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Xiao G, Huang X, Huang T, Chen Z, Huang Y, Huang R, Wang X. Hepatitis B virus X protein differentially regulates the angiogenesis of Hepatocellular Carcinoma through p53-VEGF axis according to glucose levels. Ann Hepatol 2024; 29:101543. [PMID: 39216627 DOI: 10.1016/j.aohep.2024.101543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 06/07/2024] [Accepted: 06/13/2024] [Indexed: 09/04/2024]
Abstract
INTRODUCTION AND OBJECTIVES Blood glucose fluctuates severely in the diabetes (DM) and tumor microenvironment. Our previous works have found Hepatitis B virus X protein (HBx) differentially regulated metastasis and apoptosis of hepatoma cells depending on glucose concentration. We here aimed to explore whether HBx played dual roles in the angiogenesis of hepatocellular carcinoma varying on different glucose levels. MATERIALS AND METHODS We collected conditioned medium from HBx-overexpressing cells cultured with two solubilities of glucose, and then applied to EA.hy926 cells. Alternatively, a co-culture cell system was established with hepatoma cells and EA.hy926 cells. We analyzed the angiogenesis of EA.hy926 cells with CCK8, wound-healing, transwell-migartion and tube formation experiment. ELISA was conducted to detect the secretion levels of angiogenesis-related factors. siRNAs were used to detect the P53-VEGF axis. RESULTS HBx expressed in hepatoma cells suppressed VEGF secretion, and subsequently inhibited the proliferation, migration and tube formation of EA.hy926 cells in a high glucose condition, while attenuating these in the lower glucose condition. Furthermore, the p53-VEGF axis was required for the dual role of HBx in angiogenesis. Additionally, HBx mainly regulated the nuclear p53. CONCLUSIONS These data suggest that the dual roles of HBx confer hepatoma cells to remain in a glucose-rich environment and escape from the glucose-low milieu through tumor vessels, promoting liver tumor progression overall. We exclusively revealed the dual role of HBx on the angiogenesis of liver tumors, which may shed new light on the mechanism and management strategy of HBV- and DM-related hepatocellular carcinoma.
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Affiliation(s)
- Guitao Xiao
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China; Department of Cardiology, Longyan First Affiliated Hospital of Fujian Medical University, 105, Jiuyibei Road, Xin Luo, Longyan, Fujian 364000, PR China
| | - Xiaoyun Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China; Fujian Medical University Cancer Center, Fujian Medical University, 1, Xuefubei Road, Minhou, Fuzhou, Fujian 350001, PR China
| | - Tingxuan Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China
| | - Zhixin Chen
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China
| | - Yuehong Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China
| | - Rongfeng Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China; Fujian Medical University Cancer Center, Fujian Medical University, 1, Xuefubei Road, Minhou, Fuzhou, Fujian 350001, PR China.
| | - Xiaozhong Wang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China; Fujian Medical University Cancer Center, Fujian Medical University, 1, Xuefubei Road, Minhou, Fuzhou, Fujian 350001, PR China.
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Liu B, Liu Y, Li S, Chen P, Zhang J, Feng L. Depletion of placental brain-derived neurotrophic factor (BDNF) is attributed to premature ovarian insufficiency (POI) in mice offspring. J Ovarian Res 2024; 17:141. [PMID: 38982490 PMCID: PMC11232340 DOI: 10.1186/s13048-024-01467-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 06/29/2024] [Indexed: 07/11/2024] Open
Abstract
INTRODUCTION Premature ovarian insufficiency (POI) is one of the causes of female infertility. Unexplained POI is increasingly affecting women in their reproductive years. However, the etiology of POI is diverse and remains elusive. We and others have shown that brain-derived neurotrophic factor (BDNF) plays an important role in adult ovarian function. Here, we report on a novel role of BDNF in the Developmental Origins of POI. METHODS Placental BDNF knockout mice were created using CRISPR/CAS9. Homozygous knockout (cKO(HO)) mice didn't survive, while heterozygous knockout (cKO(HE)) mice did. BDNF reduction in cKO(HE) mice was confirmed via immunohistochemistry and Western blots. Ovaries were collected from cKO(HE) mice at various ages, analyzing ovarian metrics, FSH expression, and litter sizes. In one-month-old mice, oocyte numbers were assessed using super-ovulation, and oocyte gene expression was analyzed with smart RNAseq. Ovaries of P7 mice were studied with SEM, and gene expression was confirmed with RT-qPCR. Alkaline phosphatase staining at E11.5 and immunofluorescence for cyclinD1 assessed germ cell number and cell proliferation. RESULTS cKO(HE) mice had decreased ovarian function and litter size in adulthood. They were insensitive to ovulation induction drugs manifested by lower oocyte release after superovulation in one-month-old cKO(HE) mice. The transcriptome and SEM results indicate that mitochondria-mediated cell death or aging might occur in cKO(HE) ovaries. Decreased placental BDNF led to diminished primordial germ cell proliferation at E11.5 and ovarian reserve which may underlie POI in adulthood. CONCLUSION The current results showed decreased placental BDNF diminished primordial germ cell proliferation in female fetuses during pregnancy and POI in adulthood. Our findings can provide insights into understanding the underlying mechanisms of POI.
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Affiliation(s)
- Bin Liu
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, China
- Department of Reproduction, School of Medicine, Xinhua Hospital, Shanghai Jiao-Tong University, Shanghai, China
| | - Yongjie Liu
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Shuman Li
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Pingping Chen
- Department of Reproduction, School of Medicine, Xinhua Hospital, Shanghai Jiao-Tong University, Shanghai, China
| | - Jun Zhang
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, China.
| | - Liping Feng
- Department of Obstetrics and Gynaecology, Duke University, Durham, NC, USA.
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Lan Q, Li J, Zhang H, Zhou Z, Fang Y, Yang B. Mechanistic complement of autosomal dominant polycystic kidney disease: the role of aquaporins. J Mol Med (Berl) 2024; 102:773-785. [PMID: 38668786 DOI: 10.1007/s00109-024-02446-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 04/05/2024] [Accepted: 04/09/2024] [Indexed: 05/21/2024]
Abstract
Autosomal dominant polycystic kidney disease is a genetic kidney disease caused by mutations in the genes PKD1 or PKD2. Its course is characterized by the formation of progressively enlarged cysts in the renal tubules bilaterally. The basic genetic explanation for autosomal dominant polycystic kidney disease is the double-hit theory, and many of its mechanistic issues can be explained by the cilia doctrine. However, the precise molecular mechanisms underpinning this condition's occurrence are still not completely understood. Experimental evidence suggests that aquaporins, a class of transmembrane channel proteins, including aquaporin-1, aquaporin-2, aquaporin-3, and aquaporin-11, are involved in the mechanism of autosomal dominant polycystic kidney disease. Aquaporins are either a potential new target for the treatment of autosomal dominant polycystic kidney disease, and further study into the physiopathological role of aquaporins in autosomal dominant polycystic kidney disease will assist to clarify the disease's pathophysiology and increase the pool of potential treatment options. We primarily cover pertinent findings on aquaporins in autosomal dominant polycystic kidney disease in this review.
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Affiliation(s)
- Qiumei Lan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China
| | - Jie Li
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China
| | - Hanqing Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China
| | - Zijun Zhou
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China
| | - Yaxuan Fang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China
| | - Bo Yang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China.
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China.
- Department of Nephrology, The First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, No.88, Changling Road, Xiqing District, Tianjin, 300193, China.
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Mehrabi A, Karimi A, Mashayekhan S, Samadikuchaksaraei A, Milan PB. In-situ forming hydrogel based on thiolated chitosan/carboxymethyl cellulose (CMC) containing borate bioactive glass for wound healing. Int J Biol Macromol 2022; 222:620-635. [PMID: 36167099 DOI: 10.1016/j.ijbiomac.2022.09.177] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 09/01/2022] [Accepted: 09/19/2022] [Indexed: 11/28/2022]
Abstract
Suitable wound dressings for accelerating wound healing are actively being designed and synthesised. In this study, thiolated chitosan (tCh)/oxidized carboxymethyl cellulose (OCMC) hydrogel containing Cu-doped borate bioglass (BG) was developed as a wound dressing to improve wound healing in a full-thickness skin defect of mouse animal model. Thiolation was used to incorporate thiol groups into chitosan (Ch) to enhance its water solubility and mucoadhesion characteristics. Here, the in situ forming hydrogel was successfully developed using the Schiff-based reaction, and its physio-chemical and antibacterial characteristics were examined. Borate BG was also incorporated in the generated hydrogel to promote angiogenesis and tissue regeneration at the wound site. Investigations of in vitro cytotoxicity assays demonstrated that the synthesised hydrogels showed good biocompatibility and promoted cell growth. These results inspired us to investigate the effectiveness of skin wound healing in a mouse model. On the backs of animals, two full-thickness wounds were created and treated utilising two different treatment conditions: (1) OCMC/tCh hydrogel, (2) OCMC/tCh/borate BG, and (3) control defect. The wound closure ratio, collagen deposition, and angiogenesis activity were measured after 14 days to determine the healing efficacy of the in situ hydrogels used as wound dressings. Overall, the hydrogel containing borate BG was maintained in the defect site, healing efficiency was replicable, and wound healing was apparent. In conclusion, we found consistent angiogenesis, remodelling, and accelerated wound healing, which we propose may have beneficial effects on the repair of skin defects.
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Affiliation(s)
- Arezou Mehrabi
- Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Afzal Karimi
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shoherh Mashayekhan
- Department of Chemical and Petroleum Engineering, Sharif University of Technology, Azadi Ave., Tehran, Iran
| | - Ali Samadikuchaksaraei
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Peiman Brouki Milan
- Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Chen YX, Zhang JX, Zhou CG, Liu J, Liu S, Shi HB, Zu QQ. Comparison of the Efficacy and Safety of Transarterial Chemoembolization with or without Lenvatinib for Unresectable Hepatocellular Carcinoma: A Retrospective Propensity Score–Matched Analysis. J Hepatocell Carcinoma 2022; 9:685-694. [PMID: 35937909 PMCID: PMC9354863 DOI: 10.2147/jhc.s373250] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 07/23/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- Yu-Xing Chen
- Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, People’s Republic of China
| | - Jin-Xing Zhang
- Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, People’s Republic of China
| | - Chun-Gao Zhou
- Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, People’s Republic of China
| | - Jin Liu
- Department of Clinical Medicine Research Institution, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, People’s Republic of China
| | - Sheng Liu
- Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, People’s Republic of China
| | - Hai-Bin Shi
- Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, People’s Republic of China
| | - Qing-Quan Zu
- Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, People’s Republic of China
- Correspondence: Qing-Quan Zu, Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, People’s Republic of China, Tel +86-25-68306316; +86-13913807470, Fax +86-25-83724440, Email
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Bai Y, Hu X, Ren Z, Hisai T, Yusa W, Weng L, Shiba S, Takase T. A phase I pharmacokinetic study of lenvatinib in Chinese patients with unresectable hepatocellular carcinoma. Future Oncol 2022; 18:2413-2424. [PMID: 35674480 DOI: 10.2217/fon-2022-0229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: This phase I study assessed the pharmacokinetic profile, safety and antitumor activity of lenvatinib in Chinese patients with unresectable hepatocellular carcinoma. Materials & methods: Bodyweight-based lenvatinib dosing was administered (patients <60 kg: 8 mg/day, n = 13; patients ≥60 kg: 12 mg/day, n = 12). Pharmacokinetic sampling was performed during the first cycle. Efficacy and safety were assessed. Results: There was considerable overlap between individual exposure values at steady-state in the 8 and 12 mg groups. The most common adverse events were increased blood bilirubin and decreased platelet count (48.0%). Two patients had partial responses, and 16 patients attained stable disease. Conclusion: No significant pharmacokinetic differences between dose groups were detected. Lenvatinib was tolerable, showing promising antitumor activities in Chinese patients with unresectable hepatocellular carcinoma.
