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Zhu Z, Hu S, Zhong X, Zhang Y, Wu X, Lin J, Chen F. EFNA5 suppresses cell proliferation and tumor metastasis in hepatoma via epithelial-to-mesenchymal transition. Discov Oncol 2024; 15:572. [PMID: 39424684 PMCID: PMC11489415 DOI: 10.1007/s12672-024-01454-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 10/11/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND EphrinA5 belongs to a subclass of ephrin ligands. Abnormal signal transduction of EFNA5 shows a relationship to the development of various tumors. In this study, we explored the level of EFNA5 in hepatoma cells and the influence of up regulation of EFNA5 expression level on the proliferation, invasion, and migration of HepG2 and LM3 cells. Additionally, this work focused on examining its possible mechanism of action, and future impacts on clinical practice. METHODS Immunohistochemistry was utilized to explore the connection between EFNA5 and hepatoma. Real-time quantitative polymerase chain reaction was used for determining the expression levels of EFNA5 in several hepatoma cell lines and normal hepatocytes. Cells were transfected with a pCMV3-EFNA5-flag plasmid and an EFNA5 plasmid. The expression efficiency of EFNA5 was identified through qRT-PCR. For the purpose of further identifying cell proliferation, the Cell Counting Kit-8 assay was applied. To identify changes of cell migration and invasion ability, Transwell and Boyden tests were utilized. Western blot was employed to identify the expressions mof EFNA5 and possible downstream molecules. RESULTS Data acquired from The Cancer Genome Atlas demonstrated that the level of EFNA5 in hepatoma was significantly downregulated in relative to the normal hepatocytes (P < 0.05). Upregulation of EFNA5 expression in hepatoma cells hindered the proliferative, invasive, and migratory ability of cells (P < 0.05). Additionally, EFNA5 downregulated the level of epithelial-mesenchymal transition-related molecules and EGFR. CONCLUSIONS The expression of EFNA5 was low in hepatoma cells. An increase in EFNA5 levels hinders the proliferation, invasion, and migration of hepatoma cells. These effects may occur through inhibition of hepatoma epithelial-mesenchymal transition by EFNA5. Moreover, the study on the mechanisms of proliferation, invasion and metastasis of hepatoma provides a novel theoretical basis, and may influence the clinical practice of tumor treatment in the future.
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Affiliation(s)
- Zhiqin Zhu
- Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, 510315, China
| | - Shulu Hu
- Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Xingyi Zhong
- Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, 510315, China
| | - Yangfeng Zhang
- Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, 510315, China
| | - Xiuqiong Wu
- Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, 510315, China
| | - Junhao Lin
- Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, 510315, China.
| | - Fengsheng Chen
- Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, 510315, China.
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Omar MA, Omran MM, Farid K, Tabll AA, Shahein YE, Emran TM, Petrovic A, Lucic NR, Smolic R, Kovac T, Smolic M. Biomarkers for Hepatocellular Carcinoma: From Origin to Clinical Diagnosis. Biomedicines 2023; 11:1852. [PMID: 37509493 PMCID: PMC10377276 DOI: 10.3390/biomedicines11071852] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/15/2023] [Accepted: 06/21/2023] [Indexed: 07/30/2023] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) and HCC-related deaths has increased over the last few decades. There are several risk factors of HCC such as viral hepatitis (B, C), cirrhosis, tobacco and alcohol use, aflatoxin-contaminated food, pesticides, diabetes, obesity, nonalcoholic fatty liver disease (NAFLD), and metabolic and genetic diseases. Diagnosis of HCC is based on different methods such as imaging ultrasonography (US), multiphasic enhanced computed tomography (CT), magnetic resonance imaging (MRI), and several diagnostic biomarkers. In this review, we examine the epidemiology of HCC worldwide and in Egypt as well as risk factors associated with the development of HCC and, finally, provide the updated diagnostic biomarkers for the diagnosis of HCC, particularly in the early stages of HCC. Several biomarkers are considered to diagnose HCC, including downregulated or upregulated protein markers secreted during HCC development, circulating nucleic acids or cells, metabolites, and the promising, recently identified biomarkers based on quantitative proteomics through the isobaric tags for relative and absolute quantitation (iTRAQ). In addition, a diagnostic model used to improve the sensitivity of combined biomarkers for the diagnosis of early HCC is discussed.
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Affiliation(s)
- Mona A. Omar
- Chemistry Department, Faculty of Science, Damietta University, New Damietta 34517, Egypt;
| | - Mohamed M. Omran
- Chemistry Department, Faculty of Science, Helwan University, Cairo 11795, Egypt;
| | - Khaled Farid
- Tropical Medicine Department, Faculty of Medicine, Mansoura University, Mansoura 35524, Egypt;
| | - Ashraf A. Tabll
- Microbial Biotechnology Department, National Research Centre, Cairo 12622, Egypt
- Immunology Department, Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 11517, Egypt
| | - Yasser E. Shahein
- Molecular Biology Department, National Research Centre, Cairo 12622, Egypt
| | - Tarek M. Emran
- Clinical Pathology Department, Faculty of Medicine, Al-Azhar University, New Damietta 34517, Egypt;
| | - Ana Petrovic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (A.P.); (N.R.L.); (R.S.); (T.K.)
| | - Nikola R. Lucic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (A.P.); (N.R.L.); (R.S.); (T.K.)
| | - Robert Smolic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (A.P.); (N.R.L.); (R.S.); (T.K.)
| | - Tanja Kovac
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (A.P.); (N.R.L.); (R.S.); (T.K.)
| | - Martina Smolic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (A.P.); (N.R.L.); (R.S.); (T.K.)
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Zhou C, Zhu D, Zhou S, Wang H, Huang M. Screening differential circular RNA expression profiles and the potential role of hsa_circ_0085465 in liver cancer. J Cancer Res Ther 2023; 19:548-555. [PMID: 37470573 DOI: 10.4103/jcrt.jcrt_1868_20] [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: 07/21/2023]
Abstract
Aims This study aimed to screen the circular RNAs (circRNAs) that are differentially expressed between liver cancer and paired paracarcinoma tissues and then elucidate their role in cancer progression. Materials and Methods High-throughput sequencing of cancer and paired paracarcinoma tissues was followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the parental genes of the differentially expressed circRNAs, which were also verified via real-time quantitative polymerase chain reaction analysis of the tissues. In addition, the function of selected circRNAs was determined using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4- sulfophenyl)-2H-tetrazolium (MTS) and transwell assays. Results Total 218 and 121 circRNAs were differentially upregulated and downregulated, respectively; these were mainly enriched with GO and KEGG terms related to biological functions. From five representatives of the differentially expressed circRNAs, we selected hsa_circ_0085465 for further analysis, discovering that its overexpression promoted the proliferation, migration, and invasion of 97 L cells. Conclusion Taken together, our results suggest that hsa_circ_0085465 is relevant to liver cancer progression.
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Affiliation(s)
- Churen Zhou
- Department of Interventional Radiology Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Duo Zhu
- Department of Interventional Radiology Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Sibin Zhou
- Department of Interventional Radiology Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Haofan Wang
- Department of Interventional Radiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Mingsheng Huang
- Department of Interventional Radiology Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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He M, Liao Q, Liu D, Dai X, Shan M, Yang M, Zhang Y, Zhai L, Chen L, Xiang L, He M, Li S, Chen A, Sun L, Lian J. Dihydroergotamine mesylate enhances the anti-tumor effect of sorafenib in liver cancer cells. Biochem Pharmacol 2023; 211:115538. [PMID: 37019185 DOI: 10.1016/j.bcp.2023.115538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/12/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023]
Abstract
Liver cancer is the most common and frequentlyoccurring cancer. In addition to radiotherapy, chemotherapy and surgery are recommended as part of liver cancer treatment. The efficacy of sorafenib and sorafenib-based combination treatment against tumors has been verified. Although, clinical trials have revealed that some individuals are not sensitive to sorafenib therapy, and current therapeutic approaches are ineffective. Consequently, it is urgent to explore effective drug combinations and innovative techniques for increasing the effectiveness of sorafenib in the curing of liver tumor. Herein, we show that dihydroergotamine mesylate (DHE), an anti-migraine agent, could effectively suppress liver cancer cells proliferation by inhibiting STAT3 activation. However, DHE can enhance the protein stability of Mcl-1 by activating ERK, making DHE less effective in apoptosis induction. Specifically, DHE enhances the effects of sorafenib on liver cancer cells, such as decreased viability and increased apoptosis. Furthermore, the mixture of sorafenib and DHE could enhance DHE-triggered STAT3 suppression and inhibit DHE-mediated ERK-Mcl-1 pathway activation. In vivo, the combination of sorafenib with DHE produced a substantial synergy in suppressing tumour growth and causing apoptosis, ERK inhibition and Mcl-1 degradation. These findings suggest that DHE can effectively inhibit cell proliferation and enhance sorafenib anti-cancer activity in liver cancer cells. The current study provides some new insights that DHE asa novel anti-liver cancer therapeutic agent has been shown to improve treatment outcomes of sorafenib, which might be helpful in order to advance sorafenib in liver cancer therapeutics.
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Minciuna I, van Kleef LA, Stefanescu H, Procopet B. Is Fasting Good When One Is at Risk of Liver Cancer? Cancers (Basel) 2022; 14:5084. [PMID: 36291868 PMCID: PMC9600146 DOI: 10.3390/cancers14205084] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/13/2022] [Accepted: 10/14/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related deaths worldwide, is a multistep process that usually develops in the background of cirrhosis, but also in a non-cirrhotic state in patients with non-alcoholic fatty liver disease (NAFLD) or viral hepatis. Emerging evidence suggests that intermittent fasting can reduce the risk of cancer development and could improve response and tolerance to treatment through the metabolic and hormonal adaptations induced by the low energy availability that finally impairs cancer cells' adaptability, survival and growth. The current review will outline the beneficial effects of fasting in NAFLD/NASH patients and the possible mechanisms that can prevent HCC development, including circadian clock re-synchronization, with a special focus on the possibility of applying this dietary intervention to cirrhotic patients.
