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Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer. The incidence and mortality of HCC are increasing in most Western countries as a result of an ageing cohort infected with chronic hepatitis C, and are expected to continue to rise as a consequence of the obesity epidemic. Chemopreventive strategies aimed at decreasing the risk or delaying the onset of HCC are needed. Universal immunization against HBV and antiviral therapy against HBV and HCV in patients with established disease has consistently been associated with reduced HCC risk, especially in patients who achieve sustained virologic response. However, the cost-effectiveness of antiviral therapy for primary HCC prevention is not known. Several commonly prescribed medications seem promising as chemopreventive agents against HCC, including statins, antidiabetic medications and aspirin. Dietary agents such as coffee, vitamin E and fish oil as well as phytochemicals might also be associated with reduced risk of HCC. Though randomized controlled trials are ideally needed to firmly establish efficacy, such chemoprevention trials are logistically and ethically challenging. Well-designed, prospective, population-based cohort studies might provide the best evidence for chemopreventive efficacy of these agents.
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34
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Bedossa P, Burt AD, Brunt EM, Callea F, Clouston AD, Dienes HP, Goodman ZD, Gouw ASH, Hubscher SG, Roberts EA, Roskams T, Terracciano L, Tiniakos DG, Torbenson MS, Wanless IR. Well-differentiated hepatocellular neoplasm of uncertain malignant potential: proposal for a new diagnostic category. Hum Pathol 2013; 45:658-60. [PMID: 24529331 DOI: 10.1016/j.humpath.2013.09.020] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 09/27/2013] [Indexed: 12/16/2022]
Affiliation(s)
- Pierre Bedossa
- Hopital Beaujon, Service d'Anatomie Pathologique, 92118 Clichy Cedex, France
| | - Alastair D Burt
- University of Adelaide School of Medicine, South Australia 5005, Australia
| | - Elizabeth M Brunt
- Washington University School of Medicine, Department of Pathology and Immunology, St Louis, MO 63110, USA
| | | | - Andrew D Clouston
- Centre for Liver Disease Research, School of Medicine (Southern), University of Queensland, Princess Alexandra Hospital, Ipswich Rd Woolloongabba 4109, Australia.
| | - Hans-Peter Dienes
- Institute of Pathology, Meduniwien, Medical University of Vienna, 1090 Wien, Austria
| | - Zachary D Goodman
- Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA 22042, USA
| | - Annette S H Gouw
- Department of Pathology and Medical Biology, University Medical Center Groningen, 9700 RB Groningen, The Netherlands
| | - Stefan G Hubscher
- Department of Cellular Pathology, Level-1, Queen Elizabeth Hospital Birmingham, Birmingham B15 2WB, United Kingdom
| | - Eve A Roberts
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario M5G1X8, Canada
| | - Tania Roskams
- Laboratory of Histo-Cytochem, Univ. Hospital St. Rafael, 3000 Leuven, Belgium
| | - Luigi Terracciano
- Institute of Pathology, University of Basel, 4003 Basel, Switzerland
| | - Dina G Tiniakos
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom
| | | | - Ian R Wanless
- Department of Pathology, Dalhousie University, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia B3H 1V8, Canada
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Minicis SD, Kisseleva T, Francis H, Baroni GS, Benedetti A, Brenner D, Alvaro D, Alpini G, Marzioni M. Liver carcinogenesis: rodent models of hepatocarcinoma and cholangiocarcinoma. Dig Liver Dis 2013; 45. [PMID: 23177172 PMCID: PMC3716909 DOI: 10.1016/j.dld.2012.10.008] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Hepatocellular carcinoma and cholangiocarcinoma are primary liver cancers, both represent a growing challenge for clinicians due to their increasing morbidity and mortality. In the last few years a number of in vivo models of hepatocellular carcinoma and cholangiocarcinoma have been developed. The study of these models is providing a significant contribution in unveiling the pathophysiology of primary liver malignancies. They are also fundamental tools to evaluate newly designed molecules to be tested as new potential therapeutic agents in a pre-clinical set. Technical aspects of each model are critical steps, and they should always be considered in order to appropriately interpret the findings of a study or its planning. The purpose of this review is to describe the technical and experimental features of the most significant rodent models, highlighting similarities or differences between the corresponding human diseases. The first part is dedicated to the discussion of models of hepatocellular carcinoma, developed using toxic agents, or through dietary or genetic manipulations. In the second we will address models of cholangiocarcinoma developed in rats or mice by toxin administration, genetic manipulation and/or bile duct incannulation or surgery. Xenograft or syngenic models are also proposed.