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Affiliation(s)
- Yuxian Bai
- Harbin Medical University Affiliated Cancer Hospital, Harbin, China
| | - Xichun Hu
- Fudan University Affiliated Cancer Hospital, Shanghai, China
| | - Zhenggang Ren
- Fudan University Affiliated Zhongshan Hospital, Shanghai, China
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FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance. Cancers (Basel) 2021; 13:cancers13225796. [PMID: 34830951 PMCID: PMC8616288 DOI: 10.3390/cancers13225796] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/13/2021] [Accepted: 11/16/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Deregulation of the FGF/FGFR axis is associated with many types of cancer and contributes to the development of chemoresistance, limiting the effectiveness of current treatment strategies. There are several mechanisms involved in this phenomenon, including cross-talks with other signaling pathways, avoidance of apoptosis, stimulation of angiogenesis, and initiation of EMT. Here, we provide an overview of current research and approaches focusing on targeting components of the FGFR/FGF signaling module to overcome drug resistance during anti-cancer therapy. Abstract Increased expression of both FGF proteins and their receptors observed in many cancers is often associated with the development of chemoresistance, limiting the effectiveness of currently used anti-cancer therapies. Malfunctioning of the FGF/FGFR axis in cancer cells generates a number of molecular mechanisms that may affect the sensitivity of tumors to the applied drugs. Of key importance is the deregulation of cell signaling, which can lead to increased cell proliferation, survival, and motility, and ultimately to malignancy. Signaling pathways activated by FGFRs inhibit apoptosis, reducing the cytotoxic effect of some anti-cancer drugs. FGFRs-dependent signaling may also initiate angiogenesis and EMT, which facilitates metastasis and also correlates with drug resistance. Therefore, treatment strategies based on FGF/FGFR inhibition (using receptor inhibitors, ligand traps, monoclonal antibodies, or microRNAs) appear to be extremely promising. However, this approach may lead to further development of resistance through acquisition of specific mutations, metabolism switching, and molecular cross-talks. This review brings together information on the mechanisms underlying the involvement of the FGF/FGFR axis in the generation of drug resistance in cancer and highlights the need for further research to overcome this serious problem with novel therapeutic strategies.
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Targeted inhibition of FGF19/FGFR cascade improves antitumor immunity and response rate in hepatocellular carcinoma. Hepatol Int 2021; 15:1236-1246. [PMID: 34333737 DOI: 10.1007/s12072-021-10212-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 05/09/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common liver cancer globally, claiming nearly 1 million lives each year. The overexpression of fibroblast growth factor (FGF) receptors (FGFRs) signaling cascade has been shown to contribute to tumorigenesis, metastasis, and poor prognosis in HCC. Therefore, targeted inhibition of the FGF/FGFR cascade may represent a new treatment strategy for HCC patients. METHODS HCC patient-derived xenograft (PDX) models were implanted into either severe combined immunodeficient (SCID) or CD34+hu-NSG (humanized) mice and subsequently treated with vehicle, infigratinib (FGFR1-3 inhibitor), FGF401 (FGFR4 inhibitor), or the combination of infigratinib and FGF401. Tumor progressions, overall survival of mice, lung metastasis, and drug resistance were monitored, and samples collected at the end of the treatment cycle were subjected to Western blot analyses and immunohistochemistry. RESULTS HCC PDX models expressing high levels of FGF19/FGFR4 or FGFR2/3 showed favorable initial treatment response to FGF401 and infigratinib, respectively. However, progressive disease due to acquired resistance was observed. Combination infigratinib/FGF401 augmented the antitumor activity, response rate, and overall survival of mice. This combination significantly increased the infiltration of B cells, macrophages, CD8+ T cells, and CD4+ T cells associated with granzyme-B-mediated apoptosis, delayed onset of resistance, and inhibited metastasis by potently inhibiting several critical signaling pathways involved in proliferation and metastasis. CONCLUSIONS Our findings suggest that HCC patients with high FGFR2/3 or FGF19/FGFR4 expressing tumors might benefit from a combination infigratinib/FGF401; thus, supporting its evaluation in clinical trials.
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Wang H, Yang J, Zhang K, Liu J, Li Y, Su W, Song N. Advances of Fibroblast Growth Factor/Receptor Signaling Pathway in Hepatocellular Carcinoma and its Pharmacotherapeutic Targets. Front Pharmacol 2021; 12:650388. [PMID: 33935756 PMCID: PMC8082422 DOI: 10.3389/fphar.2021.650388] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/11/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of primary liver cancer with poor prognosis, and its incidence and mortality rate are increasing worldwide. It is refractory to conventional chemotherapy and radiotherapy owing to its high tumor heterogeneity. Accumulated genetic alterations and aberrant cell signaling pathway have been characterized in HCC. The fibroblast growth factor (FGF) family and their receptors (FGFRs) are involved in diverse biological activities, including embryonic development, proliferation, differentiation, survival, angiogenesis, and migration, etc. Data mining results of The Cancer Genome Atlas demonstrate high levels of FGF and/or FGFR expression in HCC tumors compared with normal tissues. Moreover, substantial evidence indicates that the FGF/FGFR signaling axis plays an important role in various mechanisms that contribute to HCC development. At present, several inhibitors targeting FGF/FGFR, such as multikinase inhibitors, specific FGFR4 inhibitors, and FGF ligand traps, exhibit antitumor activity in preclinical or early development phases in HCC. In this review, we summarize the research progress regarding the molecular implications of FGF/FGFR-mediated signaling and the development of FGFR-targeted therapeutics in hepatocarcinogenesis.
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Affiliation(s)
- Haijun Wang
- Key Laboratory of Clinical Molecular Pathology, Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.,School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Jie Yang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Ke Zhang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Jia Liu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Yushan Li
- School of Public Health, Xinxiang Medical University, Xinxiang, China
| | - Wei Su
- Key Laboratory of Clinical Molecular Pathology, Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Na Song
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.,Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China
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FGF/FGFR Signaling in Hepatocellular Carcinoma: From Carcinogenesis to Recent Therapeutic Intervention. Cancers (Basel) 2021; 13:cancers13061360. [PMID: 33802841 PMCID: PMC8002748 DOI: 10.3390/cancers13061360] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 03/11/2021] [Accepted: 03/13/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary As the most common primary liver cancer, HCC is a tricky cancer resistant to systemic therapies. The fibroblast growth factor family and its receptors are gaining more and more attention in various cancers. Noticing an explosion in the number of studies about aberrant FGF/FGFR signaling in HCC being studied, we were encouraged to summarize them. This review discusses how FGF/FGFR signaling influences HCC development and its implications in HCC prediction and target treatment, and combination treatment. Abstract Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, ranking third in cancer deaths worldwide. Over the last decade, several studies have emphasized the development of tyrosine kinase inhibitors (TKIs) to target the aberrant pathways in HCC. However, the outcomes are far from satisfactory due to the increasing resistance and adverse effects. The family of fibroblast growth factor (FGF) and its receptors (FGFR) are involved in various biological processes, including embryogenesis, morphogenesis, wound repair, and cell growth. The aberrant FGF/FGFR signaling is also observed in multiple cancers, including HCC. Anti-FGF/FGFR provides delightful benefits for cancer patients, especially those with FGF signaling alteration. More and more multi-kinase inhibitors targeting FGF signaling, pan-FGFR inhibitors, and selective FGFR inhibitors are now under preclinical and clinical investigation. This review summarizes the aberrant FGF/FGFR signaling in HCC initiating, development and treatment status, and provide new insights into the treatment of HCC.
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Tran A, Koh TS, Prawira A, Ho RZW, Le TBU, Vu TC, Hartano S, Teo XQ, Chen WC, Lee P, Thng CH, Huynh H. Dynamic Contrast-Enhanced Magnetic Resonance Imaging as Imaging Biomarker for Vascular Normalization Effect of Infigratinib in High-FGFR-Expressing Hepatocellular Carcinoma Xenografts. Mol Imaging Biol 2021; 23:70-83. [PMID: 32909245 DOI: 10.1007/s11307-020-01531-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 07/06/2020] [Accepted: 08/09/2020] [Indexed: 12/24/2022]
Abstract
PURPOSE Overexpression of fibroblast growth factor receptor (FGFR) contributes to tumorigenesis, metastasis, and poor prognosis of hepatocellular carcinoma (HCC). Infigratinib-a pan-FGFR inhibitor-potently suppresses the growth of high-FGFR-expressing HCCs in part via alteration of the tumor microenvironment and vessel normalization. In this study, we aim to assess the utility of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) as a non-invasive imaging technique to detect microenvironment changes associated with infigratinib and sorafenib treatment in high-FGFR-expressing HCC xenografts. PROCEDURES Serial DCE-MRIs were performed on 12 nude mice bearing high-FGFR-expressing patient-derived HCC xenografts to quantify tumor microenvironment pre- (day 0) and post-treatment (days 3, 6, 9, and 15) of vehicle, sorafenib, and infigratinib. DCE-MRI data were analyzed using extended generalized kinetic model and two-compartment distributed parameter model. After treatment, immunohistochemistry stains were performed on the harvested tumors to confirm DCE-MRI findings. RESULTS By treatment day 15, infigratinib induced tumor regression (70 % volume reduction from baseline) while sorafenib induced relative growth arrest (185 % volume increase from baseline versus 694 % volume increase from baseline of control). DCE-MRI analysis revealed different changes in microcirculatory parameters upon exposure to sorafenib versus infigratinib. While sorafenib induced microenvironment changes similar to those of rapidly growing tumors, such as a decrease in blood flow (F), fractional intravascular volume (vp), and permeability surface area product (PS), infigratinib induced the exact opposite changes as early as day 3 after treatment: increase in F, vp, and PS. CONCLUSIONS Our study demonstrated that DCE-MRI is a reliable non-invasive imaging technique to monitor tumor microcirculatory response to FGFR inhibition and VEGF inhibition in high-FGFR-expressing HCC xenografts. Furthermore, the microcirculatory changes from FGFR inhibition manifested early upon treatment initiation and were reliably detected by DCE-MRI, creating possibilities of combinatorial therapy for synergistic effect.
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Affiliation(s)
- Anh Tran
- Department of Oncologic Imaging, National Cancer Centre, Singapore, Singapore
| | - Tong San Koh
- Department of Oncologic Imaging, National Cancer Centre, Singapore, Singapore
| | - Aldo Prawira
- Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore
| | - Rebecca Zhi Wen Ho
- Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore
| | - Thi Bich Uyen Le
- Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore
| | - Thanh Chung Vu
- Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore
| | - Septian Hartano
- Department of Oncologic Imaging, National Cancer Centre, Singapore, Singapore
| | - Xing Qi Teo
- Functional Metabolism Group, Agency for Science, Technology and Research, Singapore BioImaging Consortium, Singapore, Singapore
| | | | - Philip Lee
- Functional Metabolism Group, Agency for Science, Technology and Research, Singapore BioImaging Consortium, Singapore, Singapore
| | - Choon Hua Thng
- Department of Oncologic Imaging, National Cancer Centre, Singapore, Singapore.
| | - Hung Huynh
- Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore.