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Affiliation(s)
- Iulia Minciuna
- Regional Institute of Gastroenterology and Hepatology Octavian Fodor, 400394 Cluj-Napoca, Romania
- 3rd Medical Department, University of Medicine and Pharmacy Iuliu Hatieganu, 400347 Cluj-Napoca, Romania
| | - Laurens A. van Kleef
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, 3015 GD Rotterdam, The Netherlands
| | - Horia Stefanescu
- Regional Institute of Gastroenterology and Hepatology Octavian Fodor, 400394 Cluj-Napoca, Romania
| | - Bogdan Procopet
- Regional Institute of Gastroenterology and Hepatology Octavian Fodor, 400394 Cluj-Napoca, Romania
- 3rd Medical Department, University of Medicine and Pharmacy Iuliu Hatieganu, 400347 Cluj-Napoca, Romania
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Butt SS, Khan K, Badshah Y, Rafiq M, Shabbir M. Evaluation of pro-apoptotic potential of taxifolin against liver cancer. PeerJ 2021; 9:e11276. [PMID: 34113483 PMCID: PMC8162243 DOI: 10.7717/peerj.11276] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 03/24/2021] [Indexed: 12/13/2022] Open
Abstract
Liver cancer is the second most common cause of cancer-induced deaths worldwide. Liver cirrhosis and cancer are a consequence of the abnormal angio-architecture formation of liver and formation of new blood vessels. This angiogenesis is driven by overexpression of hypoxia-inducible factor 1-alpha (Hif1-α) and vascular endothelial growth factor (VEGF). Apart from this, protein kinase B (Akt) is also impaired in liver cancer. Despite the advancement in conventional treatments, liver cancer remains largely incurable. Nowadays, the use of naturally occurring anticancer agents particularly flavonoids is subject to more attention due to their enhanced physicochemical properties. Therefore, this study underlines the use of a natural anticancer agent taxifolin in the treatment of liver cancer using hepatocellular carcinoma cell line HepG2 and Huh7. The aim of our study is to devise a natural and efficient solution for the disease prevalent in Pakistan. The study involved the assessment of binding of ligand taxifolin using molecular docking. The binding of taxifolin with the proteins (Hif1-α, VEGF and Akt) was calculated by docking using Vina and Chimera. Further evaluation was performed by cell viability assay (MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) Assay), colony formation assay, cell migration assay, DNA ladder assay and flow cytometry. To see whether taxifolin directly affected expression levels, analysis of gene expression of Hif1-α, VEGF and Akt was performed using real-time polymerase chain reaction (qPCR) and western blotting. In silico docking experiments revealed that these proteins showed favorable docking scores with taxifolin. Treatment with taxifolin resulted in the inhibition of the liver cancer growth and migration, and induced apoptosis in HepG2 and Huh7 cell lines at an inhibitory concentration (IC50) value of 0.15 µM and 0.22 µM, respectively. The expression of HIF1-α, VEGF and Akt was significantly reduced in a dose- dependent manner. The inhibitory effect of taxifolin on hepatic cells suggested its chemopreventive and therapeutic potential. The studied compound taxifolin exhibited pronounced pro-apoptotic and hepatoprotective potential. Our study has confirmed the pro-apoptotic potential of taxifolin in liver cancer cell lines and will pave a way to the use of taxifolin as a chemotherapeutic agent after its further validation on the animal models and humans based epidemiological studies.
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Affiliation(s)
- Sania Safdar Butt
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Khushbukhat Khan
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Yasmin Badshah
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Mehak Rafiq
- Research Centre for Modelling and Simulation, National University of Sciences and Technology, Islamabad, Pakistan
| | - Maria Shabbir
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
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Bevacizumab Augments the Antitumor Efficacy of Infigratinib in Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:ijms21249405. [PMID: 33321903 PMCID: PMC7764786 DOI: 10.3390/ijms21249405] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/03/2020] [Accepted: 12/04/2020] [Indexed: 12/30/2022] Open
Abstract
The fibroblast growth factor (FGF) signaling cascade is one of the key signaling pathways in hepatocellular carcinoma (HCC). FGF has been shown to augment vascular endothelial growth factor (VEGF)-mediated HCC development and angiogenesis, as well as to potentially lead to resistance to VEGF/VEGF receptor (VEGFR)-targeted agents. Thus, novel agents targeting FGF/FGF receptor (FGFR) signaling may enhance and/or overcome de novo or acquired resistance to VEGF-targeted agents in HCC. Mice bearing high- and low-FGFR tumors were treated with Infigratinib (i.e., a pan-FGFR kinase inhibitor) and/or Bevacizumab (i.e., an angiogenesis inhibitor). The antitumor activity of both agents was assessed individually or in combination. Tumor vasculature, intratumoral hypoxia, and downstream targets of FGFR signaling pathways were also investigated. Infigratinib, when combined with Bevacizumab, exerted a synergistic inhibitory effect on tumor growth, invasion, and lung metastasis, and it significantly improved the overall survival of mice bearing FGFR-dependent HCC. Infigratinib/Bevacizumab promoted apoptosis, inhibited cell proliferation concomitant with upregulation of p27, and reduction in the expression of FGFR2-4, p-FRS-2, p-ERK1/2, p-p70S6K/4EBP1, Cdc25C, survivin, p-Cdc2, and p-Rb. Combining Infigratinib/Bevacizumab may provide therapeutic benefits for a subpopulation of HCC patients with FGFR-dependent tumors. A high level of FGFR-2/3 may serve as a potential biomarker for patient selection to Infigratinib/Bevacizumab.
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8
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Therapeutic effects of the PKR inhibitor C16 suppressing tumor proliferation and angiogenesis in hepatocellular carcinoma in vitro and in vivo. Sci Rep 2020; 10:5133. [PMID: 32198380 PMCID: PMC7083831 DOI: 10.1038/s41598-020-61579-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 01/21/2020] [Indexed: 11/12/2022] Open
Abstract
The therapeutic effects of C16, which is an inhibitor of RNA-dependent protein kinase (PKR), on growth of hepatocellular carcinoma (HCC) cells and tumor progression in vitro and in vivo were evaluated. Huh7 cells, a human HCC cell line, were used. The effects of C16 on cell viability were evaluated with the MTT assay, and real-time RT-PCR was performed. Huh7 cells were grafted into immunodeficient mice, and the in vivo effects of C16 on tumorigenesis were examined. C16 suppressed proliferation of HCC cells in a dose-dependent manner in vitro. Mouse models with xenograft transplantation showed that the inhibitor suppressed the growth of HCC cells in vivo. Moreover, C16 decreased angiogenesis in HCC tissue in the xenograft model. Consistent with these results in mice, transcript levels of vascular endothelial growth factor-A and factor-B, platelet-derived growth factor-A and factor-B, fibroblast growth factor-2, epidermal growth factor, and hepatocyte growth factor, which are angiogenesis-related growth factors, were significantly decreased by C16 in vitro. In conclusion, the PKR inhibitor C16 blocked tumor cell growth and angiogenesis via a decrease in mRNA levels of several growth factors. C16 may be useful in the treatment of HCC.
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9
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Lai Q, Vitale A, Manzia TM, Foschi FG, Levi Sandri GB, Gambato M, Melandro F, Russo FP, Miele L, Viganò L, Burra P, Giannini EG. Platelets and Hepatocellular Cancer: Bridging the Bench to the Clinics. Cancers (Basel) 2019; 11:1568. [PMID: 31618961 PMCID: PMC6826649 DOI: 10.3390/cancers11101568] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 10/10/2019] [Accepted: 10/14/2019] [Indexed: 02/06/2023] Open
Abstract
Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules specifically secreted by platelets are directly connected with tumor progression and neo-angiogenesis. Among them, we can list the platelet-derived growth factor, the vascular endothelial growth factor, the endothelial growth factor, and serotonin. Platelets are also involved in tumor spread, favoring endothelium permeabilization and tumor cells' extravasation and survival in the bloodstream. From the bench to the clinics, all of these aspects were also investigated in clinical series, showing an evident correlation between platelet count and size of HCC, tumor biological behavior, metastatic spread, and overall survival rates. Moreover, a better understanding of the mechanisms involved in the platelet-tumor axis represents a paramount aspect for optimizing both current tumor treatment and development of new therapeutic strategies against HCC.
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Affiliation(s)
- Quirino Lai
- Department of General Surgery and Organ Transplantation, Umberto I Hospital, Sapienza University, 00161 Rome, Italy.
| | - Alessandro Vitale
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Tommaso M Manzia
- Department of Transplant Surgery, Polyclinic Tor Vergata Foundation, Tor Vergata University, 00133 Rome, Italy.
| | - Francesco G Foschi
- Department of Internal Medicine, Ospedale per gli Infermi di Faenza, 48018 Faenza, Italy.
| | | | - Martina Gambato
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Fabio Melandro
- Hepatobiliary Surgery and Liver Transplantation Unit, University of Pisa Medical School Hospital, 56126 Pisa, Italy.
| | - Francesco P Russo
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Luca Miele
- Internal Medicine, Gastroenterology and Liver Unit, A. Gemelli Polyclinic, Sacro Cuore Catholic University, 20123 Rome, Italy.
| | - Luca Viganò
- Division of Hepatobiliary and General Surgery, Department of Surgery, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy.
| | - Patrizia Burra
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Edoardo G Giannini
- Gastroenterology Unit, Department of Internal Medicine, Università di Genova, IRCCS-Ospedale Policlinico San Martino, 16132 Genoa, Italy.
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10
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Hasanzad M, Sarhangi N, Aghaei Meybodi HR, Nikfar S, Khatami F, Larijani B. Precision Medicine in Non Communicable Diseases. INTERNATIONAL JOURNAL OF MOLECULAR AND CELLULAR MEDICINE 2019; 8:1-18. [PMID: 32351905 PMCID: PMC7175610 DOI: 10.22088/ijmcm.bums.8.2.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 07/20/2019] [Indexed: 12/12/2022]
Abstract
Non-communicable diseases (NCDs) are the leading cause of death and disease burden globally, cardiovascular diseases (CVDs) account for the major part of death related to NCDs followed by different types of cancer, chronic obstructive pulmonary disease (COPD), and diabetes. As the World Health Organization (WHO) and the United Nations have announced a 25% reduction in mortality of NCDs by 2025, different communities need to adopt preventive strategies for achieving this goal. Personalized medicine approach as a predictive and preventive strategy aims for a better therapeutic goal to the patients to maximize benefits and reduce harms. The clinical benefits of this approach are already realized in cancer targeted therapy, and its impact on other conditions needs more studies in different societies. In this review, we essentially describe the concept of personalized (or precision) medicine in association with NCDs and the future of precision medicine in prediction, prevention, and personalized treatment.