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Affiliation(s)
- Samuele De Minicis
- Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy
| | - Tatiana Kisseleva
- Division of Gastroenterology, Department of Medicine, University of California San Diego, School of Medicine, CA, United States
| | - Heather Francis
- Division Research, Central Texas Veterans Health Care System, Scott & White Digestive Disease Research Center, Department of Medicine, Division Gastroenterology, Scott & White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, United States
| | | | - Antonio Benedetti
- Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy
| | - David Brenner
- Division of Gastroenterology, Department of Medicine, University of California San Diego, School of Medicine, CA, United States
| | - Domenico Alvaro
- Division of Gastroenterology, Polo Pontino, Università degli Studi “La Sapienza”, Rome, Italy
| | - Gianfranco Alpini
- Division of Gastroenterology, Department of Medicine, University of California San Diego, School of Medicine, CA, United States,Co-corresponding author. Tel.: +1 254 743 1041/1044; fax: +1 254 743 0378/0555. (M. Marzioni)
| | - Marco Marzioni
- Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy,Corresponding author at: Department of Gastroenterology, Università Politecnica delle Marche, Nuovo Polo Didattico, III Piano, Via Tronto 10, 60020 Ancona, Italy. Tel.: +39 0712206043; fax: +39 0712206044
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Choi JW, Lee JM, Kim SJ, Yoon JH, Baek JH, Han JK, Choi BI. Hepatocellular Carcinoma: Imaging Patterns on Gadoxetic Acid–enhanced MR Images and Their Value as an Imaging Biomarker. Radiology 2013; 267:776-86. [DOI: 10.1148/radiol.13120775] [Citation(s) in RCA: 135] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Marginean EC, Gown AM, Jain D. Diagnostic Approach to Hepatic Mass Lesions and Role of Immunohistochemistry. Surg Pathol Clin 2013; 6:333-365. [PMID: 26838978 DOI: 10.1016/j.path.2013.03.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
This review provides an overview of various hepatic mass lesions and a practical diagnostic approach, including most recent immunohistochemical stains used in clinical practice. A wide variety of benign and malignant lesions present as hepatic masses, and the differential diagnosis varies. In cirrhotic liver, the commonest malignant tumor is hepatocellular carcinoma (HCC), which needs to be differentiated from macroregenerative nodules, dysplastic nodules, and other tumors. The differential diagnosis of lesions in noncirrhotic liver in younger patients includes hepatic adenoma (HA), focal nodular hyperplasia (FNH), HCC, and other primary hepatic neoplasms and metastases. In older populations, metastases remain the most common mass lesions.
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Affiliation(s)
- Esmeralda Celia Marginean
- Department of Pathology, The Ottawa Hospital, Ottawa University, CCW- Room 4251, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada.
| | | | - Dhanpat Jain
- Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8023, USA
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Fassan M, Baffa R, Kiss A. Advanced precancerous lesions within the GI tract: the molecular background. Best Pract Res Clin Gastroenterol 2013; 27:159-169. [PMID: 23809238 DOI: 10.1016/j.bpg.2013.03.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Revised: 02/14/2013] [Accepted: 03/08/2013] [Indexed: 01/31/2023]
Abstract
The mainstream carcinogenic processes involved within the gastrointestinal tract are characterized by phenotypic multistep progression cascades that eventually result in full-blown cancers. In this scenario, the understanding of the molecular dysregulations underlying the precancerous lesions is increasing but still remains incomplete. However, in recent years, the enthusiastic rise of innovative technologies (i.e., next-generation sequencing, high-throughput microarray analysis, mass spectrometry based proteomics) and the unexpected discovery of new classes of biomarkers (i.e., miRNA, long-noncoding RNAs) prompted new strength in the exploration of the accurate and comprehensive molecular characterization of premalignant and malignant neoplastic lesions. The challenge ahead lies in the reliable identification of disease progression-specific targets to enable molecular testing in the clinical management of the secondary prevention of gastrointestinal cancers.
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Affiliation(s)
- Matteo Fassan
- Department of Medicine DIMED, Surgical Pathology & Cytopathology Unit, University of Padua, 35121 Padua, Italy.