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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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Radiation-synthesis of chitosan/poly (acrylic acid) nanogel for improving the antitumor potential of rutin in hepatocellular carcinoma. Drug Deliv Transl Res 2020; 11:261-278. [PMID: 32488816 DOI: 10.1007/s13346-020-00792-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
The current study aimed to investigate the ability of chitosan/poly (acrylic acid) nanogel (CAN) to improve the bioavailability and anticancer potential of rutin. Synthesis of CAN was carried out by gamma radiation-induced polymerization of acrylic acid in an aqueous solution of chitosan. The relationship between the hydrodynamic radius of CAN and the absorbed radiation doses was also investigated. The prepared nanogels were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), X-ray diffraction (XRD), and Fourier transform infrared (FT-IR) techniques, and then, it was used as a nano-drug carrier for rutin. The developed formulation was evaluated for its antitumor activity against chemically induced hepatocarcinoma in rats. The following parameters were measured: aspartate and alanine aminotransferase, alkaline phosphatase, gamma glutamyltransferase, and total bilirubin as liver function test; vascular endothelial growth factor as an angiogenesis marker; α-fetoprotein as a tumor marker; and P53, caspase-3, Bax, and Bcl-2 as apoptosis markers. Histopathological examination was also confirmed. Significant enhanced anti-proliferative, anti-angiogenic, and apoptotic effects were observed for rutin-loaded CAN than free rutin, indicating that this formulation could provide a novel therapeutic approach to serve as a promising agent for treatment of hepatocellular carcinoma. Graphical abstract.
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Cetirizine and thalidomide synergistically inhibit mammary tumorigenesis and angiogenesis in 7,12-dimethylbenz(a)anthracene-treated rats. Anticancer Drugs 2019; 29:956-964. [PMID: 30134286 DOI: 10.1097/cad.0000000000000670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Cetirizine (CET) and thalidomide (THA) have been previously found to influence angiogenesis. The present study aimed to assess the ability of these drugs to influence mammary carcinogenesis in rats. MATERIALS AND METHODS Sixty Sprague-Dawley female rats, aged 8 weeks, received 15 mg of 7,12-dimethylbenz(a)anthracene (DMBA) intragastrically. CET and THA (1.0 and 3.0 mg/kg, respectively) were administered orally for 118 days after DMBA administration. At the end of the treatment period, mammary tumors were counted and weighed, and their morphology was analyzed using light microscopy. In tumor tissue, proliferation and apoptotic indices and microvessel density were determined using immunohistochemical techniques; the levels of angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factor, were measured by western blotting. RESULTS CET and THA, administered separately, failed to influence tumor formation and angiogenesis. In contrast, the drug combination decreased latency to first tumor (significant difference from vehicle-treated control and groups that received either drug alone, P<0.01) and significantly lowered tumor number per rat, number of malignant tumors per rat, tumor burden, and tumor number per tumor-bearing animal (P<0.05 or <0.01). In tissue of malignant tumors, the drug combination decreased the number of proliferating cells, microvessel density, and levels of vascular endothelial growth factor and basic fibroblast growth factor and stimulated apoptosis (difference from all other groups, P<0.01). CONCLUSION It was shown for the first time that H1-antagonist and THA synergistically inhibit DMBA-induced mammary carcinogenesis; this effect was associated with a decrease in tumor angiogenesis. Further study of the anticancer and antiangiogenic activity of the combination may provide a new approach to breast cancer treatment.
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Yang J, Zhang L, Jiang Z, Ge C, Zhao F, Jiang J, Tian H, Chen T, Xie H, Cui Y, Yao M, Li H, Li J. TCF12 promotes the tumorigenesis and metastasis of hepatocellular carcinoma via upregulation of CXCR4 expression. Theranostics 2019; 9:5810-5827. [PMID: 31534521 PMCID: PMC6735379 DOI: 10.7150/thno.34973] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Accepted: 07/05/2019] [Indexed: 12/24/2022] Open
Abstract
TCF12, which is known to be involved in the regulation of cell growth and differentiation, has been reported to function as an oncogene or a tumor suppressor gene in the progression of various malignant tumors. However, its function and molecular mechanism in hepatocellular carcinoma (HCC) remain unclear. Methods: Stable ectopic TCF12 expression or knockdown in HCC cell lines was established by lentiviral infection. Then, MTT, colony formation, migration, invasion and HUVECs tube formation assays as well as an orthotopic xenograft model were used to investigate the biologic function of TCF12 in HCC cells in vitro and in vivo. Subsequently, RNA-Seq analysis was utilized to explore the target genes regulated by TCF12. RT-qPCR, western blotting, a dual-luciferase reporter assay, Ch-IP, CHIP-Seq and functional rescue experiments were used to confirm the target gene regulated by TCF12. Finally, RT-qPCR, western blot and immunohistochemical (IHC) staining were performed to detect the expression level of TCF12 and to analyze the correlation of TCF12 with downstream genes as well as the clinical significance of TCF12 in human primary HCC. Results: Our functional studies revealed that stable overexpression of TCF12 in human HCC cells enhanced cell proliferation, migration and invasion in vitro and in vivo, whereas knockdown of TCF12 showed opposing effects. Mechanistically, CXCR4 was a downstream target of TCF12, and TCF12 directly bound to the CXCR4 promoter to regulate its expression. Moreover, CXCR4, with its ligand CXCL12, played a critical role in tumor progression induced by TCF12 via activation of the MAPK/ERK and PI3K/AKT signaling pathways. Clinically, IHC analysis revealed that TCF12 was significantly associated with poor survival of HCC patients and that TCF12 expression was closely correlated with CXCR4 expression in primary HCC tissues. Conclusion: Our findings are the first to indicate that TCF12 could promote the tumorigenesis and progression of HCC mainly by upregulating CXCR4 expression and is a prognostic indicator for patients with HCC.
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Abune L, Zhao N, Lai J, Peterson B, Szczesny S, Wang Y. Macroporous Hydrogels for Stable Sequestration and Sustained Release of Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor Using Nucleic Acid Aptamers. ACS Biomater Sci Eng 2019; 5:2382-2390. [PMID: 31819896 PMCID: PMC6900755 DOI: 10.1021/acsbiomaterials.9b00423] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Macroporous hydrogels have been widely studied for biological and biomedical applications such as drug delivery and tissue engineering. However, these hydrogels cannot stably sequester molecules of interest due to their high permeability. The purpose of this work was to study the feasibility of using two aptamers to sequester two protein drugs, quantify the apparent diffusivity of protein drugs in aptamer-functionalized macroporous hydrogels, and evaluate the function of aptamer-functionalized macroporous hydrogels in controlling protein release for angiogenesis. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were used as model proteins. The data show that anti-VEGF and anti-bFGF aptamers could be uniformly incorporated into macroporous hydrogels for stable and specific sequestration of VEGF and bFGF. The aptamers could reduce the apparent diffusivity of VEGF and bFGF in the macroporous hydrogels by approximately three orders of magnitude. Moreover, as the aptamers could prolong the release of these growth factors, dual aptamer-functionalized macroporous hydrogels could stimulate synergistic angiogenesis. Therefore, this work has successfully demonstrated that aptamer-functionalized macroporous hydrogels hold great potential of stably sequestering multiple molecules of interest for various biological and biomedical applications.
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Affiliation(s)
- Lidya Abune
- Department of Biomedical Engineering, The Pennsylvania State
University, University Park, PA 16802, USA
| | - Nan Zhao
- Department of Biomedical Engineering, The Pennsylvania State
University, University Park, PA 16802, USA
| | - Jinping Lai
- Department of Biomedical Engineering, The Pennsylvania State
University, University Park, PA 16802, USA
| | - Benjamin Peterson
- Department of Biomedical Engineering, The Pennsylvania State
University, University Park, PA 16802, USA
| | - Spencer Szczesny
- Department of Biomedical Engineering, The Pennsylvania State
University, University Park, PA 16802, USA
| | - Yong Wang
- Department of Biomedical Engineering, The Pennsylvania State
University, University Park, PA 16802, USA
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Huynh H, Lee LY, Goh KY, Ong R, Hao H, Huang A, Wang Y, Graus Porta D, Chow P, Chung A. Infigratinib Mediates Vascular Normalization, Impairs Metastasis, and Improves Chemotherapy in Hepatocellular Carcinoma. Hepatology 2019; 69:943-958. [PMID: 30575985 PMCID: PMC6635738 DOI: 10.1002/hep.30481] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Accepted: 12/16/2018] [Indexed: 12/21/2022]
Abstract
The fibroblast growth factor (FGF) signaling cascade is a key signaling pathway in hepatocarcinogenesis. We report high FGF receptor (FGFR) expression in 17.7% (11 of 62) of hepatocellular carcinoma (HCC) models. Infigratinib, a pan-FGFR inhibitor, potently suppresses the growth of high-FGFR-expressing and sorafenib-resistant HCCs. Infigratinib inhibits FGFR signaling and its downstream targets, cell proliferation, the angiogenic rescue program, hypoxia, invasion, and metastasis. Infigratinib also induces apoptosis and vessel normalization and improves the overall survival of mice bearing FGFR-driven HCCs. Infigratinib acts in synergy with the microtubule-depolymerizing drug vinorelbine to promote apoptosis, suppress tumor growth, and improve the overall survival of mice. Increased expression levels of FGFR-2 and FGFR-3 through gene amplification correlate with treatment response and may serve as potential biomarkers for patient selection. Conclusion: Treatments with Infigratinib alone or in combination with vinorelbine may be effective in a subset of patients with HCC with FGFR-driven tumors.
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Affiliation(s)
- Hung Huynh
- Laboratory of Molecular Endocrinology, Division of Molecular and Cellular ResearchNational Cancer CentreSingapore
| | - Liek Yeow Lee
- Laboratory of Molecular Endocrinology, Division of Molecular and Cellular ResearchNational Cancer CentreSingapore
| | - Kah Yong Goh
- Laboratory of Molecular Endocrinology, Division of Molecular and Cellular ResearchNational Cancer CentreSingapore
| | - Richard Ong
- Laboratory of Molecular Endocrinology, Division of Molecular and Cellular ResearchNational Cancer CentreSingapore
| | | | - Alan Huang
- Novartis Institutes for Biomedical ResearchCambridgeMA
| | - Youzhen Wang
- Oncology Drug Discovery PharmacologyNovartis Institutes for Biomedical ResearchCambridgeMA
| | - Diana Graus Porta
- Oncology Translational Research, Novartis Institutes for Biomedical Research at BaselBaselSwitzerland
| | - Pierce Chow
- Department of General SurgerySingapore General HospitalSingapore
| | - Alexander Chung
- Department of General SurgerySingapore General HospitalSingapore
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18
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Ali MM, H Borai I, Ghanem HM, H Abdel-Halim A, Mousa FM. The prophylactic and therapeutic effects of Momordica charantia methanol extract through controlling different hallmarks of the hepatocarcinogenesis. Biomed Pharmacother 2017; 98:491-498. [PMID: 29287196 DOI: 10.1016/j.biopha.2017.12.096] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 12/17/2017] [Accepted: 12/19/2017] [Indexed: 02/08/2023] Open
Abstract
Inspite of the wide facilities for controlling cancer growth, there are little drugs to inhibit its metastasis or prevent its angiogenesis. Discovering such natural or synthetic multi-targeted agent that might strike different targets is considered as a vital goal for tumor controlling. In a previous study, the chemoprotective effect of methanol extract of Momordicacharantia (MEMC) on albino western rats bearing hepatocarcinogenesis was evaluated. The mechanism by which MEMC exert its anticancer properties was unknown. Therefore, we aimed in this study to investigate the possible role of MEMC as anti-proliferative, anti-angiogenic and anti-metastatic agent to exert its chemoprotective effect. The study was conducted on sixty albino western rats divided into six groups, 10 rats each. Diethylnitrosamine (DENA) was injected intraperitoneally (i.p.) at a dose of 200 mg/kg body weight once, 2 weeks later rats were received carbon tetrachloride (CCl4) subcutaneously (3 ml/kg/week) continued for 10 weeks. MEMC was orally produced to rats (40 mg/kg) alone, as well as before, at the same time and after DENA injection. Cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), caspase-3,-8 (Casp-3,-8), histone deacetylase (HDAC) and matrixmetalloproteinases-2,-9 (MMP-2,-9) were evaluated. MEMC treatment significantly decreased Cox-2, VEGF, HDAC and MMP-2,-9 and increased Casp-3,-8 as compared to DENAgroup,which demonstrated that the anticancer effect of MEMC may be through the inhibition of angiogenesis, proliferation and metastasis and the activation of apoptosis. The improvement in before-treated group was more pronounced than that in after- and simultaneous-treated groups, indicating thatMEMC may act as a prophylactic agent more than being a therapeutic agent.