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Affiliation(s)
- Mandana Hasanzad
- Medical Genomics Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.,Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Negar Sarhangi
- Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Reza Aghaei Meybodi
- Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Shekoufeh Nikfar
- Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.,Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Khatami
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.,Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Friedman Ohana R, Hurst R, Rosenblatt M, Levin S, Machleidt T, Kirkland TA, Encell LP, Robers MB, Wood KV. Utilizing a Simple Method for Stoichiometric Protein Labeling to Quantify Antibody Blockade. Sci Rep 2019; 9:7046. [PMID: 31065015 PMCID: PMC6504924 DOI: 10.1038/s41598-019-43469-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 04/23/2019] [Indexed: 12/13/2022] Open
Abstract
Ligand binding assays routinely employ fluorescently-labeled protein ligands to quantify the extent of binding. These ligands are commonly generated through chemical modification of accessible lysine residues, which often results in heterogeneous populations exhibiting variable binding properties. This could be remedied by quantitative, site-specific labeling. Recently, we reported on a single-step method integrating recombinant protein purification with 2-cyanobenzothiazole (CBT) condensation for labeling a proteolytically exposed N-terminal cysteine. Here, using three growth factors, we show that unlike random lysine labeling, this site-specific approach yielded homogeneous populations of growth factors that were quantitatively labeled at their N-termini and retained their binding characteristics. We demonstrate the utility of this labeling method through the development of a novel assay that quantifies the capacity of antibodies to block receptor-ligand interactions (i.e. antibody blockade). The assay uses bioluminescence resonance energy transfer (BRET) to detect binding of CBT-labeled growth factors to their cognate receptors genetically fused to NanoLuc luciferase. The ability of antibodies to block these interactions is quantified through decrease in BRET. Using several antibodies, we show that the assay provides reliable quantification of antibody blockade in a cellular context. As demonstrated here, this simple method for generating uniformly-labeled proteins has potential to promote more accurate and robust ligand binding assays.
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Affiliation(s)
| | - Robin Hurst
- Promega Corporation, 2800 Woods Hollow Rd, Madison, WI, 53711, USA
| | - Mike Rosenblatt
- Promega Corporation, 2800 Woods Hollow Rd, Madison, WI, 53711, USA
| | - Sergiy Levin
- Promega Biosciences LLC, 277 Granada Dr, San Luis Obispo, CA, 93401, USA
| | - Thomas Machleidt
- Promega Corporation, 2800 Woods Hollow Rd, Madison, WI, 53711, USA
| | - Thomas A Kirkland
- Promega Biosciences LLC, 277 Granada Dr, San Luis Obispo, CA, 93401, USA
| | - Lance P Encell
- Promega Corporation, 2800 Woods Hollow Rd, Madison, WI, 53711, USA
| | - Matthew B Robers
- Promega Corporation, 2800 Woods Hollow Rd, Madison, WI, 53711, USA
| | - Keith V Wood
- Promega Corporation, 2800 Woods Hollow Rd, Madison, WI, 53711, USA
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12
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Pottakkat B, Ashokachakkaravarthy K. Sorafenib resistance and autophagy in hepatocellular carcinoma: A concealed threat. JOURNAL OF CANCER RESEARCH AND PRACTICE 2019. [DOI: 10.4103/jcrp.jcrp_6_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Thomas MB, Garrett-Mayer E, Anis M, Anderton K, Bentz T, Edwards A, Brisendine A, Weiss G, Siegel AB, Bendell J, Baron A, Duddalwar V, El-Khoueiry A. A Randomized Phase II Open-Label Multi-Institution Study of the Combination of Bevacizumab and Erlotinib Compared to Sorafenib in the First-Line Treatment of Patients with Advanced Hepatocellular Carcinoma. Oncology 2018; 94:329-339. [PMID: 29719302 PMCID: PMC7725004 DOI: 10.1159/000485384] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 11/06/2017] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To investigate the clinical efficacy and tolerability of the combination of bevacizumab (B) and erlotinib (E) compared to sorafenib (S) as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). METHODS A total of 90 patients with advanced HCC, Child-Pugh class A-B7 cirrhosis, and no prior systemic therapy were randomly assigned (1: 1) to receive either 10 mg/kg B intravenously every 14 days and 150 mg E orally daily (n = 47) (B+E) or 400 mg S orally twice daily (n = 43). The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), objective response rate based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1), time to progression, and safety and tolerability. RESULTS The median OS was 8.55 months (95% CI: 7.00-13.9) for patients treated with B+E and 8.55 months (95% CI: 5.69-12.2) for patients receiving S. The hazard ratio (HR) for OS was 0.92 (95% CI: 0.57-1.47). The median EFS was 4.37 months (95% CI: 2.99-7.36) for patients receiving B+E and 2.76 months (95% CI: 1.84-4.80) for patients receiving S. The HR for EFS was 0.67 (95% CI: 0.42-1.07; p = 0.09), favoring B+E over S. When OS was assessed among patients who were Child-Pugh class A, the median OS was 11.4 months (95% CI: 7.5-15.7) for patients treated with B+E (n = 39) and 10.26 months (95% CI: 5.9-13.0) for patients treated with S (n = 38) (HR = 0.88; 95% CI: 0.53-1.46). CONCLUSIONS There was no difference in efficacy between the B+E and S arms, although the safety and tolerability profile tended to favor B+E over S based on competing risk analysis.
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Affiliation(s)
- Melanie B Thomas
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA,
- Gibbs Cancer Center and Research Institute, Spartanburg Regional Healthcare System, Spartanburg, South Carolina, USA,
| | - Elizabeth Garrett-Mayer
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Munazza Anis
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Kate Anderton
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Tricia Bentz
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Andie Edwards
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Alan Brisendine
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Geoffrey Weiss
- Department of Oncology, University of Virginia, Charlottesville, Virginia, USA
| | - Abby B Siegel
- New York-Presbyterian Hospital, Columbia University, New York, New York, USA
| | - Johanna Bendell
- GI Oncology Research, Sarah Canon Research Institute, Nashville, Tennessee, USA
| | - Ari Baron
- California Pacific Medical Center, San Francisco, California, USA
| | - Vinay Duddalwar
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA
| | - Anthony El-Khoueiry
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA
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14
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Current Status and Future Prospects of Biomarkers in the Diagnosis of Hepatocellular Carcinoma. Int J Biol Markers 2017; 32:e361-e369. [PMID: 28967065 DOI: 10.5301/ijbm.5000299] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2017] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) has one of the highest death rates of any cancer in the world, and its incidence is increasing worldwide. Early-stage diagnosis of HCC is thus crucial for medical treatment. Detection of tumor biomarkers is one of the main methods for the early diagnosis of HCC. At present, α-fetoprotein (AFP) is the most practical serum biomarker for HCC diagnosis. However, the diagnostic accuracy of HCC with serum AFP exhibits both sensitivity and specificity far below satisfaction, especially with small sizes of HCC. As a result, the discovery of new biomarkers and/or their combination to enhance both the sensitivity and specificity for laboratory diagnosis of HCC is a crucial goal. With the development of new technology and advances in research, a number of new and specific biomarkers of HCC have been discovered. These biomarkers and their applications for the diagnosis, treatment monitoring and prognosis prediction of HCC, are reviewed in this article.
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15
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Teng CF, Wu HC, Shyu WC, Jeng LB, Su IJ. Pre-S2 Mutant-Induced Mammalian Target of Rapamycin Signal Pathways as Potential Therapeutic Targets for Hepatitis B Virus-Associated Hepatocellular Carcinoma. Cell Transplant 2017; 26:429-438. [PMID: 28195035 PMCID: PMC5657708 DOI: 10.3727/096368916x694382] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 01/06/2017] [Indexed: 12/15/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Pre-S2 mutant represents an HBV oncoprotein that is accumulated in the endoplasmic reticulum (ER) and manifests as type II ground glass hepatocytes (GGHs). Pre-S2 mutant can induce ER stress and initiate multiple ER stress-dependent or -independent cellular signal pathways, leading to growth advantage of type II GGH. Importantly, the mammalian target of rapamycin (mTOR) signal pathways are consistently activated throughout the liver tumorigenesis in pre-S2 mutant transgenic mice and in human HCC tissues, leading to hepatocyte proliferation, metabolic disorders, and HCC tumorigenesis. In this review, we summarize the pre-S2 mutant-induced mTOR signal pathways and its implications in HBV-related HCC tumorigenesis. Clinically, the presence of pre-S2 mutant exhibits a high resistance to antiviral treatment and carries a high risk of HCC development in patients with chronic HBV infection. Targeting at pre-S2 mutant-induced mTOR signal pathways may thus provide potential strategies for the prevention or therapy of HBV-associated HCC.
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Affiliation(s)
- Chiao-Fang Teng
- Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan
| | - Han-Chieh Wu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan
| | - Woei-Cherng Shyu
- Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
| | - Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan
| | - Ih-Jen Su
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
- Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan
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16
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Wang X, Ding J, Feng Y, Weng L, Zhao G, Xiang J, Zhang M, Xing D. Targeting of growth factors in the treatment of hepatocellular carcinoma: The potentials of polysaccharides. Oncol Lett 2017; 13:1509-1517. [PMID: 28454283 DOI: 10.3892/ol.2017.5602] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 08/19/2016] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has become a leading cause of cancer-associated mortality worldwide and is thus of great concern. Although various chemotherapeutic drugs are currently used for the treatment of HCC, severe side effects associated with these treatments have prompted interest in novel therapies, including the use of certain biological macromolecules such as polysaccharides. Several studies have shown that polysaccharides have anticancer and antiproliferative effects on HCC. Vascular endothelial growth factor, transforming growth factor β, epidermal growth factor and fibroblast growth factor may be effective targets for polysaccharides and may modulate tumor growth and immunity through increasing the expression levels of cytokines. The present review focuses on the ways in which growth factors contribute to the development of HCC, and on the anti-growth factor activities of natural and synthetic polysaccharides, as well as their effect on proinflammatory cytokines.
