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Yi Y, Song P, Li Z, Ju J, Sun G, Ren Q, Zhou K, Liu L, Wu HC. Nanopore-based enzyme-linked immunosorbent assay for cancer biomarker detection. NATURE NANOTECHNOLOGY 2025:10.1038/s41565-025-01918-z. [PMID: 40369343 DOI: 10.1038/s41565-025-01918-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 03/25/2025] [Indexed: 05/16/2025]
Abstract
Enzyme-linked immunosorbent assay (ELISA) has been widely used in cancer diagnostics due to its specificity, sensitivity and high throughput. However, conventional ELISA is semiquantitative and has an insufficiently low detection limit for applications requiring ultrahigh sensitivity. In this study, we developed an α-hemolysin-nanopore-based ELISA for detecting cancer biomarkers. After forming the immuno-sandwich complex, peptide probes carrying enzymatic cleavage sites are introduced, where they interact with enzymes conjugated to the detection antibodies within the complex. These probes generate distinct current signatures when translocated through the nanopore after enzymatic cleavage, enabling precise biomarker quantification. This approach offers a low detection limit of up to 0.03 fg ml-1 and the simultaneous detection of six biomarkers, including antigen and antibody biomarkers in blood samples. Overall, the nanopore-based ELISA demonstrates high sensitivity and multiplexing capability, making it suitable for next-generation diagnostic and point-of-care testing applications.
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Affiliation(s)
- Yakun Yi
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Peng Song
- Department of Medical Oncology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Ziyi Li
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jinzhou Ju
- University of Chinese Academy of Sciences, Beijing, China
- Beijing National Laboratory for Molecular Sciences, Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Guixiang Sun
- Department of Laboratory Medicine, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Qianyuan Ren
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Ke Zhou
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Lei Liu
- College of Food and Bioengineering, Xihua University, Chengdu, China.
| | - Hai-Chen Wu
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
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Pahwa P, Sharma D, Yadav P, Thomas SS, Hora S, Preedia Babu E, Ramakrishna G, Sarin SK, Trehanpati N. Prognostic Role of Serum Vascular Endothelial Growth Factor and Hepatocyte Growth Factor Post Stereotactic Body Radiation in Advanced Hepatocellular Carcinoma. J Clin Exp Hepatol 2025; 15:102444. [PMID: 39654812 PMCID: PMC11625295 DOI: 10.1016/j.jceh.2024.102444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 10/17/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND/AIMS Stereotactic body radiation therapy (SBRT) has evolved as a treatment alternative for advanced hepatocellular carcinoma (HCC) patients who are ineligible for other local therapies. Posttreatment responses are assessed by imaging modalities, serum AFP, and protein induced by vitamin K absence-II (PIVKA) II levels. Despite good specificity, both AFP and PIVKA-II have low to medium sensitivity. The study aimed to find more effective biomarkers that have an impact on the survival outcomes of the patients. METHODS We have prospectively collected blood samples from 18 patients undergoing SBRT. Serum levels of hepatocyte growth factor (HGF) and vascular endothelial growth factor-A (VEGF-A) were analyzed kinetically pre-SBRT following day 5 and day 30 post-SBRT. Local control (LC), overall survival (OS), progression free survival (PFS), and postprocedure adverse events were recorded. RESULTS The cohort had a median follow-up duration of 12.5 months (range 4-30 months). In the entire cohort, the estimated mean OS was 21.2 months (95% confidence interval [CI], 15.9-26.4), and the median progression free survival (mPFS) was 8 months (95% CI, 1.7-14.2). Patients with higher PIVKA-II levels (pre- and post-SBRT) also showed increased concentrations of VEGF-A and HGF. Patients with metastasis at presentation had higher HGF (P = 0.028) and VEGF-A (P = 0.027) concentrations compared to the nonmetastatic group. Patients with increased levels of VEGF-A and HGF at day 30 post-SBRT compared to day 5 had poor PFS. Indeed, the mPFS was 22 months vs 6 months (P = 0.301) in patients with low VEGF-A post SBRT on day 30 compared to day 5. Similarly, mPFS in patients with increase in HGF was 6 months as compared to 22 months (P = 0.326) in patients in whom HGF was reduced post-SBRT. CONCLUSION We conclude that in addition to PIVKA-II, HGF, and VEGF-A can be used as prognostic and predictive markers for early progression of disease post-SBRT. However, further prospective trials are warranted in the future to validate the results.