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Affiliation(s)
- Mamdouh M Ali
- Biochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki, 12622, Giza, Egypt.
| | - Ibrahim H Borai
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hala M Ghanem
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Abeer H Abdel-Halim
- Biochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki, 12622, Giza, Egypt
| | - Fatma M Mousa
- Biochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki, 12622, Giza, Egypt
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Hollenbach M. The Role of Glyoxalase-I (Glo-I), Advanced Glycation Endproducts (AGEs), and Their Receptor (RAGE) in Chronic Liver Disease and Hepatocellular Carcinoma (HCC). Int J Mol Sci 2017; 18:ijms18112466. [PMID: 29156655 PMCID: PMC5713432 DOI: 10.3390/ijms18112466] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 11/16/2017] [Accepted: 11/17/2017] [Indexed: 12/12/2022] Open
Abstract
Glyoxalase-I (Glo-I) and glyoxalase-II (Glo-II) comprise the glyoxalase system and are responsible for the detoxification of methylglyoxal (MGO). MGO is formed non-enzymatically as a by-product, mainly in glycolysis, and leads to the formation of advanced glycation endproducts (AGEs). AGEs bind to their receptor, RAGE, and activate intracellular transcription factors, resulting in the production of pro-inflammatory cytokines, oxidative stress, and inflammation. This review will focus on the implication of the Glo-I/AGE/RAGE system in liver injury and hepatocellular carcinoma (HCC). AGEs and RAGE are upregulated in liver fibrosis, and the silencing of RAGE reduced collagen deposition and the tumor growth of HCC. Nevertheless, data relating to Glo-I in fibrosis and cirrhosis are preliminary. Glo-I expression was found to be reduced in early and advanced cirrhosis with a subsequent increase of MGO-levels. On the other hand, pharmacological modulation of Glo-I resulted in the reduced activation of hepatic stellate cells and therefore reduced fibrosis in the CCl₄-model of cirrhosis. Thus, current research highlighted the Glo-I/AGE/RAGE system as an interesting therapeutic target in chronic liver diseases. These findings need further elucidation in preclinical and clinical studies.
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Affiliation(s)
- Marcus Hollenbach
- Department of Medicine, Neurology and Dermatology, Division of Gastroenterology and Rheumatology, University of Leipzig, Liebigstrasse 20, D-04103 Leipzig, Germany.
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Yılmaz Y, Güneş A, Topel H, Atabey N. Signaling Pathways as Potential Therapeutic Targets in Hepatocarcinogenesis. J Gastrointest Cancer 2017; 48:225-237. [PMID: 28819741 DOI: 10.1007/s12029-017-9958-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Yeliz Yılmaz
- Izmir International Biomedicine & Genome Institute (iBG-izmir), Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
- Department of Medical Biology and Genetics, Institute of Health Sciences, Dokuz Eylul University, 35340, Izmir, Turkey
| | - Ayşim Güneş
- Izmir International Biomedicine & Genome Institute (iBG-izmir), Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
| | - Hande Topel
- Izmir International Biomedicine & Genome Institute (iBG-izmir), Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
- Department of Medical Biology and Genetics, Institute of Health Sciences, Dokuz Eylul University, 35340, Izmir, Turkey
| | - Neşe Atabey
- Izmir International Biomedicine & Genome Institute (iBG-izmir), Dokuz Eylul University, Balcova, 35340, Izmir, Turkey.
- Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, 35340, Izmir, Turkey.
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A phase II evaluation of brivanib in the treatment of persistent or recurrent carcinoma of the cervix: An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol 2017; 146:554-559. [PMID: 28728751 DOI: 10.1016/j.ygyno.2017.05.033] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 05/25/2017] [Indexed: 11/20/2022]
Abstract
BACKGROUND Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients. METHODS Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) >6months and objective tumor response. RESULTS Of 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had >2cycles of brivanib with 4 (14%) receiving >10cycles (range: 1-20). Seven (25%) patients had PFS >6months (90% CI: 7.3%-33.9%). Two (7%) (90% CI: 1.3%-20.8%) patients had partial tumor response with duration of 8 and 22months and 12 (43%) had stable disease. The median PFS was 3.2months (90% CI: 2.1-4.4). The median overall survival was 7.9months (90% CI: 6.1-11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension. CONCLUSIONS Based on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability.
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Dianhydrogalactitol, a potential multitarget agent, inhibits glioblastoma migration, invasion, and angiogenesis. Biomed Pharmacother 2017; 91:1065-1074. [PMID: 28525947 DOI: 10.1016/j.biopha.2017.05.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 04/24/2017] [Accepted: 05/05/2017] [Indexed: 11/22/2022] Open
Abstract
The complexity of cancer has led to single-target agents exhibiting lower-than-desired clinical efficacy. Drugs with multiple targets provide a feasible option for the treatment of complex tumors. Multitarget anti-angiogenesis agents are among the new generation of anticancer drugs and have shown favorable clinical efficacy. Dianhydrogalactitol (DAG) is a chemotherapeutic agent for chronic myeloid leukemia and lung cancer. Recently, it has been tested in phase II trials of glioblastoma treatment; however, mechanisms of DAG in glioblastoma have not been elucidated. Here we show that DAG could inhibit the migration and invasion of U251 cell line by inhibiting matrix metalloproteinase-2 (MMP2) expression. Furthermore, DAG could also inhibit tumor angiogenesis in vitro as well as in the zebrafish model. Mechanistic studies reveal that DAG inhibited both VEGFR2 and FGFR1 pathways. Our results suggest that DAG may be a potential multitarget agent that can inhibit tumor migration, invasion, and angiogenesis, and the anti-angiogenic effects may be involved in dual-suppression VEGF/VEGFR2 and FGF2/FGFR1 signal pathways.
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Xu J, Liang J, Meng YM, Yan J, Yu XJ, Liu CQ, Xu L, Zhuang SM, Zheng L. Vascular CXCR4 Expression Promotes Vessel Sprouting and Sensitivity to Sorafenib Treatment in Hepatocellular Carcinoma. Clin Cancer Res 2017; 23:4482-4492. [DOI: 10.1158/1078-0432.ccr-16-2131] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 09/14/2016] [Accepted: 02/16/2017] [Indexed: 11/16/2022]
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Affo S, Yu LX, Schwabe RF. The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2016; 12:153-186. [PMID: 27959632 DOI: 10.1146/annurev-pathol-052016-100322] [Citation(s) in RCA: 490] [Impact Index Per Article: 54.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Liver cancer is the second leading cause of cancer mortality worldwide, causing more than 700,000 deaths annually. Because of the wide landscape of genomic alterations and limited therapeutic success of targeting tumor cells, a recent focus has been on better understanding and possibly targeting the microenvironment in which liver tumors develop. A unique feature of liver cancer is its close association with liver fibrosis. More than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers, suggesting an important role of liver fibrosis in the premalignant environment (PME) of the liver. Cholangiocarcinoma (CCA), in contrast, is characterized by a strong desmoplasia that typically occurs in response to the tumor, suggesting a key role of cancer-associated fibroblasts (CAFs) and fibrosis in its tumor microenvironment (TME). Here, we discuss the functional contributions of myofibroblasts, CAFs, and fibrosis to the development of HCC and CCA in the hepatic PME and TME, focusing on myofibroblast- and extracellular matrix-associated growth factors, fibrosis-associated immunosuppressive pathways, as well as mechanosensitive signaling cascades that are activated by increased tissue stiffness. Better understanding of the role of myofibroblasts in HCC and CCA development and progression may provide the basis to target these cells for tumor prevention or therapy.
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Affiliation(s)
- Silvia Affo
- Department of Medicine, Columbia University, New York, NY 10032;
| | - Le-Xing Yu
- Department of Medicine, Columbia University, New York, NY 10032;
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York, NY 10032;
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Tavana S, Azarnia M, Valojerdi MR, Shahverdi A. Hyaluronic acid-based hydrogel scaffold without angiogenic growth factors enhances ovarian tissue function after autotransplantation in rats. ACTA ACUST UNITED AC 2016; 11:055006. [PMID: 27710922 DOI: 10.1088/1748-6041/11/5/055006] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
One of the problems encountered during ovarian transplantation is that the number of primordial follicles in the grafts is considerably reduced 2 d after transplantation due to post-transplantation ischemia. This study investigates if the use of hyaluronic acid-based hydrogel (HABH) with and without vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) could prevent or minimize ischemia-induced follicle loss during ovarian autotransplantation and thereby restore ovarian tissue function in the rat model. In this study, twenty four female rats were subjected to bilateral ovariectomy and were randomly divided into 3 groups for ovarian tissue autotransplantation. Group A included rats with ovarian tissue without HABH, VEGF and bFGF, group B comprised rats with ovarian tissue encapsulated with HABH and group C had rats with ovarian tissue encapsulated with HABH containing VEGF and bFGF. Three days after transplantation, the grafts were assessed through histological and hormonal analyses. Apoptotic, angiogenic and maturation genes expressions were also analyzed. The mean number of follicles in all developmental stages increased in group B (P < 0.05). The level of FSH decreased in group B (P < 0.05) whereas, the expression level of VEGF gene increased in group B (P < 0.05). No significant changes were observed in the expression levels of maturation and apoptotic genes in all groups. In conclusion, ovarian encapsulation with HABH alone can prevent or minimize ischemia-induced follicle loss, preserve the follicular pool, promote follicular survival, facilitate angiogenesis, and restore hormone levels. However, its efficiency in a clinical setting and in comparison with other hydrogels needs further investigation.
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Affiliation(s)
- Somayeh Tavana
- Faculty of Biological Sciences, Department of Animal Biology, Kharazmi University, Tehran, Iran
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Cheng AL, Thongprasert S, Lim HY, Sukeepaisarnjaroen W, Yang TS, Wu CC, Chao Y, Chan SL, Kudo M, Ikeda M, Kang YK, Pan H, Numata K, Han G, Balsara B, Zhang Y, Rodriguez AM, Zhang Y, Wang Y, Poon RTP. Randomized, open-label phase 2 study comparing frontline dovitinib versus sorafenib in patients with advanced hepatocellular carcinoma. Hepatology 2016; 64:774-84. [PMID: 27082062 DOI: 10.1002/hep.28600] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Revised: 03/22/2016] [Accepted: 04/02/2016] [Indexed: 12/13/2022]
Abstract
UNLABELLED Angiogenesis inhibition by the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) inhibitor sorafenib provides survival benefit in hepatocellular carcinoma (HCC); however, angiogenic escape from sorafenib may occur due to angiogenesis-associated fibroblast growth factor receptor (FGFR) pathway activation. In addition to VEGFR and PDGFR, dovitinib inhibits FGFR. Frontline oral dovitinib (500 mg/day, 5 days on, 2 days off; n = 82) versus sorafenib (400 mg twice daily; n = 83) was evaluated in an open-label, randomized phase 2 study of Asian-Pacific patients with advanced HCC. The primary and key secondary endpoints were overall survival (OS) and time to tumor progression (TTP) as determined by a local investigator, respectively. Patients included in the study were ineligible for surgical and/or locoregional therapies or had disease progression after receiving these therapies. The median OS (95% confidence interval [CI]) was 8.0 (6.6-9.1) months for dovitinib and 8.4 (5.4-11.3) months for sorafenib. The median TTP (95% CI) per investigator assessment was 4.1 (2.8-4.2) months and 4.1 (2.8-4.3) months for dovitinib and sorafenib, respectively. Common any-cause adverse events included diarrhea (62%), decreased appetite (43%), nausea (41%), vomiting (41%), fatigue (35%), rash (34%), and pyrexia (30%) for dovitinib and palmar-plantar erythrodysesthesia syndrome (66%) and decreased appetite (31%) for sorafenib. Subgroup analysis revealed a significantly higher median OS for patients in the dovitinib arm who had baseline plasma soluble VEGFR1 (sVEGFR1) and hepatocyte growth factor (HGF) below median levels versus at or above the median levels (median OS [95% CI]: sVEGFR1, 11.2 [9.0-13.8] and 5.7 [4.3-7.0] months, respectively [P = .0002]; HGF, 11.2 [8.9-13.8] and 5.9 [5.0-7.6] months, respectively [P = 0.0002]). CONCLUSION Dovitinib was well tolerated, but activity was not greater than sorafenib as a frontline systemic therapy for HCC. Based on these data, no subsequent phase 3 study has been planned. (Hepatology 2016;64:774-784).