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Affiliation(s)
- Xuan Wang
- Radiology Department, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Jieyu Ding
- Radiology Department, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Yuanyuan Feng
- Oncology Department, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200021, P.R. China
| | - Lingling Weng
- Radiology Department, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Guangqiang Zhao
- Radiology Department, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Jianfeng Xiang
- Radiology Department, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Minguang Zhang
- Radiology Department, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Dongwei Xing
- Radiology Department, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
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17
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Abbas M, Saeed F, Anjum FM, Afzaal M, Tufail T, Bashir MS, Ishtiaq A, Hussain S, Suleria HAR. Natural polyphenols: An overview. INTERNATIONAL JOURNAL OF FOOD PROPERTIES 2016. [DOI: 10.1080/10942912.2016.1220393] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Munawar Abbas
- Institute of Home and Food Sciences, Government College University, Faisalabad, Pakistan
| | - Farhan Saeed
- Institute of Home and Food Sciences, Government College University, Faisalabad, Pakistan
| | - Faqir Muhammad Anjum
- Institute of Home and Food Sciences, Government College University, Faisalabad, Pakistan
| | - Muhammad Afzaal
- Institute of Home and Food Sciences, Government College University, Faisalabad, Pakistan
| | - Tabussam Tufail
- Institute of Home and Food Sciences, Government College University, Faisalabad, Pakistan
| | - Muhammad Shakeel Bashir
- Institute of Agricultural Sciences, Department of Food Science and Nutrition, University of the Punjab, Lahore-Pakistan, King Saud University, Riyadh, SA
| | - Adnan Ishtiaq
- Institute of Agricultural Sciences, Department of Food Science and Nutrition, University of the Punjab, Lahore-Pakistan, King Saud University, Riyadh, SA
| | - Shahzad Hussain
- UQ School of Medicine, The University of Queensland, Australia
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18
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Ribback S, Sailer V, Böhning E, Günther J, Merz J, Steinmüller F, Utpatel K, Cigliano A, Peters K, Pilo MG, Evert M, Calvisi DF, Dombrowski F. The Epidermal Growth Factor Receptor (EGFR) Inhibitor Gefitinib Reduces but Does Not Prevent Tumorigenesis in Chemical and Hormonal Induced Hepatocarcinogenesis Rat Models. Int J Mol Sci 2016; 17:ijms17101618. [PMID: 27669229 PMCID: PMC5085651 DOI: 10.3390/ijms17101618] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Revised: 08/27/2016] [Accepted: 09/14/2016] [Indexed: 02/07/2023] Open
Abstract
Activation of the epidermal growth factor receptor (EGFR) signaling pathway promotes the development of hepatocellular adenoma (HCA) and carcinoma (HCC). The selective EGFR inhibitor Gefitinib was found to prevent hepatocarcinogenesis in rat cirrhotic livers. Thus, Gefitinib might reduce progression of pre-neoplastic liver lesions to HCC. In short- and long-term experiments, administration of N-Nitrosomorpholine (NNM) or intrahepatic transplantation of pancreatic islets in diabetic (PTx), thyroid follicles in thyroidectomized (TTx) and ovarian fragments in ovariectomized (OTx) rats was conducted for the induction of foci of altered hepatocytes (FAH). Gefitinib was administered for two weeks (20 mg/kg) or three and nine months (10 mg/kg). In NNM-treated rats, Gefitinib administration decreased the amount of FAH when compared to controls. The amount of HCA and HCC was decreased, but development was not prevented. Upon all transplantation models, proliferative activity of FAH was lower after administration of Gefitinib in short-term experiments. Nevertheless, the burden of HCA and HCC was not changed in later stages. Thus, EGFR inhibition by Gefitinib diminishes chemical and hormonal also induced hepatocarcinogenesis in the initiation stage in the non-cirrhotic liver. However, progression to malignant hepatocellular tumors was not prevented, indicating only a limited relevance of the EGFR signaling cascade in later stages of hepatocarcinogenesis.
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Affiliation(s)
- Silvia Ribback
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Verena Sailer
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
- Englander Institut for Precision Medicine, Weill Cornell University of Medicine, New York, NY 10065, USA.
| | - Enrico Böhning
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Julia Günther
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Jaqueline Merz
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Frauke Steinmüller
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
- Pathologisches Institut Diakonie-Krankenhaus, 27356 Rotenburg (Wümme), Germany.
| | - Kirsten Utpatel
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
- Institut für Pathologie, Universitätsklinikum Regensburg, 93053 Regensburg, Germany.
| | - Antonio Cigliano
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Kristin Peters
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Maria G Pilo
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Matthias Evert
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
- Institut für Pathologie, Universitätsklinikum Regensburg, 93053 Regensburg, Germany.
| | - Diego F Calvisi
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Frank Dombrowski
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
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19
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Mizuguchi Y, Takizawa T, Yoshida H, Uchida E. Dysregulated miRNA in progression of hepatocellular carcinoma: A systematic review. Hepatol Res 2016; 46:391-406. [PMID: 26490438 DOI: 10.1111/hepr.12606] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 10/13/2015] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most frequent cancer and the third cause of cancer-related mortality worldwide. The primary risk factor for HCC is liver cirrhosis secondary to persistent infection with hepatitis B virus or hepatitis C virus. Although a number of cellular phenomena and molecular events have been reported to facilitate tumor initiation, progression and metastasis, the exact etiology of HCC has not yet been fully uncovered. miRNA, a class of non-coding RNA, negatively regulate post-transcriptional processes that participate in crucial biological processes, including development, differentiation, apoptosis and proliferation. In the liver, specific miRNA can be negative regulators of gene expression. Recent studies have uncovered the contribution of miRNA to cancer pathogenesis as they can function as oncogenes or tumor suppressor genes. In addition, other studies have demonstrated their potential value in the clinical management of patients with HCC as some miRNA may be used as prognostic or diagnostic markers. In this review, we summarize the current knowledge about the roles of miRNA in the carcinogenesis and progression of HCC.
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Affiliation(s)
| | | | - Hiroshi Yoshida
- Department of Surgery, Nippon Medical School Hospital, Tokyo, Japan
| | - Eiji Uchida
- Department of Surgery, Nippon Medical School Hospital, Tokyo, Japan
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20
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Zheng N, Wei W, Wang Z. Emerging roles of FGF signaling in hepatocellular carcinoma. Transl Cancer Res 2016; 5:1-6. [PMID: 27226954 PMCID: PMC4876964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Affiliation(s)
- Nana Zheng
- The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou 215123, China
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Zhiwei Wang
- The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou 215123, China
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21
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Zhang J, Jiang X, Jiang Y, Guo M, Zhang S, Li J, He J, Liu J, Wang J, Ouyang L. Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs. Eur J Med Chem 2015; 108:495-504. [PMID: 26717201 DOI: 10.1016/j.ejmech.2015.12.016] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 12/05/2015] [Accepted: 12/10/2015] [Indexed: 02/05/2023]
Abstract
Vascular endothelial growth factor receptor (VEGFR) is a very important receptor tyrosine kinase (RTK) that can induce angiogenesis, increase cell growth and metastasis, reduce apoptosis, alter cytoskeletal function, and affect other biologic changes. Moreover, it is identified to be deregulated in varieties of human cancers. Therefore, VEGFR turn out to be a remarkable target of significant types of anticancer drugs in clinical trials. On the other side, c-Met is the receptor of hepatocyte growth factor (HGF) and a receptor tyrosine kinase. Previous studies have shown that c-Met elicits many different signaling pathways mediating cell proliferation, migration, differentiation, and survival. Furthermore, the correlation between aberrant signaling of the HGF/c-Met pathway and aggressive tumor growth, poor prognosis in cancer patients has been established. Recent reports had shown that c-Met/HGF and VEGFR/VEGF (vascular endothelial growth factor) can act synergistically in the progression of many diseases. They were also found to be over expressed in many human cancers. Thus, in a variety of malignancies, VEGFR and c-Met receptor tyrosine kinases have acted as therapeutic targets. With the development of molecular biology techniques, further understanding of the human tumor disease pathogenesis and interrelated signaling pathways known to tumor cells, using a single target inhibitors have been difficult to achieve the desired therapeutic effect. At this point, with respect to the combination of two inhibitors, a single compound which is able to inhibit both VEGFR and c-Met may put forward the advantage of raising anticancer activity. With the strong interest in these compounds, this review represents a renewal of previous works on the development of dual VEGFR and c-Met small molecule inhibitors as novel anti-cancer agents. Newly collection derivatives have been mainly describing in their biological profiles and chemical structures.
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Affiliation(s)
- Jin Zhang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Xiangdong Jiang
- Department of Information Engineering, Chongqing Vocational Institute of Safety Technology, Chongqing, 404020, China
| | - Yingnan Jiang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Mingrui Guo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Shouyue Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Jingjing Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Jun He
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Jie Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Jinhui Wang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Liang Ouyang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
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Mizuguchi Y, Takizawa T, Uchida E. Host cellular microRNA involvement in the control of hepatitis B virus gene expression and replication. World J Hepatol 2015; 7:696-702. [PMID: 25866606 PMCID: PMC4388997 DOI: 10.4254/wjh.v7.i4.696] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 11/28/2014] [Accepted: 01/19/2015] [Indexed: 02/06/2023] Open
Abstract
A large number of studies have demonstrated that the synergistic collaboration of a number of microRNAs (miRNAs), their growth factors and their downstream agents is required for the initiation and completion of pathogenesis in the liver. miRNAs are thought to exert a profound effect on almost every aspect of liver biology and pathology. Accumulating evidence indicates that several miRNAs are involved in the hepatitis B virus (HBV) life cycle and infectivity, in addition to HBV-associated liver diseases including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). In turn, HBV can modulate the expression of several cellular miRNAs, thus promoting a favorable environment for its replication and survival. In this review, we focused on the involvement of host cellular miRNAs that are directly and indirectly associated with HBV RNA or HBV associated transcription factors. Exploring different facets of the interactions among miRNA, HBV and HCV infections, and the carcinogenesis and progress of HCC, could facilitate the development of novel and effective treatment approaches for liver disease.
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23
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Tivantinib, a new option for second-line treatment of advanced hepatocellular carcinoma? The experience of Italian centers. TUMORI JOURNAL 2015; 101:139-43. [PMID: 25838254 DOI: 10.5301/tj.5000217] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2014] [Indexed: 12/22/2022]
Abstract
In the last decades the management of hepatocellular carcinoma (HCC) has undergone significant changes following the introduction of novel therapies such as sorafenib, which have improved patient survival. Nevertheless, HCC is still the third most common cause of cancer-related death worldwide. The evidence-based therapy for advanced HCC that is unsuitable for locoregional treatment is limited to sorafenib, with no second-line option available. This article focuses on the development of the MET inhibitor tivantinib in HCC as a promising treatment option for patients who failed sorafenib. A randomized, placebo-controlled phase II study showed activity of tivantinib in patients with high MET expression. Based on these results, the METIV-HCC phase III study in second-line treatment for MET-high patients was initiated to demonstrate the survival advantage of tivantinib compared to placebo.