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Affiliation(s)
- Prabhjyoti Pahwa
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Deepti Sharma
- Department of Radiation Oncology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Pushpa Yadav
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sherin S. Thomas
- Department of Biochemistry, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sandhya Hora
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - E. Preedia Babu
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Gayatri Ramakrishna
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Nirupama Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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Wang J, Liu C, Hu R, Wu L, Li C. Statin therapy: a potential adjuvant to immunotherapies in hepatocellular carcinoma. Front Pharmacol 2024; 15:1324140. [PMID: 38362156 PMCID: PMC10867224 DOI: 10.3389/fphar.2024.1324140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 01/23/2024] [Indexed: 02/17/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and accounts for more than 90% of primary liver cancer. The advent of immune checkpoint inhibitor (ICI)-related therapies combined with angiogenesis inhibition has revolutionized the treatment of HCC in late-stage and unresectable HCC, as ICIs alone were disappointing in treating HCC. In addition to the altered immune microenvironment, abnormal lipid metabolism in the liver has been extensively characterized in various types of HCC. Stains are known for their cholesterol-lowering properties and their long history of treating hypercholesterolemia and reducing cardiovascular disease risk. Apart from ICI and other conventional therapies, statins are frequently used by advanced HCC patients with dyslipidemia, which is often marked by the abnormal accumulation of cholesterol and fatty acids in the liver. Supported by a body of preclinical and clinical studies, statins may unexpectedly enhance the efficacy of ICI therapy in HCC patients through the regulation of inflammatory responses and the immune microenvironment. This review discusses the abnormal changes in lipid metabolism in HCC, summarizes the clinical evidence and benefits of stain use in HCC, and prospects the possible mechanistic actions of statins in transforming the immune microenvironment in HCC when combined with immunotherapies. Consequently, the use of statin therapy may emerge as a novel and valuable adjuvant for immunotherapies in HCC.
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Affiliation(s)
- Jiao Wang
- Department of Laboratory Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chengyu Liu
- Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ronghua Hu
- Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Licheng Wu
- School of Clinical Medicine, Nanchang Medical College, Nanchang, China
| | - Chuanzhou Li
- Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Dios-Barbeito S, González R, Cadenas M, García LF, Victor VM, Padillo FJ, Muntané J. Impact of nitric oxide in liver cancer microenvironment. Nitric Oxide 2022; 128:1-11. [DOI: 10.1016/j.niox.2022.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 07/16/2022] [Accepted: 07/19/2022] [Indexed: 11/25/2022]
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Llovet JM, Vogel A, Madoff DC, Finn RS, Ogasawara S, Ren Z, Mody K, Li JJ, Siegel AB, Dubrovsky L, Kudo M. Randomized Phase 3 LEAP-012 Study: Transarterial Chemoembolization With or Without Lenvatinib Plus Pembrolizumab for Intermediate-Stage Hepatocellular Carcinoma Not Amenable to Curative Treatment. Cardiovasc Intervent Radiol 2022; 45:405-412. [PMID: 35119481 PMCID: PMC8940827 DOI: 10.1007/s00270-021-03031-9] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 10/21/2021] [Indexed: 02/08/2023]
Abstract
PURPOSE Transarterial chemoembolization (TACE) is the standard of care for patients with intermediate-stage hepatocellular carcinoma (HCC). Lenvatinib, a multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, have shown efficacy and tolerability in patients with HCC, and adding this combination to TACE may enhance clinical benefit. PROTOCOL LEAP-012 is a prospective, double-blind randomized phase 3 study. Adults with confirmed HCC localized to the liver without portal vein thrombosis and not amenable to curative treatment, ≥ 1 measurable tumor per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1), Eastern Cooperative Oncology Group performance status 0 or 1, Child-Pugh class A and no previous systemic treatment for HCC are eligible. Patients will be randomly assigned to lenvatinib once daily plus pembrolizumab every 6 weeks plus TACE or placebos plus TACE. Dual primary endpoints are overall survival and progression-free survival per RECIST 1.1 by blinded independent central review (BICR). Secondary endpoints are progression-free survival, objective response rate, disease control rate, duration of response and time to progression per modified RECIST by BICR; objective response rate, disease control rate, duration of response and time to progression per RECIST 1.1 by BICR; and safety. STATISTICS The planned sample size, 950 patients, was calculated to permit accumulation of sufficient overall survival events in 5 years to achieve 90% power for the overall survival primary endpoint. DISCUSSION LEAP-012 will evaluate the clinical benefit of adding lenvatinib plus pembrolizumab to TACE in patients with intermediate-stage HCC not amenable to curative treatment. CLINICALTRIALS gov NCT04246177.