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Affiliation(s)
- Ann-Lii Cheng
- National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan
| | | | | | | | | | | | - Yee Chao
- Taipei Veterans General Hospital, Taipei, Taiwan
| | - Stephen L Chan
- Prince of Wales Hospital and The Chinese University of Hong Kong, Shatin, Hong Kong
| | | | | | | | - Hongming Pan
- Sir Run Run Shaw Hospital, Zhejiang University Medical College, Zhejiang, China
| | - Kazushi Numata
- Yokohama City University Medical Center, Yokohama, Japan
| | - Guohong Han
- Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | | | - Yong Zhang
- Novartis Pharmaceuticals Corporation, East Hanover, NJ
| | | | - Yi Zhang
- Novartis Pharmaceuticals Corporation, East Hanover, NJ
| | - Yongyu Wang
- Novartis Pharmaceuticals Corporation, East Hanover, NJ
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Falcon BL, Chintharlapalli S, Uhlik MT, Pytowski B. Antagonist antibodies to vascular endothelial growth factor receptor 2 (VEGFR-2) as anti-angiogenic agents. Pharmacol Ther 2016; 164:204-25. [PMID: 27288725 DOI: 10.1016/j.pharmthera.2016.06.001] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Interaction of numerous signaling pathways in endothelial and mesangial cells results in exquisite control of the process of physiological angiogenesis, with a central role played by vascular endothelial growth factor receptor 2 (VEGFR-2) and its cognate ligands. However, deregulated angiogenesis participates in numerous pathological processes. Excessive activation of VEGFR-2 has been found to mediate tissue-damaging vascular changes as well as the induction of blood vessel expansion to support the growth of solid tumors. Consequently, therapeutic intervention aimed at inhibiting the VEGFR-2 pathway has become a mainstay of treatment in cancer and retinal diseases. In this review, we introduce the concepts of physiological and pathological angiogenesis, the crucial role played by the VEGFR-2 pathway in these processes, and the various inhibitors of its activity that have entered the clinical practice. We primarily focus on the development of ramucirumab, the antagonist monoclonal antibody (mAb) that inhibits VEGFR-2 and has recently been approved for use in patients with gastric, colorectal, and lung cancers. We examine in-depth the pre-clinical studies using DC101, the mAb to mouse VEGFR-2, which provided a conceptual foundation for the role of VEGFR-2 in physiological and pathological angiogenesis. Finally, we discuss further clinical development of ramucirumab and the future of targeting the VEGF pathway for the treatment of cancer.
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Tavana S, Valojerdi MR, Azarnia M, Shahverdi A. Restoration of ovarian tissue function and estrous cycle in rat after autotransplantation using hyaluronic acid hydrogel scaffold containing VEGF and bFGF. Growth Factors 2016; 34:97-106. [PMID: 27362476 DOI: 10.1080/08977194.2016.1194835] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
This study investigates the effect of hyaluronic acid (HA) containing VEGF and bFGF on restoration of ovarian function after ovarian autotransplantation. Twenty-four rats were randomly divided into three groups for ovarian autotransplantation: group A (ovaries without HA, VEGF and bFGF), group B (ovaries encapsulated with HA) and group C (ovaries encapsulated with HA containing VEGF and bFGF). The grafts were assessed using vaginal smears, histological, hormonal, and the genes expression analysis. The duration of first estrous cycle was shorter in group C than in group A (p < 0.01). The mean number of primordial follicles was protected in group C. The level of estradiol was higher in group A than in group C (p < 0.01). The expression level of Cellular-Myelocytomatosis (C-Myc) in group C was lower than in group B (p < 0.05). HA containing VEGF and bFGF can ensure follicular survival, decrease apoptosis and recover ovarian function after auto-transplantation.
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Affiliation(s)
- Somayeh Tavana
- a Department of Embryology , Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR , Tehran , Iran
- b Department of Animal Biology , Faculty of Biological Sciences, Kharazmi University , Tehran , Iran , and
| | - Mojtaba Rezazadeh Valojerdi
- a Department of Embryology , Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR , Tehran , Iran
- c Department of Anatomy , Faculty of Medical Sciences, Tarbiat Modares University , Tehran , Iran
| | - Mahnaz Azarnia
- b Department of Animal Biology , Faculty of Biological Sciences, Kharazmi University , Tehran , Iran , and
| | - Abdolhossein Shahverdi
- a Department of Embryology , Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR , Tehran , Iran
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Li SH, Hwu YM, Lu CH, Chang HH, Hsieh CE, Lee RKK. VEGF and FGF2 Improve Revascularization, Survival, and Oocyte Quality of Cryopreserved, Subcutaneously-Transplanted Mouse Ovarian Tissues. Int J Mol Sci 2016; 17:ijms17081237. [PMID: 27483256 PMCID: PMC5000635 DOI: 10.3390/ijms17081237] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Revised: 07/25/2016] [Accepted: 07/26/2016] [Indexed: 12/11/2022] Open
Abstract
This study was conducted to investigate the effect of the vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) on revascularization, survival, and oocyte quality of cryopreserved, subcutaneously-transplanted mouse ovarian tissue. Autologous subcutaneous transplantation of vitrified-thawed mouse ovarian tissues treated with (experimental group) or without (control group) VEGF and FGF2 was performed. After transplantation to the inguinal region for two or three weeks, graft survival, angiogenesis, follicle development, and oocyte quality were examined after gonadotropin administration. VEGF coupled with FGF2 (VEGF/FGF2) promoted revascularization and significantly increased the survival rate of subcutaneously-transplanted cryopreserved ovarian tissues compared with untreated controls. The two growth factors did not show long-term effects on the ovarian grafts. In contrast to the untreated ovarian grafts, active folliculogenesis was revealed as the number of follicles at various stages and of mature oocytes in antral follicles after gonadotropin administration were remarkably higher in the VEGF/FGF2-treated groups. Although the fertilization rate was similar between the VEGF/FGF2 and control groups, the oocyte quality was much better in the VEGF/FGF2-treated grafts as demonstrated by the higher ratio of blastocyst development. Introducing angiogenic factors, such as VEGF and FGF2, may be a promising strategy to improve revascularization, survival, and oocyte quality of cryopreserved, subcutaneously-transplanted mouse ovarian tissue.
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Affiliation(s)
- Sheng-Hsiang Li
- Department of Medical Research, Mackay Memorial Hospital, Tamsui District, New Taipei City 251, Taiwan.
- Mackay Junior College of Medicine, Nursing, and Management, Beitou District, Taipei City 112, Taiwan.
| | - Yuh-Ming Hwu
- Department of Medical Research, Mackay Memorial Hospital, Tamsui District, New Taipei City 251, Taiwan.
- Mackay Junior College of Medicine, Nursing, and Management, Beitou District, Taipei City 112, Taiwan.
- Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei City 104, Taiwan.
- Mackay Medical College, Sanzhi District, New Taipei City 252, Taiwan.
| | - Chung-Hao Lu
- Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei City 104, Taiwan.
| | - Hsiao-Ho Chang
- Department of Medical Research, Mackay Memorial Hospital, Tamsui District, New Taipei City 251, Taiwan.
| | - Cheng-En Hsieh
- Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei City 104, Taiwan.
| | - Robert Kuo-Kuang Lee
- Department of Medical Research, Mackay Memorial Hospital, Tamsui District, New Taipei City 251, Taiwan.
- Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei City 104, Taiwan.
- Department of Obstetrics and Gynecology, Taipei Medical University, Taipei City 110, Taiwan.
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Grasys J, Kim BS, Pallua N. Content of Soluble Factors and Characteristics of Stromal Vascular Fraction Cells in Lipoaspirates from Different Subcutaneous Adipose Tissue Depots. Aesthet Surg J 2016; 36:831-41. [PMID: 26906346 DOI: 10.1093/asj/sjw022] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2016] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Although fat grafting has emerged as a major force in plastic, reconstructive, and aesthetic surgery, some questions regarding its reliability and regenerative potential remain unanswered. OBJECTIVES The authors examined the influence of three anatomic areas on various lipoaspirate properties to identify the most appropriate harvest site for fat-grafting procedures. METHODS Lipoaspirates from 25 healthy patients were harvested from the abdomen, inner thigh, and knee. The authors measured the content of soluble factors in the lipoaspirate followed by the assessment of the yield, adipogenic differentiation, proliferation of stromal vascular fraction (SVF) cells, and the percentage of adipose-derived stem cells (ASC) in the SVF. The results also were correlated with the age and body mass index of the donors. RESULTS Lipoaspirates from the abdomen showed significantly higher concentrations of matrix metalloproteinase (MMP)-9 compared with the knee. The content of basic fibroblast growth factor (b-FGF), platelet-derived growth factor (PDGF)-BB, and insulin-like growth factor (IGF)-1 tended to be highest in the abdomen but did not reach statistical significance. Vascular endothelial growth factor (VEGF)-A and bFGF-2 contents both correlated negatively with age in lipoaspirates from at least two different anatomic areas. CONCLUSIONS The authors' results indicate that the abdomen may be a slight favorite over the inner thigh and knee because of its richer content of soluble factors. However, because only the difference of MMP-9 content actually reached statistical significance and because no differences in SVF characteristics were observed, a decision primarily based on other criteria appears to be justifiable.
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Affiliation(s)
- Justinas Grasys
- From the Department of Plastic and Reconstructive Surgery, Hand Surgery - Burn Center, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Bong-Sung Kim
- From the Department of Plastic and Reconstructive Surgery, Hand Surgery - Burn Center, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Norbert Pallua
- From the Department of Plastic and Reconstructive Surgery, Hand Surgery - Burn Center, Medical Faculty, RWTH Aachen University, Aachen, Germany
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31
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Van ND, Falk CS, Sandmann L, Vondran FWR, Helfritz F, Wedemeyer H, Manns MP, Ciesek S, von Hahn T. Modulation of HCV reinfection after orthotopic liver transplantation by fibroblast growth factor-2 and other non-interferon mediators. Gut 2016; 65:1015-23. [PMID: 25800783 PMCID: PMC4893125 DOI: 10.1136/gutjnl-2014-308003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 02/12/2015] [Indexed: 01/11/2023]
Abstract
OBJECTIVE In HCV infected individuals graft infection occurs shortly after orthotopic liver transplantation (OLT). We aimed to describe the composition of the inflammatory response at this time, how it affects the HCV replication cycle and identify novel proviral and antiviral factors. DESIGN We used a Luminex assay to quantify 50 inflammatory mediators in sera before and shortly after OLT. In vitro grown HCV based on the JFH-1 isolate were used to characterise the effects of patient sera and individual mediators on HCV. RESULTS Although the mediator composition is highly variable between individuals, sera drawn immediately post-OLT significantly enhance HCV infectivity compared with control sera from before OLT in about half of the cases. Among 27 non-interferon inflammatory mediators fibroblast growth factor (FGF)-2 stood out as it enhanced HCV RNA replication and release of infectious particles. The effect was concentration-dependent and detectable in dividing and non-dividing cells. Moreover, pharmacological inhibition of FGF-2 receptor signalling abrogated the enhancing effect of FGF-2 and inhibited HCV replication in the absence of serum FGF-2 suggesting that HCV replication is dependent on basal activation of the FGF-2 triggered signalling pathway. Finally, in individuals with chronic HCV infection with high viral load, serum FGF-2 was significantly higher compared with those with low viral load. CONCLUSIONS Although no single mediator may account for this effect, serum shortly post-OLT enhances HCV infection. FGF-2 is a novel endogenous driver of HCV replication and a potential therapeutic target.