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24
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Li X, Dai D, Song X, Liu J, Zhu L, Xu W. A meta-analysis of cytokine-induced killer cells therapy in combination with minimally invasive treatment for hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2014; 38:583-91. [PMID: 24924902 DOI: 10.1016/j.clinre.2014.04.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 04/08/2014] [Accepted: 04/27/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVE There was a continuing controversy on whether the adoptive transfusion of cytokine-induced killer cells (CIK) therapy should have been recommended to reduce the recurrence and metastasis of hepatocellular carcinoma (HCC) after minimally invasive therapy such as TACE (transarterial chemoembolization) or TACE plus RFA (radiofrequency ablation) treatment. The meta-analysis was conducted to compare the effectiveness of CIK cells transfusion therapy combined with TACE or TACE plus RFA treatment with that of minimally invasive therapy alone. METHODS Relevant studies were identified by electronic search using a combination of "hepatocellular carcinoma" and "cytokine-induced killer cells". Overall survival (OS) rates and recurrence-free survival (RFS) rates were compared as the major outcome measures. The meta-analysis was divided into two sub-studies (sub-study 1: CIK+TACE+RFA versus TACE+RFA; sub-study 2: CIK+TACE versus TACE) to avoid the risk of bias as we could. RESULTS Meta-analysis data suggested that CIK cells transfusion therapy combined with TACE plus RFA treatment was associated with higher 1-year RFS rate (odds ratio [OR]=2.46) and 1-year, 2-year OS rates (OR: 1-year=2.09; 3-year=2.16) than TACE plus RFA treatment alone in sub-study 1. For sub-study 2, there were significant differences between CIK+TACE group and TACE group for OS rates (OR: half-year=3.29; 1-year=3.71; 2-year=7.37). CONCLUSION CIK cells transfusion therapy truly showed a synergistic effect for HCC patients after minimally invasive treatment especially for a long-term survival.
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Affiliation(s)
- Xiaofeng Li
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huan-Hu-Xi Road, 300060 Ti-Yuan-Bei, He Xi District, Tianjin, PR China
| | - Dong Dai
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huan-Hu-Xi Road, 300060 Ti-Yuan-Bei, He Xi District, Tianjin, PR China
| | - Xiuyu Song
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huan-Hu-Xi Road, 300060 Ti-Yuan-Bei, He Xi District, Tianjin, PR China
| | - Jianjing Liu
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huan-Hu-Xi Road, 300060 Ti-Yuan-Bei, He Xi District, Tianjin, PR China
| | - Lei Zhu
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huan-Hu-Xi Road, 300060 Ti-Yuan-Bei, He Xi District, Tianjin, PR China
| | - Wengui Xu
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huan-Hu-Xi Road, 300060 Ti-Yuan-Bei, He Xi District, Tianjin, PR China.
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25
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Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Worldwide progressive population aging demands consensus development for decision making when treating elderly patients. Age itself might not be a critical determinant for the selection of a therapeutic option. In the past few years, the mechanisms of hepato-carcinogenesis have been elucidated, and the involvement of a number of pathways, including angiogenesis, aberrant signal transduction, and dysregulated cell cycle control, have been demonstrated, leading to evaluation of the activity and toxicity of some of the new molecularly targeted agents. Sorafenib was demonstrated to significantly increase the survival of patients with advanced HCC in two prospective, randomized, placebo-controlled trials. Subsequently, a number of retrospective or prospective studies have indicated that the effectiveness of sorafenib therapy in the treatment of HCC is similar in elderly and non-elderly patients. The aim of this review is to describe the impact of age on the effects of sorafenib-targeted therapy in patients with HCC, and the next treatment options with new targeted agents (everolimus, tivantinib, linifanib, etc.).
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Germano D, Daniele B. Systemic therapy of hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol 2014; 20:3087-3099. [PMID: 24696596 PMCID: PMC3964381 DOI: 10.3748/wjg.v20.i12.3087] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 10/31/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
The management of hepatocellular carcinoma (HCC) has substantially changed in the past few decades, the introduction of novel therapies (such as sorafenib) have improved patient survival. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. Decision-making largely relies on evidence-based criteria, as showed in the US and European clinical practice guidelines, which endorse five therapeutic recommendations:resection; transplantation; radiofrequency ablation; chemoembolization; and sorafenib. Many molecularly targeted agents that inhibit angiogenesis, epidermal growth factor receptor, and mammalian target of rapamycin are at different stages of clinical development in advanced HCC. Future research should continue to unravel the mechanism of hepatocarcinogenesis and to identify key relevant molecular targets for therapeutic intervention. Identification and validation of potential surrogate and predictive biomarkers hold promise to individualize patient’s treatment to maximize clinical benefit and minimize the toxicity and cost of targeted agents.
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Liu Q, Liu J. Signaling pathways in hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2014; 22:59-66. [DOI: 10.11569/wcjd.v22.i1.59] [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
Hepatocellular carcinoma is a complex multistep process involving progressive abnormalities of hepatocellular survival, proliferation, apoptosis and differentiation. Currently, accumulating evidence has demonstrated that the development of hepatocellular carcinoma is closely associated with dysregulation of several signaling pathways. Aberrant activation of these signaling cascades often leads to the over-expression of oncogenes and down-regulation of tumor suppressor genes, thus promoting cell cycle progression and apoptosis evasion. Here, we discuss some signaling pathways in hepatocellular carcinoma.
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Zhu J, Wang Y, Yu Y, Wang Z, Zhu T, Xu X, Liu H, Hawke D, Zhou D, Li Y. Aberrant fucosylation of glycosphingolipids in human hepatocellular carcinoma tissues. Liver Int 2014; 34:147-60. [PMID: 23902602 DOI: 10.1111/liv.12265] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Accepted: 06/20/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUNDS & AIMS Glycosylation promoting or inhibiting tumour cell invasion and metastasis is of crucial importance in current cancer research. Tumour-associated carbohydrate antigens are predominantly expressed on the tumour cell surface. Glycosphingolipids (GSLs) are members of the family. To perform glycosphingolipidomic assays on neutral GSLs obtained from solid hepatocellular carcinoma (HCC) tissues and paired peritumoural tissues by linear ion trap quadrupole-electrospray ionization mass spectrometry. METHODS Qualitative and quantitative analysis of fucosylated neutral GSLs was performed in the positive ion mode on the LTQ-XL mass spectrometer and MALDI-TOF-MS. RESULTS A group of fucosylated neutral GSLs in HCC was found to be expressed higher in the tumour tissues, as their proportion in total cellular GSLs was 3.3-fold higher in the tumour tissues than in the peritumoural tissues (P < 0.01). Moreover, qualitative analysis of the aberrant fucosylated GSLs were completed, and seven types of fucosylated GSLs that contained terminal Fuca2Gal- structure were identified by mass spectrometry. CONCLUSIONS Our results may lead to improved immunotherapy of HCC and contribute to understanding the role of aberrant fucosylated GSLs in the development and progress of HCC in following studies.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antigens, Tumor-Associated, Carbohydrate/analysis
- Carcinoma, Hepatocellular/chemistry
- Carcinoma, Hepatocellular/enzymology
- Carcinoma, Hepatocellular/genetics
- Ceramides/analysis
- Ceramides/chemistry
- Female
- Fucosyltransferases/genetics
- Glycosylation
- Humans
- Liver Neoplasms/chemistry
- Liver Neoplasms/enzymology
- Liver Neoplasms/genetics
- Male
- Middle Aged
- Molecular Structure
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Spectrometry, Mass, Electrospray Ionization
- Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
- Up-Regulation
- Galactoside 2-alpha-L-fucosyltransferase
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Affiliation(s)
- Jian Zhu
- Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
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Li Z, Tang M, Ling B, Liu S, Zheng Y, Nie C, Yuan Z, Zhou L, Guo G, Tong A, Wei Y. Increased expression of S100A6 promotes cell proliferation and migration in human hepatocellular carcinoma. J Mol Med (Berl) 2013; 92:291-303. [PMID: 24281831 DOI: 10.1007/s00109-013-1104-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Revised: 10/20/2013] [Accepted: 11/13/2013] [Indexed: 02/05/2023]
Abstract
UNLABELLED High levels of S100A6 have been associated with poor outcome in some types of human cancers, but the role of S100A6 in the molecular pathogenesis of these cancers is largely unknown. This study was performed to explore the expression and functional roles of S100A6 in hepatocellular carcinoma (HCC). The expression level of S100A6 in HCC tumor and corresponding peritumoral tissues were determined by immunohistochemistry analysis. The potential functions of S100A6 in tumorigenesis and metastasis were analyzed by cell proliferation, migration, and invasion assays in human liver cancer cells. Moreover, through expression and purification of S100A6 recombinant protein tagged with cell-penetrating peptide, we analyzed its complex extracellular/intracellular effects in a S100A6-silenced cellular model. As a result, the expression of S100A6 was up-regulated in human HCC compared with adjacent peritumoral tissues. S100A6 silencing inhibited the growth and motility of HCC cells, while intracellular re-expression of S100A6 could rescue the proliferation and migration defects. Intracellular over-expression of S100A6 resulted in down-regulation of E-cadherin expression and promoted nuclear accumulation of β-catenin. Moreover, we found that the enhanced cell proliferation and motility after S100A6 stimulation were dependent on the activation of PI3K/AKT pathway. These results suggest that S100A6 may be involved in promotion and progression of human liver cancer. KEY MESSAGES S100A6 is overexpressed in human hepatocellular carcinoma clinical specimens. S100A6 promotes proliferation and migration of human hepatoma cells. Overexpression of S100A6 results in alteration of E-cadherin and β-catenin. The multi-effects of S100A6 may be mediated in part by PI3K/AKT pathway activation.
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Affiliation(s)
- Ziqiang Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China,
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Shi JH, Liu SZ, Wierød L, Scholz H, Anmarkrud JA, Huitfeldt HS, Zhang SJ, Line PD. RAF-targeted therapy for hepatocellular carcinoma in the regenerating liver. J Surg Oncol 2013; 107:393-401. [PMID: 22927239 DOI: 10.1002/jso.23224] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Accepted: 06/25/2012] [Indexed: 01/19/2023]
Abstract
BACKGROUND Post-operative liver regeneration may contribute to tumor recurrence. There is a theoretical need for an adjuvant therapy that can suppress tumor growth without adversely affecting post-operative liver regeneration. OBJECTIVE To evaluate the effect of RAF inhibitor Sorafenib on cell viability and proliferation of hepatoma cells and hepatocytes in vitro and in an in vivo rat model. METHODS Cell viability, DNA synthesis, and RAF/MAPK kinase activity in the primary hepatocyte and hepatoma cell lines were investigated after Sorafenib exposure. Sequence analysis of the B-RAF gene in hepatic cells was determined. Tumor markers were compared within the rats after 70% hepatectomy with or without daily oral gavages of Sorafenib. Liver regeneration was assessed by liver function tests and proliferation markers. RESULTS Primary hepatocytes showed higher cell viability, proliferation rate, and stronger RAF/MAPK kinase activity compared with hepatoma cell lines. The in vivo tumor volumes, size, and metastases were significantly decreased (P < 0.05) whereas no significant change in liver regeneration related to Sorafenib exposure was found (P > 0.05). B-RAF V600E mutation was not detected neither in the hepatic cells nor untransformed hepatocytes. CONCLUSIONS The RAF targeted inhibitor can reduce tumor growth without retarding liver regeneration in this experiment.