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Affiliation(s)
- Josep M Llovet
- Mount Sinai Liver Cancer Program, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, Icahn (East) Building, 11th Floor, Room 11-70A, 1425 Madison Ave, New York, NY, 10029, USA.
- Translational Research in Hepatic Oncology, IDIBAPS, Hospital Clinic Barcelona, University of Barcelona, Barcelona, Catalonia, Spain.
- Institució Catalana d'Estudis Avançats (ICREA), Barcelona, Spain.
| | | | - David C Madoff
- Yale School of Medicine and Yale Cancer Center/Smilow Cancer Hospital, New Haven, CT, USA
| | - Richard S Finn
- David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | | | - Zhenggang Ren
- Zhongshan Hospital Fudan University, Shanghai, China
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Cucarull B, Tutusaus A, Rider P, Hernáez-Alsina T, Cuño C, García de Frutos P, Colell A, Marí M, Morales A. Hepatocellular Carcinoma: Molecular Pathogenesis and Therapeutic Advances. Cancers (Basel) 2022; 14:cancers14030621. [PMID: 35158892 PMCID: PMC8833604 DOI: 10.3390/cancers14030621] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/18/2022] [Accepted: 01/22/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most common form of liver cancer, continues to be a serious medical problem with poor prognosis, without major therapeutic improvement for years and increasing incidence. Fortunately, advances in systemic treatment options are finally arriving for HCC patients. After a decade of sorafenib as a standard therapy for advanced HCC, several tyrosine kinase inhibitors (TKIs), antiangiogenic antibodies, and immune checkpoint inhibitors have reached the clinic. Although infections by hepatitis B virus and hepatitis C virus remain principal factors for HCC development, the rise of non- alcoholic steatohepatitis from diabetes mellitus or metabolic syndrome is impeding HCC decline. Knowledge of specific molecular mechanisms, based on the etiology and the HCC microenvironment that influence tumor growth and immune control, will be crucial for physician decision-making among a variety of drugs to prescribe. In addition, markers of treatment efficacy are needed to speed the movement of patients towards other potentially effective treatments. Consequently, research to provide scientific data for the evidence-based management of liver cancer is guaranteed in the coming years and discussed here.
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Affiliation(s)
- Blanca Cucarull
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | - Anna Tutusaus
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | - Patricia Rider
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | | | - Carlos Cuño
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | - Pablo García de Frutos
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Unidad Asociada (IMIM), IIBB-CSIC, CIBERCV, IDIBAPS, 08036 Barcelona, Spain
| | - Anna Colell
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), 08036 Barcelona, Spain
| | - Montserrat Marí
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Correspondence: (M.M.); (A.M.); Tel.: +34-932558314 (M.M. & A.M.)
| | - Albert Morales
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic of Barcelona, University of Barcelona, CIBEREHD, IDIBAPS, 08036 Barcelona, Spain
- Correspondence: (M.M.); (A.M.); Tel.: +34-932558314 (M.M. & A.M.)