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Affiliation(s)
- Nguyen Dinh Van
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany,Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany
| | - Christine S Falk
- Institute of Transplant Immunology, IFB-Tx, Medizinische Hochschule Hannover, Hannover, Germany
| | - Lisa Sandmann
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
| | - Florian W R Vondran
- German Center for Infection Research (DZIF), Hannover, Germany,Department of General, Visceral and Transplantation Surgery, Medizinische Hochschule Hannover, Hannover, Germany
| | - Fabian Helfritz
- German Center for Infection Research (DZIF), Hannover, Germany,Department of General, Visceral and Transplantation Surgery, Medizinische Hochschule Hannover, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany
| | - Sandra Ciesek
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany
| | - Thomas von Hahn
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany,Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany
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Bioglass promotes wound healing by affecting gap junction connexin 43 mediated endothelial cell behavior. Biomaterials 2016; 84:64-75. [DOI: 10.1016/j.biomaterials.2016.01.033] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 01/12/2016] [Accepted: 01/15/2016] [Indexed: 02/08/2023]
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Yu H, Peng J, Xu Y, Chang J, Li H. Bioglass Activated Skin Tissue Engineering Constructs for Wound Healing. ACS APPLIED MATERIALS & INTERFACES 2016; 8:703-715. [PMID: 26684719 DOI: 10.1021/acsami.5b09853] [Citation(s) in RCA: 164] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Wound healing is a complicated process, and fibroblast is a major cell type that participates in the process. Recent studies have shown that bioglass (BG) can stimulate fibroblasts to secrete a multitude of growth factors that are critical for wound healing. Therefore, we hypothesize that BG can stimulate fibroblasts to have a higher bioactivity by secreting more bioactive growth factors and proteins as compared to untreated fibroblasts, and we aim to construct a bioactive skin tissue engineering graft for wound healing by using BG activated fibroblast sheet. Thus, the effects of BG on fibroblast behaviors were studied, and the bioactive skin tissue engineering grafts containing BG activated fibroblasts were applied to repair the full skin lesions on nude mouse. Results showed that BG stimulated fibroblasts to express some critical growth factors and important proteins including vascular endothelial growth factor, basic fibroblast growth factor, epidermal growth factor, collagen I, and fibronectin. In vivo results revealed that fibroblasts in the bioactive skin tissue engineering grafts migrated into wound bed, and the migration ability of fibroblasts was stimulated by BG. In addition, the bioactive BG activated fibroblast skin tissue engineering grafts could largely increase the blood vessel formation, enhance the production of collagen I, and stimulate the differentiation of fibroblasts into myofibroblasts in the wound site, which would finally accelerate wound healing. This study demonstrates that the BG activated skin tissue engineering grafts contain more critical growth factors and extracellular matrix proteins that are beneficial for wound healing as compared to untreated fibroblast cell sheets.
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Affiliation(s)
- Hongfei Yu
- Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University , 1954 Huashan Road, Shanghai 200030, China
| | - Jinliang Peng
- School of Pharmacy, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China
| | - Yuhong Xu
- School of Pharmacy, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China
| | - Jiang Chang
- Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University , 1954 Huashan Road, Shanghai 200030, China
- Shanghai Institute of Ceramics, Chinese Academy of Sciences , 1295 Dingxi Road, Shanghai 200050, China
| | - Haiyan Li
- Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University , 1954 Huashan Road, Shanghai 200030, China
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Cho Y, Yoon JH, Yoo JJ, Lee M, Lee DH, Cho EJ, Lee JH, Yu SJ, Kim YJ, Kim CY. Fucoidan protects hepatocytes from apoptosis and inhibits invasion of hepatocellular carcinoma by up-regulating p42/44 MAPK-dependent NDRG-1/CAP43. Acta Pharm Sin B 2015; 5:544-53. [PMID: 26713269 PMCID: PMC4675821 DOI: 10.1016/j.apsb.2015.09.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 08/21/2015] [Accepted: 09/07/2015] [Indexed: 02/07/2023] Open
Abstract
Fucoidan is a traditional Chinese medicine suggested to possess anti-tumor effects. In this study the anti-metastatic effects of fucoidan were investigated in vitro in human hepatocellular carcinoma (HCC) cells (Huh-7 and SNU-761) under normoxic and hypoxic conditions and in vivo using a distant liver metastasis model involving injection of MH134 cells into spleen via the portal vein. Its ability to protect hepatocytes against bile acid (BA)-induced apoptosis was investigated in primary hepatocytes. Fucoidan was found to suppress the invasion of HCC cells through up-regulation of p42/44 MAPK-dependent NDRG-1/CAP43 and partly, under normoxic conditions, through up-regulation of p42/44 MAPK-dependent VMP-1 expression. It also significantly decreased liver metastasis in vivo. As regards its hepatoprotective effect, fucoidan decreased BA-induced hepatocyte apoptosis as shown by the attenuation of caspase-8, and -7 cleavages and suppression of the mobilization of caspase-8 and Fas associated death domain (FADD) into the death-inducing signaling complex. In summary, fucoidan displays inhibitory effects on proliferation of HCC cells and protective effects on hepatocytes. The results suggest fucoidan is a potent suppressor of tumor invasion with hepatoprotective effects.
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Key Words
- BA, bile acid
- CXCL, chemokine ligand
- Cultured hepatocyte
- DISC, death-inducing signaling complex
- DMEM, Dulbecco׳s modified Eagle׳s medium
- DNA, deoxyribonucleic acid
- ELISA, enzyme-linked immunosorbent assay
- FADD, Fas associated death domain
- FBS, fetal bovine serum
- FCS, fetal calf serum
- Fucoidan
- GAPDH, glyceraldehyde-3-phosphate dehydrogenase
- GP, glypican
- HCC, hepatocellular carcinoma
- Hepatocellular carcinoma
- Hepatoprotective
- Hypoxia
- IHC, immunohistochemistry
- Invasion
- JNK, c-Jun NH2-terminal kinase
- MAPK, mitogen-activated protein kinase
- MTS, 3,4-(5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt
- NDRG, N-myc downstream-regulated gene
- NDRG-1/CAP43
- PCR, polymerase chain reaction
- RNA, ribonucleic acid
- SD, standard deviation
- SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis
- VMP, vacuole membrane protein
- VMP-1
- WME, William's medium E
- cDNA, complementary DNA
- siRNA, small interfering RNA
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Affiliation(s)
| | - Jung-Hwan Yoon
- Corresponding author. Tel.: +82 2 2072 2228; fax: +82 2 743 6701.
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Gao J, Huang Y, Li M, Zhao H, Zhao Y, Li R, Yan J, Yu Y, Qiao J. Effect of Local Basic Fibroblast Growth Factor and Vascular Endothelial Growth Factor on Subcutaneously Allotransplanted Ovarian Tissue in Ovariectomized Mice. PLoS One 2015. [PMID: 26208097 PMCID: PMC4514621 DOI: 10.1371/journal.pone.0134035] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Objective One of the major obstacles to ovarian tissue preservation is delayed angiogenesis that leads follicles lost after transplantation. The aim of the present study was to investigate the effects of bFGF and VEGF on heterotopic transplanted ovarian tissue using a mouse model. Methods Female mice underwent bilateral ovariectomy. Ovarian tissues encapsulated by fibrin hydrogels were transplanted subcutaneously into recipient mice, in which ovarian hormonal cyclicity was absent. The fibrinogen solution was mixed with bFGF, VEGF, or a mixture of bFGF and VEGF. The grafts were recovered 21 days after transplantation. Follicle morphology and follicle numbers were observed by H&E staining. Blood vessels were observed in transplanted intra-ovarian tissue by CD31 antibody IHC staining. Daily vaginal cytology was performed to determine estrous cycle and functional restoration of transplanted ovarian tissue. Blood was collected weekly and serum FSH levels were measured with a radioimmunoassay kit. Apoptosis analysis was performed by anti-AC-3 staining and survivin mRNA expression. Results The number of primordial follicles and secondary follicles in the bFGF+VEGF group was significantly higher than in the control group. The vascular density in the bFGF+VEGF groups were significantly higher than in the bFGF and the VEGF groups; there was no significant difference between the bFGF and VEGF groups. Estrous cycle was earlier in the bFGF+VEGF group compared with the control group; all mice in this group restored ovarian function. Serum FSH levels in the bFGF+VEGF group were significantly lower than in the control group by day 14 post-transplantation. The AC-3-positive in control group was significantly higher compared with bFGF group and VEGF group, and in bFGF+VEGF group was significantly lower than bFGF group and VEGF group. Survivin mRNA expression in bFGF+VEGF group was significantly higher than control group. Conclusion The combination of bFGF and VEGF has beneficial effects on follicle survival, angiogenesis, and resumption of estrous cycles.
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Affiliation(s)
- Jiangman Gao
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China
- Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing, 100191, China
| | - Ying Huang
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China
- Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing, 100191, China
| | - Min Li
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China
| | - Hongcui Zhao
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China
| | - Yue Zhao
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China
- Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing, 100191, China
| | - Rong Li
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China
- Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing, 100191, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China
| | - Jie Yan
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China
- * E-mail: (YY); (JY)
| | - Yang Yu
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China
- Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing, 100191, China
- * E-mail: (YY); (JY)
| | - Jie Qiao
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China
- Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing, 100191, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China
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Abstract
Hepatitis C virus (HCV) is one of the major etiologic agents of liver cancer. HCV is an RNA virus that, unlike hepatitis B virus, is unable to integrate into the host genome. Through complex interactions between viral and host proteins that induce host responses and promote inflammation, fibrosis, and ultimately cirrhosis, HCV infection can result in the development of hepatocellular carcinoma (HCC). The HCV oncogenic process involves genetic and epigenetic alterations and oncogenic effects mediated by viral proteins in the activation of cellular oncogenes, inactivation of tumor-suppressor genes, and dysregulation of multiple signal-transduction pathways. Advances in genetics and gene expression profiling have enhanced our current understanding of the pathways involved in HCV-associated liver cancer development. In this review, we summarize the current understanding of mechanisms of hepatocarcinogenesis induced by HCV infection.