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Primary liver sarcomatous carcinoma: report of two cases and review of the literature. Pathol Res Pract 2013; 209:249-54. [PMID: 23484778 DOI: 10.1016/j.prp.2013.01.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Revised: 11/28/2012] [Accepted: 01/02/2013] [Indexed: 01/12/2023]
Abstract
Primary liver sarcomatous carcinomas (PLSCs) are very aggressive tumors. They are characterized by a fast clinical course, and therefore need a prompt histological diagnosis. Here, we report two cases of PLSC. One arises in a non-cirrhotic liver and the other in cirrhosis, with differences in onset and histological features. Special emphasis is put on the expression of albumin and HCC markers, and their possible usefulness in the diagnosis. The English literature of the last 20 years was revised (92 cases). Immunohistochemistry was performed manually or automatically; in situ hybridization (ISH) technique for albumin mRNA detection was carried out. The sarcomatoid components in both cases were immunoreactive for K8/18, Glutamine Synthetase and EZH2, and negative for Glypican 3, SMA, caldesmon, desmin, DOG-1, CD34, CD31, CD117, CD56, and alpha-fetoprotein. The detection of albumin mRNA by ISH was negative in the sarcomatoid component in both cases. PLSC represents a diagnostic challenge for pathologists, especially in its "pure" form: neither albumin mRNA detection nor HCC markers are useful for the diagnosis: positivity for K8/18 and the negativity for the mesenchymal markers seem to represent the main tools for the histological diagnosis.
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Song YJ, Liu XT, Feng LL, Wang X, Bai HF, Tian MQ, Zhang W, Zu CZ, Zhao X, Cai DY, Wang YQ. Definition of diethylnitrosamine-induced rat hepatic precancerous lesions with atypia index. Shijie Huaren Xiaohua Zazhi 2012; 20:2562-2569. [DOI: 10.11569/wcjd.v20.i27.2562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To define diethylnitrosamine-induced hepatic precancerous lesions with atypia index in rats.
METHODS: After normalization of the body weight, 100 male Wistar rats were equally and randomly divided into five groups and were intraperitoneally injected with different doses of diethylnitrosamine in normal saline (0, 25, 50, 75, 100 mg/kg) twice weekly. The rats in each group were further divided into 10 subgroups with end-points ranging from d00 to d126 with an interval of 14 days. Liver samples were fixed, sectioned, and stained with hematoxylin and eosin. After being evaluated pathologically, the volume ratios of portal triad (R1), hepatic cord (R2) and hepatic nucleus (R3) were obtained under an Olympus microscope with 10-, 20-, and 40-amplification, respectively, by use of Image-Pro Plus software. Hepatic mitotic figures were counted under high magnification. The atypia index of hepatocytes was calculated as the volume ratio of nucleus to cytoplasm in precancerous lesions using the formula [(1-R1)-1∙(R2)-1∙(R3)]. By using Graph Pad Prism version 4 for Windows, the half effective durations and the area under curve of the atypia indexes were regressed in Sigmoidal time-response (variable slope) from the logarithm of end-point hours [11.4 + Time (d) ×24 h/d] for each of 5 doses, so did the half effective doses of the area under curves from the logarithm of dosages [10 + Dose (mg/kg) ×1000 (μg/kg)]. The atypia indexes were regressed linearly with the mitotic counts to confirm their specificity in predicting hepatic carcinogenesis.
RESULTS: From the atypia index of hepatocytes (corrected volume ratio of nucleus to cytoplasm), the half effective durations of diethylnitrosamine at 0, 25, 50, 75, and 100 mg/kg to induce hepatic precancerous lesions were 70 347, 1 734, 1 536, 1 530 and 1 183 h, respectively. The areas under curves were 0.0064, 0.0084, 0.0123, 0.0165 and 0.0167 [(atypia index) × log(h)], respectively. From the area under curve, the half effective dose of diethylnitrosamine to induce hepatic precancerous lesions was 48.225 mg/kg. The atypia indexes in rats treated with 50 mg/kg diethylnitrosamine correlated positively with mitotic counts in hepatic precancerous lesions (y = 0.0023x-0.0056, r = 0.9217, n = 10, P < 0.01).
CONCLUSION: The atypia index might be used to define hepatic precancerous lesions. A rat model of hepatic precancerous lesions could be replicated by intraperitoneal injection of diethylnitrosamine at a dose of 48.225 mg/kg twice a week for 9 wk. The specificity of the model to predict hepatic carcinogenesis can be confirmed with mitotic counts in hepatic precancerous lesions.
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Aghemo A, Colombo M. Hepatocellular carcinoma in chronic hepatitis C: from bench to bedside. Semin Immunopathol 2012; 35:111-20. [DOI: 10.1007/s00281-012-0330-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Accepted: 07/01/2012] [Indexed: 02/07/2023]
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