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Affiliation(s)
- Ji-Hua Shi
- Department of Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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31
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Zhu K, Dai Z, Zhou J. Biomarkers for hepatocellular carcinoma: progression in early diagnosis, prognosis, and personalized therapy. Biomark Res 2013; 1:10. [PMID: 24252133 PMCID: PMC4177612 DOI: 10.1186/2050-7771-1-10] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2012] [Accepted: 02/02/2013] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Currently, surgical resection, liver transplantation, and local ablation are considered curative therapeutic practices for HCC. The diagnosis of HCC without pathologic confirmation is achieved by analyzing serum alpha-fetoprotein (AFP) levels combined with imaging techniques, including ultrasonography, magnetic resonance imaging, and computerized tomography. Although progress has been made in the diagnosis and management of HCC, its prognosis remains dismal. Various new technologies have identified numerous novel biomarkers with potential diagnostic as well as prognostic value, including Dickkopf-1 and Golgi protein 73. These biomarkers not only help in the early diagnosis and prediction of prognosis, but also assist in identifying potential targets for therapeutic interventions. In this article, we provide an up-to-date review of the biomarkers that are used for early diagnosis, prognosis prediction, and personalized treatment of HCC.
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Affiliation(s)
- Kai Zhu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China
| | - Zhi Dai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
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Kohi MP, Fidelman N, Naeger DM, LaBerge JM, Gordon RL, Kerlan RK. Hepatotoxicity after transarterial chemoembolization and transjugular intrahepatic portosystemic shunt: do two rights make a wrong? J Vasc Interv Radiol 2012. [PMID: 23176968 DOI: 10.1016/j.jvir.2012.08.032] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
PURPOSE To compare the rates of hepatotoxicity after transarterial chemoembolization for hepatocellular carcinoma (HCC) in patients with and without a transjugular intrahepatic portosystemic shunt (TIPS) who were stratified into comparable risk groups. MATERIALS AND METHODS A retrospective review of patients with HCC who were treated with transarterial chemoembolization between January 2005 and December 2009 was performed. Of 158 patients with comparable model for end-stage liver disease (MELD) scores, 10 had a patent TIPS. Hepatobiliary severe adverse events (SAEs) occurring after transarterial chemoembolization were documented. In addition, 1-year survival and liver transplantation rate after transarterial chemoembolization were calculated in each group. RESULTS The incidence of hepatobiliary SAEs after transarterial chemoembolization was nearly two times higher in patients with a TIPS (70%) than in patients without a TIPS (36%; P=.046). The liver transplantation rate 1 year after transarterial chemoembolization was 2.5 times higher in patients with a TIPS (80%) than in patients without a TIPS (32%; P=.004). There was no significant difference in 1-year survival between the two groups after transarterial chemoembolization. CONCLUSIONS Patients with HCC and a patent TIPS are more likely to develop significant hepatotoxicity after transarterial chemoembolization than comparable patients without a TIPS in place.
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Affiliation(s)
- Maureen P Kohi
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA.
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Kudo M. Signaling pathway/molecular targets and new targeted agents under development in hepatocellular carcinoma. World J Gastroenterol 2012; 18:6005-17. [PMID: 23155330 PMCID: PMC3496878 DOI: 10.3748/wjg.v18.i42.6005] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Revised: 06/15/2011] [Accepted: 06/21/2011] [Indexed: 02/06/2023] Open
Abstract
Advances in molecular cell biology over the last decade have clarified the mechanisms involved in cancer growth, invasion, and metastasis, and enabled the development of molecular-targeted agents. To date, sorafenib is the only molecular-targeted agent whose survival benefit has been demonstrated in two global phase III randomized controlled trials, and has been approved worldwide. Phase III clinical trials of other molecular targeted agents comparing them with sorafenib as first-line treatment agents are ongoing. Those agents target the vascular endothelial growth factor, platelet-derived growth factor receptors, as well as target the epidermal growth factor receptor, insulin-like growth factor receptor and mammalian target of rapamycin, in addition to other molecules targeting other components of the signal transduction pathways. In addition, the combination of sorafenib with standard treatment, such as resection, ablation, transarterial embolization, and hepatic arterial infusion chemotherapy are ongoing. This review outlines the main pathways involved in the development and progression of hepatocellular carcinoma and the new agents that target these pathways. Finally, the current statuses of clinical trials of new agents or combination therapy with sorafenib and standard treatment will also be discussed.
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Salvadori M. Antineoplastic effects of mammalian target of rapamycine inhibitors. World J Transplant 2012; 2:74-83. [PMID: 24175199 PMCID: PMC3782237 DOI: 10.5500/wjt.v2.i5.74] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Revised: 08/08/2012] [Accepted: 10/20/2012] [Indexed: 02/05/2023] Open
Abstract
Cancer after transplantation is the third cause of death and one of the more relevant comorbidities. Aim of this review is to verify the role of different pathogenetic mechanisms in cancer development in transplant patients and in general population as well. In particular has been outlined the different role exerted by two different families of drug as calcineurin inhibitor and mammalian target of rapamycin (mTOR) inhibitor. The role of mTOR pathways in cell homeostasis is complex but enough clear. As a consequence the mTOR pathway deregulation is involved in the genesis of several cancers. Hence the relevant role of mTOR inhibitors. The authors review the complex mechanism of action of mTOR inhibitors, not only for what concerns the immune system but also other cells as endothelial, smooth muscle and epithelial cells. The mechanism of action is still now not completely defined and understood. It implies the inhibition of mTOR pathway at different levels, but mainly at level of the phosphorylation of several intracellular kinases that contribute to activate mTOR complex. Many prospective and retrospective studies in transplant patients document the antineoplastic role of mTOR inhibition. More recently mTOR inhibitors proven to be effective in the treatment of some cancers also in general population. Kidney cancers, neuroendocrine tumors and liver cancers seem to be the most sensitive to these drugs. Best results are obtained with a combination treatment, targeting the mTOR pathway at different levels.
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Affiliation(s)
- Maurizio Salvadori
- Maurizio Salvadori, Renal Unit, Careggi University Hospital, Viale Pieraccini 18, Florence 50139, Italy
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35
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Li C, Ge M, Yin Y, Luo M, Chen D. Silencing expression of ribosomal protein L26 and L29 by RNA interfering inhibits proliferation of human pancreatic cancer PANC-1 cells. Mol Cell Biochem 2012; 370:127-39. [PMID: 22868929 DOI: 10.1007/s11010-012-1404-x] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Accepted: 07/25/2012] [Indexed: 01/24/2023]
Abstract
Oncogenic KRAS, an important target for antitumor therapy, contributes to pancreatic cancer tumorigenesis, progression and maintenance. However, intracellular compensation regulation can help cells to resist the targeted therapy. Gene knockdown method such as RNAi may help to understand this intracellular regulatory system and discover novel therapeutic approach. In this study, two stable transfected cell lines were constructed through lentivirus-mediated shRNA targeting KRAS of PANC-1 cells, to investigate cell response to the knockdown of KRAS. Human whole genome microarray was then used to compare the gene expression profile. As a result, ribosomal proteins L26 and L29 (RPL26 and RPL29) were dramatically upregulated by KRAS-shRNA specifically. To identify whether RPL26 or RPL29 was critical for PANC-1 cells, siRNAs against RPL26 and RPL29 were designed and transfected in vitro. The results showed that knockdown of RPL26 or RPL29 expression significantly suppressed cell proliferation, induced cell arrest at G0/G1 phase and enhanced cell apoptosis. Reactive oxygen species (ROS) assay indicated that silencing of RPL26 or RPL29 markedly decreased the intracellular ROS generation. Our findings imply that siRNA interference against RPL26 and RPL29 is of potential value for intervention of pancreatic cancer.
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Affiliation(s)
- Chaodong Li
- School of Biotechnology, East China University of Science and Technology, Shanghai, People's Republic of China
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36
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Wang TH, Ng KF, Yeh TS, Wang YL, Liang KH, Yeh CT, Chen TC. Peritumoral small ephrinA5 isoform level predicts the postoperative survival in hepatocellular carcinoma. PLoS One 2012; 7:e41749. [PMID: 22860012 PMCID: PMC3408466 DOI: 10.1371/journal.pone.0041749] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2012] [Accepted: 06/25/2012] [Indexed: 12/22/2022] Open
Abstract
Background EphrinA5, a member of Eph/Ephrin family, possesses two alternative isoforms, large ephrinA5 isoform (ephrinA5L) and small ephrinA5 isoform (ephrinA5S). EphrinA5L is a putative tumor suppressor in several types of human cancers. However, the role of ephrinA5S in hepato-carcinogenesis remains unclear. In this study, we evaluate the role of ephrinA5 isoforms in human hepatocellular carcinomas (HCC). Methodology/Principal Findings A total of 142 paired HCCs and peritumoral liver tissue was examined for relative expression of ephrinA5L and ephrinA5S by using quantitative real-time polymerase chain reaction. We analyzed their expression in relation to clinical parameters, disease-free survival and overall survival. Functional assays were performed to dissect the possible underlying mechanisms. Both ephrinA5L and ephrinA5S were significantly downregulated in HCCs, as compared to those in peritumoral tissue (p = 0.013 and 0.001). Univariate analysis demonstrated that ephrinA5S was positively correlated with old age and histological grade. In multivariate analysis, high ephrinA5S expression in peritumoral tissue had better disease-free survival (p = 0.002) and overall survival (p = 0.045) in patients with HCC after surgical resection. Functional analysis in HCC cell lines revealed that ephrinA5S had a more potent suppressive effect than ephrinA5L on cell proliferation (p<0.05) and migration (p<0.01). Furthermore, forced expression of both ephrinA5 isoforms in HCC cell lines significantly down-regulated epidermal growth factor receptor (EGFR) expression by promoting c-Cbl-mediated EGFR degradation. Conclusions/Significance EphrinA5S might be a useful prognostic biomarker for HCCs after surgical resection. EphrinA5, especially ephrinA5S, acts as a tumor suppressor in hepatocarcinogenesis. Peritumoral small ephrinA5 isoform level could determine the postoperative survival in hepatocellular carcinoma.