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Affiliation(s)
- Ming V Lin
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; , ,
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Yoshiji H, Noguchi R, Namisaki T, Moriya K, Kitade M, Aihara Y, Douhara A, Kawaratani H, Nishimura N, Fukui H. Combination of sorafenib and angiotensin-II receptor blocker attenuates preneoplastic lesion development in a non-diabetic rat model of steatohepatitis. J Gastroenterol 2014; 49:1421-1429. [PMID: 24197250 DOI: 10.1007/s00535-013-0906-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Accepted: 10/21/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND Given the well-documented adverse side effects of sorafenib, many sorafenib-treated patients may need the reduced initial dose of the compound, and an alternative sorafenib-based therapy, which exerts similar clinical benefit, is anticipated. An angiostatic therapy with sorafenib is considered one of the promising approaches for chemoprevention of hepatocellular carcinoma. The aim of the current study was to elucidate the combination effect of low dose of sorafenib and angiotensin-II receptor blocker (ARB) on hepatocarcinogenesis, especially in conjunction with angiogenesis. METHODS The chemopreventive effect on the development of liver preneoplastic lesions, angiogenesis, and several indices was elucidated in rats. We also performed several sets of in vitro experiments to examine the mechanisms involved. RESULTS Using a non-diabetic rat model of steatohepatitis with choline deficient L-amino acid-defined diet, sorafenib demonstrated marked inhibition of preneoplastic lesions in a dose dependent manner. Combined treatment with ARB (losartan) at a clinically comparable dose and half dose of sorafenib resulted in the inhibitory effect equivalent to that of common dose of sorafenib along with suppression of hepatic neovascularization and potent angiogenic factor, vascular endothelial growth factor. Furthermore, similar combined inhibitory outcomes were observed in several sets of in vitro studies. CONCLUSION Since the combinatorial treatment using low doses of sorafenib and ARB could sufficiently induce inhibitory effect on the development of preneoplastic lesions at the magnitude similar to the conventional dose of sorafenib, this regimen may provide new strategy for patients intolerant of the usual dose of sorafenib in the future.
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MESH Headings
- Angiotensin II Type 1 Receptor Blockers/therapeutic use
- Animals
- Anticarcinogenic Agents/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/prevention & control
- Cell Proliferation/drug effects
- Dose-Response Relationship, Drug
- Drug Evaluation, Preclinical/methods
- Hep G2 Cells
- Humans
- Liver Neoplasms, Experimental/etiology
- Liver Neoplasms, Experimental/pathology
- Liver Neoplasms, Experimental/prevention & control
- Losartan/administration & dosage
- Male
- Neovascularization, Pathologic/pathology
- Niacinamide/administration & dosage
- Niacinamide/analogs & derivatives
- Non-alcoholic Fatty Liver Disease/complications
- Non-alcoholic Fatty Liver Disease/pathology
- Phenylurea Compounds/administration & dosage
- Precancerous Conditions/etiology
- Precancerous Conditions/pathology
- Precancerous Conditions/prevention & control
- Rats, Inbred F344
- Sorafenib
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Affiliation(s)
- Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan,
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Liu M, Jiang L, Guan XY. The genetic and epigenetic alterations in human hepatocellular carcinoma: a recent update. Protein Cell 2014; 5:673-91. [PMID: 24916440 PMCID: PMC4145080 DOI: 10.1007/s13238-014-0065-9] [Citation(s) in RCA: 130] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 04/13/2014] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent human malignancies worldwide with very poor prognosis. It is generally accepted that the progression of HCC is a long-term process with accumulation of multiple genetic and epigenetic alterations, which further lead to the activation of critical oncogenes or inactivation of tumor suppressor genes. HCC is characterized with multiple cancer hallmarks including their ability to proliferate, anti-apoptosis, invade, metastasis, as well as the emerging features such as stem cell properties and energy metabolic switch. The irreversible alterations at genetic level could be detected as early as in the pre-neoplastic stages and accumulate during cancer progression. Thus, they might account for the cancer initiating steps and further malignant transformation. In addition to genetic alterations, epigenetic alterations can affect the cancer transcriptome more extensively. Alterations in DNA methylation, histone modification, miRNAs, RNA editing, and lncRNAs might result in disrupted gene regulation networks and substantially contribute to HCC progression. In this review, the genetic and epigenetic alterations which significantly contribute to the malignant capabilities of HCC will be updated and summarized in detail. Further characterization of those critical molecular events might better elucidate the pathogenesis of HCC and provide novel therapeutic targets for treatment of this deadly disease.
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Affiliation(s)
- Ming Liu
- Department of Clinical Oncology, University of Hong Kong, Hong Kong, China
| | - Lingxi Jiang
- Department of Clinical Oncology, University of Hong Kong, Hong Kong, China
| | - Xin-Yuan Guan
- Department of Clinical Oncology, University of Hong Kong, Hong Kong, China
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40
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Liu M, Jiang L, Guan XY. The genetic and epigenetic alterations in human hepatocellular carcinoma: a recent update. Protein Cell 2014. [PMID: 24916440 DOI: 10.1007/s13238- 014-0065-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent human malignancies worldwide with very poor prognosis. It is generally accepted that the progression of HCC is a long-term process with accumulation of multiple genetic and epigenetic alterations, which further lead to the activation of critical oncogenes or inactivation of tumor suppressor genes. HCC is characterized with multiple cancer hallmarks including their ability to proliferate, anti-apoptosis, invade, metastasis, as well as the emerging features such as stem cell properties and energy metabolic switch. The irreversible alterations at genetic level could be detected as early as in the pre-neoplastic stages and accumulate during cancer progression. Thus, they might account for the cancer initiating steps and further malignant transformation. In addition to genetic alterations, epigenetic alterations can affect the cancer transcriptome more extensively. Alterations in DNA methylation, histone modification, miRNAs, RNA editing, and lncRNAs might result in disrupted gene regulation networks and substantially contribute to HCC progression. In this review, the genetic and epigenetic alterations which significantly contribute to the malignant capabilities of HCC will be updated and summarized in detail. Further characterization of those critical molecular events might better elucidate the pathogenesis of HCC and provide novel therapeutic targets for treatment of this deadly disease.
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Affiliation(s)
- Ming Liu
- Department of Clinical Oncology, University of Hong Kong, Hong Kong, China
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41
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Coleman SJ, Grose RP, Kocher HM. Fibroblast growth factor family as a potential target in the treatment of hepatocellular carcinoma. J Hepatocell Carcinoma 2014; 1:43-54. [PMID: 27508175 PMCID: PMC4918266 DOI: 10.2147/jhc.s48958] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular cancer (HCC) is currently the third leading cause of cancer death worldwide. The prognosis of patients diagnosed with late-stage disease is dismal due to high resistance to conventional systemic therapies. The introduction of sorafenib, despite its limited efficacy, as the standard systemic therapy for advanced HCC has paved a way for targeted molecular therapies for HCC. Fibroblast growth factor (FGF) signaling plays an important role in the developing embryo and the adult. The FGF signaling pathway is often hijacked by cancer cells, including HCC. Several alterations in FGF signaling correlate with poor outcome in HCC patients, suggesting that this family of signaling molecules plays an important role in the development of HCC. Multikinase inhibitors targeting FGF signaling are currently under investigation in clinical trials. This review discusses the current understanding of the biological and clinical implications of aberrant FGF signaling in the prognosis, diagnosis, and treatment of HCC.
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Affiliation(s)
- Stacey J Coleman
- Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London, UK
| | - Richard P Grose
- Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London, UK
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London, UK; Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London, UK
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42
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Zacharoulis D, Hatzitheofilou C, Athanasiou E, Zacharoulis S. Antiangiogenic strategies in hepatocellular carcinoma: current status. Expert Rev Anticancer Ther 2014; 5:645-56. [PMID: 16111465 DOI: 10.1586/14737140.5.4.645] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma is a leading cause of cancer death worldwide in both adult and pediatric patients. Despite many options, no ideal treatment exists for this highly malignant tumor, and management strategies have varied accordingly. Angiogenesis, the formation of new blood vessels, is an essential component of hepatocellular carcinoma biology. Innovative approaches such as targeting the nontransformed, less resistant, tumor-supporting endothelial cells are currently under investigation in hepatocellular carcinoma. This review will focus on the current knowledge of the pathophysiology of hepatocellular carcinoma angiogenesis, as well as the reported data with angiogenesis inhibitors against hepatocellular carcinoma.
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Tsuchiya K, Asahina Y, Matsuda S, Muraoka M, Nakata T, Suzuki Y, Tamaki N, Yasui Y, Suzuki S, Hosokawa T, Nishimura T, Ueda K, Kuzuya T, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Enomoto N, Izumi N. Changes in plasma vascular endothelial growth factor at 8 weeks after sorafenib administration as predictors of survival for advanced hepatocellular carcinoma. Cancer 2013; 120:229-37. [PMID: 24122122 PMCID: PMC4209122 DOI: 10.1002/cncr.28384] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Revised: 08/10/2013] [Accepted: 08/15/2013] [Indexed: 02/06/2023]
Abstract
Background A new predictive biomarker for determining prognosis in patients with hepatocellular carcinoma (HCC) who receive sorafenib is required, because achieving a reduction in tumor size with sorafenib is rare, even in patients who have a favorable prognosis. Vascular endothelial growth factor (VEGF) receptor is a sorafenib target. In the current study, the authors examined changes in plasma VEGF concentrations during sorafenib treatment and determined the clinical significance of VEGF as a prognostic indicator in patients with HCC. Methods Plasma VEGF concentrations were serially measured in 63 patients with advanced HCC before and during sorafenib treatment. A plasma VEGF concentration that decreased >5% from the pretreatment level at 8 weeks was defined as a “VEGF decrease.” An objective tumor response was determined using modified Response Evaluation Criteria in Solid Tumors 1 month after the initiation of therapy and every 3 months thereafter. Results Patients who had a VEGF decrease at week 8 (n = 14) had a longer median survival than those who did not have a VEGF decrease (n = 49; 30.9 months vs 14.4 months; P = .038). All patients who had a VEGF decrease survived for >6 months, and the patients who had both a VEGF decrease and an α-fetoprotein response (n = 6) survived during the observation period (median, 19.7 months; range, 6.5-31.0 months). In univariate analyses, a VEGF decrease, radiologic findings classified as progressive disease, and major vascular invasion were associated significantly with 1-year survival; and, in multivariate analysis, a VEGF decrease was identified as an independent factor associated significantly with survival. Conclusions A plasma VEGF concentration decrease at 8 weeks after starting sorafenib treatment may predict favorable overall survival in patients with advanced HCC.
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Affiliation(s)
- Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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Lu Q, Wang C, Pan R, Gao X, Wei Z, Xia Y, Dai Y. Histamine synergistically promotes bFGF-induced angiogenesis by enhancing VEGF production via H1 receptor. J Cell Biochem 2013; 114:1009-19. [PMID: 23225320 DOI: 10.1002/jcb.24440] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2012] [Accepted: 10/24/2012] [Indexed: 11/06/2022]
Abstract
Histamine, a major mediator present in mast cells that is released into the extracellular milieu upon degranulation, is well known to possess a wide range of biological activities in several classic physiological and pathological processes. However, whether and how it participates in angiogenesis remains obscure. In the present study, we observed its direct and synergistic action with basic fibroblast growth factor (bFGF), an important inducer of angiogenesis, on in vitro angiogenesis models of endothelial cells. Data showed that histamine (0.1, 1, 10 µM) itself was absent of direct effects on the processes of angiogenesis, including the proliferation, migration, and tube formation of endothelial cells. Nevertheless, it could concentration-dependently enhance bFGF-induced angiogenesis as well as production of vascular endothelial growth factor (VEGF) from endothelial cells. The synergistic effect of histamine on VEGF production could be reversed by pretreatments with diphenhydramine (H1-receptor antagonist), SB203580 (selective p38 mitogen-activated protein kinase (MAPK) inhibitor) and L-NAME (nitric oxide synthase (NOS) inhibitor), but not with cimetidine (H2-receptor antagonist) and indomethacin (cyclooxygenase (COX) inhibitor). Moreover, histamine could augment bFGF-incuced phosphorylation and degradation of IκBα, a key factor accounting for the activation and translocation of nuclear factor κB (NF-κB) in endothelial cells. These findings indicated that histamine was able to synergistically augment bFGF-induced angiogenesis, and this action was linked to VEGF production through H1-receptor and the activation of endothelial nitric oxide synthase (eNOS), p38 MAPK, and IκBα in endothelial cells.