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Affiliation(s)
- Tong-Hong Wang
- Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
| | - Kwai-Fong Ng
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
| | - Ta-Sen Yeh
- Department of General Surgery, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
| | - Yu-Ling Wang
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
| | - Kung-Hao Liang
- Department of Hepato-Gastroenterology, Liver Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Chau-Ting Yeh
- Department of Hepato-Gastroenterology, Liver Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan
- * E-mail: (TCC); (CTY)
| | - Tse-Ching Chen
- Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
- * E-mail: (TCC); (CTY)
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Ma Y, Xu YC, Tang L, Zhang Z, Wang J, Wang HX. Cytokine-induced killer (CIK) cell therapy for patients with hepatocellular carcinoma: efficacy and safety. Exp Hematol Oncol 2012; 1:11. [PMID: 23210562 PMCID: PMC3514101 DOI: 10.1186/2162-3619-1-11] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Accepted: 04/26/2012] [Indexed: 12/24/2022] Open
Abstract
Purpose To evaluate the efficacy of cytokine-induced killer (CIK) cell therapy in the treatment of hepatocellular carcinoma. Materials and methods Randomized phase II and III trials on CIK cell-based therapy were identified by electronic searches using a combination of "hepatocellular carcinoma" and "cytokine-induced killer cells". Results The analysis showed significant survival benefit (one-year survival, p < 0.001; two-year survival, p < 0.001; median overall survival, p < 0.001) in favor of CIK-based therapy. Comparison of CIK group versus non-CIK group resulted in a significantly prolonged progression-free survival (PFS) (p < 0.01). A favored disease control rate (DCR) and overall response rate (ORR) were also observed in patients receiving CIK cell therapy (p < 0.01). Meanwhile, patients in the CIK group showed better quality of life (QoL), diminished HBV-DNA content and AFP level (p < 0.01). Comparing T-lymphocyte subsets in peripheral blood, the analysis showed the ratio of CD3+, CD4+, CD4+CD8+ and CD3+CD4+ T cells significantly increased in the CIK group, compared with the non-CIK group (p < 0.01). Conclusions CIK cell therapy demonstrated a significant superiority in prolonging the median overall survival, PFS, DCR, ORR and QoL of HCC patients. These results support further larger scale randomized controlled trials for HCC patients with or without the combination of other therapeutic methods.
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Affiliation(s)
- Yue Ma
- Department of Oncology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
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Lack of amino acids in mouse hepatocytes in culture induces the selection of preneoplastic cells. Cell Signal 2012; 24:325-32. [DOI: 10.1016/j.cellsig.2011.09.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Accepted: 09/12/2011] [Indexed: 11/22/2022]
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Sengupta B, Siddiqi S. Hepatocellular carcinoma: important biomarkers and their significance in molecular diagnostics and therapy. Curr Med Chem 2012; 19:3722-9. [PMID: 22680921 PMCID: PMC11447867 DOI: 10.2174/092986712801661059] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Revised: 02/06/2012] [Accepted: 02/28/2012] [Indexed: 11/22/2022]
Abstract
The increasing incidence of hepatocellular carcinoma (HCC) is of great concern not only in the United States but throughout the world because of two major reasons: firstly, HCC is one of the most lethal form of malignancies with less than 10% survival rate and secondly, a lack of prudent diagnostics makes early detection of HCC nearly impossible. The poor prognosis of HCC accentuates the need to develop new diagnostic markers and therapeutic approaches. In this review we discuss recent advances made in the discovery of molecular biomarkers and their significance in the detection of HCC. We focus on three major classes of biomarkers: serological, tumor, peri-tumoral tissue and cancer stem cell markers. Considerable progress has been made recently in our understanding of HCC at the molecular level increasing the potential of molecular targeted therapy. A number of molecular targets have been identified that have been showing promising results. Of particular interest is Sorafenib, a multi-tyrosine kinase inhibitor that has been approved for the HCC treatment. Inhibitors of other molecular targets such as VEGF, EGFR, mTOR etc. are emerging as plausible therapeutic agents for the treatment of HCC and are discussed in this review.
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Affiliation(s)
- B. Sengupta
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
| | - S.A. Siddiqi
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
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Coexpression of PDGFR-alpha, PDGFR-beta and VEGF as a prognostic factor in patients with hepatocellular carcinoma. Int J Biol Markers 2011; 26:108-16. [PMID: 21574155 DOI: 10.5301/jbm.2011.8322] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/30/2011] [Indexed: 12/16/2022]
Abstract
AIMS To evaluate the prognostic value of vascular endothelial growth factor (VEGF), platelet-derived growth factor receptor-alpha (PDGFR-a) and beta (PDGFR-ß) expression in patients with hepatocellular carcinoma (HCC).? METHODS The expression of PDGFR-a, PDGFR-ß and VEGF in 63 HCC patients who underwent curative resection was examined by immunohistochemistry (IHC). The correlations between the expression of these biomarkers and the clinicopathological characteristics were analyzed. Patient survival was analyzed by univariate analysis and Cox proportional hazards model.? RESULTS Univariate survival analysis showed that PDGFR-a or PDGFR-ß overexpression was of no prognostic significance in predicting disease-free survival (DFS) and overall survival (OS) (p>0.05), while VEGF overexpression and PDGFR-a/PDGFR-ß/VEGF coexpression were significantly correlated with worse DFS and poorer OS in HCC patients (p<0.05). More importantly, PDGFR-a/PDGFR-ß/VEGF coexpression was an independent prognostic marker for poor survival as indicated by multivariate Cox regression analysis (DFS, hazard ratio 3.122, p=0.001; OS, hazard ratio 4.260, p=0.000).? CONCLUSIONS Coexpression of PDGFR-a, PDGFR-ß and VEGF could be considered an independent prognostic biomarker for predicting DFS and OS in HCC patients. This result could be used to identify patients at a higher risk of tumor recurrence and poor prognosis, and help to select therapeutic schemes for the treatment of HCC.
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Scheele JS, Harder J, Stankovic Z, Räpple D, Dorn A, Spangenberg HC, Blum HE. Clinical response to Auron Misheil Therapy in a man with advanced multifocal hepatocellular carcinoma: A case report. J Med Case Rep 2011; 5:478. [PMID: 21943068 PMCID: PMC3204300 DOI: 10.1186/1752-1947-5-478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2010] [Accepted: 09/24/2011] [Indexed: 11/10/2022] Open
Abstract
Introduction Auron Misheil Therapy was developed based on similarities between carcinogenesis and inflammation. Auron Misheil Therapy is a combination of natural and synthetic compounds, including anti-inflammatory drugs and insulin, expected to exhibit synergistic effects. Case presentation Here, we report the case of a 78-year-old Caucasian male patient who presented with multifocal hepatocellular carcinoma and chronic hepatitis C virus infection. Over a four-year period our patient was treated with radiofrequency ablation and transarterial chemoembolization. After these treatments there was tumor progression, with new hyperperfused lesions without evidence of extrahepatic tumor involvement. Our patient refused sorafenib therapy. Therefore, he received twice daily intramuscular injections of Auron Misheil Therapy on an outpatient basis for two months. Partial remission of the hepatic lesions was observed eight weeks after the start of treatment, and confirmed four weeks later. Unfortunately, at that time our patient refused therapy due to dizziness. During follow-up two target lesions remained stable, but one lesion increased in size. At the latest follow-up, one year later, there was still tumor control. Conclusion While the mechanisms underlying the antitumor effects of Auron Misheil Therapy are not fully understood, stable disease and remissions have been observed in different types of tumors, including hepatocellular carcinoma.
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Affiliation(s)
- Jürgen S Scheele
- Department of Hematology and Oncology, University Medical Center Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
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Abstract
In recent years, molecular-targeted agents have been used clinically to treat various malignant tumors. In May 2009, sorafenib (Nexavar®) was approved in Japan for 'unresectable hepatocellular carcinoma (HCC)', and was the first molecular-targeted agent for use in HCC. To date, sorafenib is the only molecular-targeted agent whose survival benefit has been demonstrated in two global phase III randomized controlled trials, and has now been approved worldwide. Phase III clinical trials of other molecular-targeted agents comparing them with sorafenib as first-line treatment agents are now ongoing. Those agents target the vascular endothelial growth factor, platelet-derived growth factor receptors, as well as target the epidermal growth factor receptor, insulin-like growth factor receptor and mammalian target of rapamycin, in addition to other molecules targeting other components of the signal transduction pathways. This review outlines the main pathways involved in the development and progression of HCC and the agents that target these pathways. Finally, current status and future perspective will also be discussed.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan.
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Abstract
This article highlights the current knowledge of mTOR biology and provides new insights into the role of mTOR in different cancers. An active mTOR coordinates a response in cell growth directly through its effects on cell cycle regulators and indirectly by sustaining nutrient supply into the cell through the production of nutrient transporters and also through the promotion of angiogenesis. A primary way that mTOR exerts its regulatory effects on cell proliferation is by controlling the production of cyclin D1. mTOR increases the translation of hypoxia-inducible factor 1 (HIF-1)/HIF-2. The HIF transcription factors drive the expression of hypoxic stress response genes, including angiogenic growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor β (PDGF-β), and transforming growth factor a (TGF-α). mTOR also increases the surface expression of nutrient transporters proteins. An increase in these proteins results in greater uptake of amino acids and other nutrients by the cell leading to adequate nutrient support to abnormal cell growth and survival. There is also emerging evidence that mTOR activation may play a role in promoting cell survival through the activation of antiapoptotic proteins that contribute to tumor progression. Given that the mTOR pathway is deregulated in a number of cancers, it is anticipated that mTOR inhibitors will have broad therapeutic application across many tumor types. Until now, no treatment demonstrated Phase III evidence after disease progression on an initial VEGF-targeted therapy in advanced renal cell carcinoma. Everolimus is the first and only therapy with Phase III evidence after failure of VEGF-targeted therapy. Everolimus is a once-daily, oral inhibitor of mTOR (mammalian target of rapamycin) indicated for the treatment of advanced renal cell carcinoma in patients, whose disease has progressed on or after treatment with VEGF-targeted therapy.