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Affiliation(s)
- Qian Lu
- Department of Pharmacology of Chinese Materia Medica, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
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Nomura T, Morishita A, Jian G, Mimura S, Kato K, Nomura K, Tani J, Miyoshi H, Yoneyama H, Sakamoto T, Fujita K, Maeda E, Kobara H, Mori H, Iwama H, Masaki T. Expression of angiogenic factors in hepatocarcinogenesis: Identification by antibody arrays. Oncol Rep 2013; 30:2476-80. [PMID: 23970062 DOI: 10.3892/or.2013.2674] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 06/21/2013] [Indexed: 11/05/2022] Open
Abstract
Angiogenesis plays a pivotal role in the progression and metastasis of hepatocellular carcinoma (HCC). However, the expression of a wide range of angiogenic factors remains obscure in HCC. The purpose of the present study was to determine the expression of various angiogenic factors related to hepatocarcinogenesis. We examined the expression of 19 angiogenic factors using antibody arrays in human tissues of various liver diseases, including HCC. We also studied the expression of 19 angiogenic factors in the human HCC cell lines PLC/PRF/5, Hep 3B, HuH7, HLE, HLF and Li-7 and the normal hepatocyte cell line ACBRI3716. In human tissues, although the expression of acidic fibroblast growth factor (aFGF) was found to increase from normal liver to chronic hepatitis, its expression remained unchanged in the transition from chronic hepatitis to HCC. Vascular endothelial growth factor (VEGF) was elevated in liver cirrhosis, but the amounts remained unchanged in the transition from liver cirrhosis to HCC. In contrast, either interleukin-8 (IL-8) or basic fibroblast growth factor (bFGF) was upregulated in HCC. In the HCC cell lines PLC/PRF/5, Hep 3B and HuH-7, the expression of IL-8 was elevated. Although IL-8 was not elevated, bFGF was upregulated in the other HCC cell lines HLE, HLF and Li-7. Thus, either IL-8 or bFGF was upregulated in HCC cell lines and in HCC tissue samples. These data suggest that the upregulation of either IL-8 or bFGF is closely related to the transition from liver cirrhosis into HCC. Therefore, the analysis of the expression of these cytokines using protein arrays may identify novel therapies for individual patients with HCC.
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Affiliation(s)
- Takako Nomura
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
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Yoshiji H, Noguchi R, Namisaki T, Moriya K, Kitade M, Aihara Y, Douhara A, Yamao J, Fujimoto M, Toyohara M, Mitoro A, Sawai M, Yoshida M, Morioka C, Uejima M, Uemura M, Fukui H. Branched-chain amino acids suppress the cumulative recurrence of hepatocellular carcinoma under conditions of insulin-resistance. Oncol Rep 2013; 30:545-552. [PMID: 23708326 PMCID: PMC3816550 DOI: 10.3892/or.2013.2497] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Accepted: 04/17/2013] [Indexed: 12/31/2022] Open
Abstract
Branched-chain amino acids (BCAAs) reportedly inhibit the incidence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and obesity that is frequently associated with insulin resistance (IR). We previously reported that BCAAs exert a chemopreventive effect against HCC under IR conditions in rats. The aim of the present study was to examine the effect of BCAAs on the cumulative recurrence of HCC under IR conditions in the clinical practice. BCAA granules (Livact®, 12 g/day) were administered for 60 months following the local curative therapy for HCC, and several indices were determined. Treatment with BCAAs markedly inhibited the cumulative recurrence of HCC in patients with a high IR index [homeostasis model assessment (HOMA)-IR >2.5], but not in patients with HOMA-IR of ≤2.5. BCAA also improved the HOMA-IR, and the inhibitory effect was observed regardless of the serum albumin (Alb) levels. Similarly, BCAA treatment revealed a marked suppressive effect in patients with high fasting insulin [immune reactive insulin (IRI)>15 U/ml], but not with IRI of ≤15. BCAA treatment did not result in differences in HCC recurrence in patients with high and low glucose levels [fasting blood sugar (FBS)>110 and ≤110, respectively]. Furthermore, serum levels of the soluble form of vascular endothelial growth factor receptor 2 (sVEGFR2) were significantly inhibited along with these clinical effects. Our findings indicate that the inhibitory effect of BCAAs was achieved, at least partly, by coordinated effects of anti-angiogenesis and IR improvement. Since BCAAs are widely and safely used in clinical practice to treat patients with chronic liver diseases, BCAAs may represent a new strategy for secondary chemoprevention for HCC patients with IR. Moreover, our findings suggest that sVEGFR2 may be a useful clinical predictive marker for BCAA treatment under IR conditions.
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MESH Headings
- Amino Acids, Branched-Chain/therapeutic use
- Angiogenesis Inhibitors/therapeutic use
- Biomarkers, Tumor/blood
- Blood Glucose/metabolism
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/prevention & control
- Chemoprevention/methods
- Female
- Humans
- Insulin Resistance/physiology
- Liver Neoplasms/blood
- Liver Neoplasms/drug therapy
- Liver Neoplasms/metabolism
- Liver Neoplasms/prevention & control
- Male
- Middle Aged
- Neoplasm Recurrence, Local/blood
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/ethnology
- Neoplasm Recurrence, Local/prevention & control
- Serum Albumin/metabolism
- Vascular Endothelial Growth Factor B/blood
- Vascular Endothelial Growth Factor Receptor-2/blood
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Affiliation(s)
- Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan.
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Noguchi R, Yoshiji H, Ikenaka Y, Kaji K, Aihara Y, Shirai Y, Namisaki T, Kitade M, Douhara A, Moriya K, Fukui H. Dual blockade of angiotensin-II and aldosterone suppresses the progression of a non-diabetic rat model of steatohepatitis. Hepatol Res 2013; 43:765-774. [PMID: 23163573 DOI: 10.1111/hepr.12008] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Revised: 10/15/2012] [Accepted: 10/15/2012] [Indexed: 12/15/2022]
Abstract
AIM Both angiotensin-II (AT-II) and aldosterone (Ald) play pivotal roles in the pathogenesis of diseases in several organs including the liver. We previously reported that suppression of AT-II and Ald with angiotensin-converting enzyme inhibitor (ACE-I) and selective Ald blocker (SAB), respectively, attenuated the rat liver fibrogenesis and hepatocarcinogenesis. The aim of our current study was to elucidate the combined effects of ACE-I and SAB in the progression of a non-diabetic rat model of steatohepatitis, and the possible mechanisms involved. METHODS In the choline-deficient L-amino acid-defined (CDAA) diet-induced model, the effects of ACE-I and SAB on liver fibrosis development and hepatocarcinogenesis were elucidated, especially in conjunction with neovascularization. RESULTS Treatment with both ACE-I and SAB suppressed the development of liver fibrosis and glutathione-S-transferase placental form (GST-P) positive pre-neoplastic lesions. The combined treatment with both agents exerted more inhibitory effects as compared with either a single agent along with suppression of the activated hepatic stellate cells (Ac-HSC) and neovascularization, both of which play important roles in these processes. Our in vitro study showed that AT-II type 1 receptor blocker (ARB) and SAB inhibited Ac-HSC proliferation and in vitro angiogenesis along with suppression of the in vivo studies. CONCLUSION Dual blockade of AT-II and Ald suppresses the progression of a non-diabetic rat model of steatohepatitis. Because both agents are widely and safely used in clinical practice, this combination therapy could be an effective new strategy against steatohepatitis in the future.
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Affiliation(s)
- Ryuichi Noguchi
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
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Colombo M, Raoul JL, Lencioni R, Galle PR, Zucman-Rossi J, Bañares R, Seehofer D, Neuhaus P, Johnson P. Multidisciplinary strategies to improve treatment outcomes in hepatocellular carcinoma: a European perspective. Eur J Gastroenterol Hepatol 2013; 25:639-51. [PMID: 23628963 DOI: 10.1097/meg.0b013e32835e33bb] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) is a complex disease with a poor prognosis. Incidence and mortality rates are increasing in many geographical regions, indicating a need for better management strategies. Among several risk factors for HCC, the most common are cirrhosis because of chronic hepatitis B virus or hepatitis C virus infection and alcohol consumption, obesity, and diabetes. In some patients, combined risk factors present additional challenges to the prevention and treatment of HCC. Screening and surveillance of high-risk populations varies widely by geographic regions, and access to optimal surveillance is critical for early diagnosis. The treatment choice for HCC depends on the cancer stage, patient performance status, and liver function and requires a multidisciplinary approach and close cooperation among specialists for the best patient outcomes. Despite advances in surgical treatments and locoregional therapies, recurrence and liver failure remain significant challenges. The pathogenesis of HCC is a multistep and complex process, wherein angiogenesis plays an important role. The multikinase inhibitor sorafenib is the only approved targeted agent for advanced HCC, although promising results have been obtained with other targeted agents and combinations, and the results of ongoing trials are eagerly awaited. Clinical trials with rigorous study designs, including molecular classification and validation of new molecular biomarkers, are required to improve the personalized treatment of HCC. This article provides an overview of HCC and was developed through a review of relevant literature, clinical trial data, and updated clinical guidelines.
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Affiliation(s)
- Massimo Colombo
- 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
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Chong DQ, Tan IB, Choo SP, Toh HC. The evolving landscape of therapeutic drug development for hepatocellular carcinoma. Contemp Clin Trials 2013; 36:605-15. [PMID: 23591326 DOI: 10.1016/j.cct.2013.03.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Revised: 03/12/2013] [Accepted: 03/15/2013] [Indexed: 12/16/2022]
Abstract
Currently, only one drug, sorafenib, is FDA approved for the treatment of advanced hepatocellular carcinoma (HCC), achieving modest objective response rates while still conferring an overall survival benefit. Unlike other solid tumors, no oncogenic addiction loops have been validated as clinically actionable targets in HCC. Outcomes of HCC could potentially be improved if critical molecular subclasses with distinct therapeutic vulnerabilities can be identified, biomarkers that predict recurrence or progression early can be determined and key epigenetic, genetic or microenvironment drivers that determine best response to a specific targeting treatment can be uncovered. Our group and others have examined the molecular heterogeneity of hepatocellular carcinoma. We have developed a panel of patient derived xenograft models to enable focused pre-clinical drug development of rationally designed therapies in specific molecular subgroups. We observed unique patterns, including synergies, of drug activity across our molecularly diverse HCC xenografts, pointing to specific therapeutic vulnerabilities for individual tumors. These efforts inform clinical trial designs and catalyze therapeutic development. It also argues for efficient strategic allocation of patients into appropriate enriched clinical trials. Here, we will discuss some of the recent important therapeutic studies in advanced HCC and also some of the potential strategies to optimize clinical therapeutic development moving forward.
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Affiliation(s)
- Dawn Qingqing Chong
- Department of Medical Oncology, National Cancer Centre Singapore, Singapore.
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Abstract
Hepatocellular carcinoma (HCC) is a significant cause of death worldwide. HCC is a highly vascular tumor, and proangiogenic cytokines such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor may play crucial roles in this disease. Sorafenib, a multikinase inhibitor that blocks VEGF and PDGF signaling, was the first systemic therapy to demonstrate improved survival in patients with advanced HCC. Several other drugs targeting VEGF are in development. Because of the anticipation of eventual resistance to anti-VEGF therapies, drugs that also target alternative proangiogenic pathways are being investigated. Recent clinical and preclinical data along with ongoing studies are reviewed.
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Affiliation(s)
- Keeran R Sampat
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA
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