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Affiliation(s)
- S H Advani
- Jaslok Hospital and Research Centre, Mumbai, Maharashtra, India
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Chua CWL, Choo SP. Targeted therapy in hepatocellular carcinoma. Int J Hepatol 2011; 2011:348297. [PMID: 21994852 PMCID: PMC3170762 DOI: 10.4061/2011/348297] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2011] [Accepted: 03/01/2011] [Indexed: 12/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the commonest cancers worldwide, as well as a common cause of cancer-related death. HCC frequently occurs in the setting of a diseased cirrhotic liver and many patients present at an advanced stage of disease. Together with a poor functional status, this often precludes the use of systemic therapy, especially conventional cytotoxic drugs. Moreover, HCC is known to be a relatively chemo-refractory tumor. There have been many targeted drugs that have shown potential in the treatment of HCC. Many clinical trials have been carried out with many more in progress. They include trials evaluating a single targeted therapy alone, two or more targeted therapy in tandem or a combination of targeted therapy and conventional chemotherapy. In this article, we seek to review some of the more important trials examining the use of targeted therapy in HCC and to look into what the future holds in terms of targeted treatment of HCC.
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Affiliation(s)
- Clarinda W. L. Chua
- Department of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, 169610, Singapore
| | - Su Pin Choo
- Department of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, 169610, Singapore
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Abstract
Liver resection and liver transplantation are the treatment modalities with the greatest potential for curing hepatocellular carcinoma (HCC). Tumor recurrence after resection for HCC is, however, a major problem, and an increased rate of recurrence after living donor transplantation versus cadaveric whole liver transplantation has been suggested. Factors involved in liver regeneration may stimulate the growth of occult tumors. The aim of this project was to test the hypothesis that a microscopic HCC tumor in the setting of partial hepatectomy would show enhanced growth and signs of increased invasiveness corresponding to the size of the liver resection. Hepatectomy was performed to various degrees in groups of Buffalo rats with the concomitant implantation of a fixed number of hepatoma cells in the remnant liver; a control group underwent only resection. After 21 days, the sizes and numbers of the tumors and the expression of alpha-fetoprotein (AFP), cyclin D1, calpain small subunit 1 (CAPNS1), CD34 (a microvessel density marker), vascular endothelial growth factor (VEGF), and vascular endothelial growth factor receptor 2 (VEGFR2) were evaluated and compared between the groups. The tumor volume and number increased significantly with the size of the partial hepatectomy (P < 0.05). The largest resections were also associated with increased hepatoma cell infiltration in the lungs and significant up-regulation of cyclin D1, AFP, CAPNS1, CD34, VEGF, and VEGFR2. The results suggest that liver regeneration after partial hepatectomy facilitates the growth and malignant transformation of microscopic HCC, and this could be significant for liver resection and partial liver transplantation strategies for HCC.
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Affiliation(s)
- Ji-Hua Shi
- Department of Organ Transplantation, Rikshospitalet, Oslo University Hospital, Oslo, Norway
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Cuevas MJ, Tieppo J, Marroni NP, Tuñón MJ, González-Gallego J. Suppression of amphiregulin/epidermal growth factor receptor signals contributes to the protective effects of quercetin in cirrhotic rats. J Nutr 2011; 141:1299-305. [PMID: 21562239 DOI: 10.3945/jn.111.140954] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The hepatic wound-healing response to chronic noxious stimuli may lead to liver fibrosis, a key feature of the preneoplastic cirrhotic liver. Fibrogenic cells activate in response to a variety of cytokines, growth factors, and inflammatory mediators. The involvement of members of the epidermal growth factor family in this process has been suggested. Amphiregulin is an epidermal growth factor receptor (EGFR) ligand specifically induced upon liver injury. We investigated the effects of quercetin on the amphiregulin/EGFR signal and on the activation of downstream pathways leading to cell growth. Rats were divided into 4 groups (8 rats/group): rats subjected to common bile duct ligation (CBDL), Sham (rats subjected to simulated CBDL), quercetin-treated sham, and quercetin-treated CBDL (CBDL-Q). Quercetin (50 mg/kg i.p. injection) was administered daily for 2 wk starting on d 14 after surgery. Overexpression of amphiregulin, EGFR, TNFα, IL-6, TGFβ, platelet-derived growth factor (PDGF), extracellular regulated kinase, protein kinase B (Akt), cycloxygenase (COX)-2, and glioma-associated oncogenes (GLI)-1 and-2 were observed in liver of CBDL rats after 4 wk of bile duct ligation. CBDL-Q rats had a significantly diminished expression of amphiregulin and EGFR compared with untreated CBDL rats. Furthermore, mRNA levels of TNFα, IL-6, TGFβ, and PDGF and the protein content of COX-2, GLI-1, and GLI-2 were significantly lower in CBDL-Q rats than in untreated CBDL rats. The findings indicate that quercetin ameliorated activation of survival pathways and downregulated the expression of genes related to inflammation and precancerous conditions. Suppression of amphiregulin/EGFR signals may contribute to this effect.
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Affiliation(s)
- María J Cuevas
- Institute of Biomedicine, University of León, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, 24071 León, Spain
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Wilczynski J, Duechler M, Czyz M. Targeting NF-κB and HIF-1 pathways for the treatment of cancer: part I. Arch Immunol Ther Exp (Warsz) 2011; 59:289-99. [PMID: 21625848 DOI: 10.1007/s00005-011-0131-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2010] [Accepted: 03/02/2011] [Indexed: 02/06/2023]
Abstract
The process of chronic inflammation is a common link which connects different kinds of environmental pollutants and infections with tumorigenesis. Transcription factor NF-κB is a common final target for many inflammatory and cell proliferation pathways, independent of the source of stimuli (e.g., cytokines, growth factors, environmental carcinogens, radiation, hypoxia, bacteria, and viruses). Over-activation of NF-κB has been confirmed in many tumors, resulting in worse prognosis for patient survival. Therefore, inhibition of cellular pathways for NF-κB activation is nowadays considered as a promising anti-cancer therapy and is extensively studied in clinical trials, or even has been adopted as an approved therapy in some kinds of cancer.
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Affiliation(s)
- Jacek Wilczynski
- "Polish Mother's Health Center" Research Institute, Lodz, Poland.
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Montella L, Addeo R, Caraglia M, Del Prete S. Latest developments in targeted therapy for hepatocellular carcinoma. Expert Rev Anticancer Ther 2011; 10:1635-46. [PMID: 20942634 DOI: 10.1586/era.10.146] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The advent of sorafenib can be considered as a turning point in the history of advanced hepatocellular carcinoma. After unfortunate attempts at using chemotherapy, drugs targeting key pathways have generated new perspectives in this field. This means not only killing both tumor cells and cirrhotic fragile tissue, but killing them selectively; more than was previously possible. This seems like the Copernican Revolution. However, hepatocellular carcinoma is pathogenetically complicated, resulting from the number of mutations. Until now, there has not been a single drug able to block and reverse abnormally activated signaling in hepatocellular carcinoma cells. In this article, we describe the most promising targeted drugs being studied in hepatocellular carcinoma and depict the possible future scenarios.
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Affiliation(s)
- Liliana Montella
- Medical Oncology Unit, San Giovanni di Dio Hospital, via D. Pirozzi, 80027 Frattamaggiore, Naples, Italy.
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Maass T, Thieringer FR, Mann A, Longerich T, Schirmacher P, Strand D, Hansen T, Galle PR, Teufel A, Kanzler S. Liver specific overexpression of platelet-derived growth factor-B accelerates liver cancer development in chemically induced liver carcinogenesis. Int J Cancer 2011; 128:1259-68. [PMID: 20506153 DOI: 10.1002/ijc.25469] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
A genetic basis of hepatocellular carcinoma (HCC) has been well-established and major signaling pathways, such as p53, Wnt-signaling, transforming growth factor-β (TGF-β) and Ras pathways, have been identified to be essential to HCC development. Lately, the family of platelet-derived growth factors (PDGFs) has shifted to the center of interest. We have reported on spontaneously developing liver fibrosis in PDGF-B transgenic mice. Since HCC rarely occurs in healthy liver, but dramatically increases at the cirrhosis stage of which liver fibrosis is a preliminary stage, we investigated liver cancer development in chemically induced liver carcinogenesis in these mice. HCC induction was performed by treatment of the mice with diethylnitrosamine and phenobarbital. At an age of 6 months, the tumor development of these animals was analyzed. Not only the development of dysplastic lesions in PDGF-B transgenic mice was significantly increased but also their malignant transformation to HCC. Furthermore, we were able to establish a key role of PDGF-B signaling at diverse stages of liver cancer development. Here, we show that development of liver fibrosis is likely through upregulation of TGF-β receptors by PDGF-B. Additionally, overexpression of PDGF-B also leads to an increased expression of β-catenin as well as vascular endothelial growth factor and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), all factors with established roles in carcinogenesis. We were able to extend the understanding of key genetic regulators in HCC development by PDGF-B and decode essential downstream signals.
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Affiliation(s)
- Thorsten Maass
- Department of Medicine I, Johannes Gutenberg-University, Mainz, Germany
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Beljanski V, Lewis CS, Smith CD. Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts. Cancer Biol Ther 2011; 11:524-34. [PMID: 21258214 DOI: 10.4161/cbt.11.5.14677] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The balance between the pro-apoptotic lipids ceramide and sphingosine and the pro-survival lipid sphingosine 1-phosphate (S1P) is termed the "sphingosine rheostat". Two isozymes, sphingosine kinase 1 and 2 (SK1 and SK2), are responsible for phosphorylation of pro-apoptotic sphingosine to form pro-survival S1P. We have previously reported the antitumor properties of an SK2 selective inhibitor, ABC294640, alone or in combination with the multikinase inhibitor sorafenib in mouse models of kidney carcinoma and pancreatic adenocarcinoma. Here we evaluated the combined antitumor effects of the aforementioned drug combination in two mouse models of hepatocellular carcinoma. Although combining the SK2 inhibitor, ABC294640, and sorafenib in vitro only afforded additive drug-drug effects, their combined antitumor properties in the mouse model bearing HepG2 cells mirrored effects previously observed in animals bearing kidney carcinoma and pancreatic adenocarcinoma cells. Combining ABC294640 and sorafenib led to a decrease in the levels of phosphorylated ERK in SK-HEP-1 cells, indicating that the antitumor effect of this drug combination is likely mediated through a suppression of the MAPK pathway in hepatocellular models. We also measured levels of S1P in the plasma of mice treated with two different doses of ABC294640 and sorafenib. We found decreases in the levels of S1P in plasma of mice treated daily with 100 mg/kg of ABC294640 for 5 weeks, and this decrease was not affected by co-administration of sorafenib. Taken together, these data support combining ABC294640 and sorafenib in clinical trials in HCC patients. Furthermore, monitoring levels of S1P may provide a pharmacodynamic marker of ABC294640 activity.
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Affiliation(s)
- Vladimir Beljanski
- Drug Discovery Core; Hollings Cancer Center, Medical University of South Carolina, Charleston, USA
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