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Barathan M, Riazalhosseini B, Iyadorai T, Vellasamy KM, Vadivelu J, Chang LY, Zulpa AK, Larsson M, Shankar EM, Mohamed R. Comparative expression of pro-inflammatory and apoptotic biosignatures in chronic HBV-infected patients with and without liver cirrhosis. Microb Pathog 2021; 161:105231. [PMID: 34619310 DOI: 10.1016/j.micpath.2021.105231] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 09/22/2021] [Accepted: 10/01/2021] [Indexed: 11/30/2022]
Abstract
The interplay of immune mediators is paramount to optimal host anti-viral immune responses, especially against chronic hepatitis B virus (HBV) infection. Here, we investigated the dynamic changes in host immune responses in chronic HBV-infected individuals with and without liver cirrhosis by examining the signatures of apoptosis and plasma levels of pro-inflammatory cytokines, chemokines, and cytotoxic proteins. A total of 40 chronic HBV patients with and without liver cirrhosis were studied for plasma levels of immune mediators, and signatures of apoptosis in peripheral blood mononuclear cells (PBMCs). The intracellular concentrations of reactive oxygen species (ROS) in patients with chronic HBV with liver cirrhosis was relatively higher as compared to chronic HBV patients. The onset of apoptosis was sustained due to ongoing liver inflammation in concert with plasma TNF-α and IL-6 levels. Plasma VEGF was upregulated among chronic HBV patients with liver cirrhosis, whereas CCL2, CCL5 and granzyme B levels were down-regulated. High levels of ROS, IL-6 and TNF-α correlated with ongoing inflammation among chronic HBV patients with liver cirrhosis, which likely attributed to the expression of biosignatures of apoptosis and activation in immune cells.
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Affiliation(s)
- Muttiah Barathan
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia
| | - Behnaz Riazalhosseini
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia
| | - Thevambiga Iyadorai
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia
| | - Kumutha Malar Vellasamy
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia
| | - Jamuna Vadivelu
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia
| | - Li-Yen Chang
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia
| | - Ahmad Khusairy Zulpa
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia
| | - Marie Larsson
- Division of Molecular Medicine and Virology, Department of Biomedicine and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Esaki M Shankar
- Infection Biology, Department of Life Sciences, Central University of Tamil Nadu, Thiruvarur, 610 005, India.
| | - Rosmawati Mohamed
- Department of Medicine, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia.
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Okubo S, Shindoh J, Kobayashi Y, Umino R, Akabane M, Kojima K, Hashimoto M. Adipose Tissue Distribution Predicts Prognosis of Cirrhotic Patients Undergoing Hepatectomy for Hepatocellular Carcinoma. Ann Surg Oncol 2021; 28:6738-6746. [PMID: 33554286 DOI: 10.1245/s10434-021-09658-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 01/09/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND Body composition data are reportedly correlated with patient prognosis for various cancers. However, little is known about the prognostic impact of adipose tissue distribution among patients with hepatocellular carcinoma (HCC). METHODS Data for 181 consecutive cirrhotic patients who underwent hepatectomy for HCC were retrospectively reviewed. The clinical significance of the visceral-to-subcutaneous adipose tissue ratio (VSR) was investigated through analysis of short- and long-term surgical outcomes. RESULTS Of the 181 patients, 60 (33%) were classified as the high-VSR group and 121 (67%) as the low-VSR group. Although VSR was not correlated with a risk of postoperative morbidity, multivariate analysis confirmed that a higher VSR was significantly correlated with a shorter time to interventional failure (hazard ratio [HR] 2.24; P = 0.008) and overall survival (HR 2.65; P = 0.001) independently of American Joint Committed on Cancer stage or preoperative nutritional status. Analysis of the recurrence patterns showed that the proportion of unresectable recurrence at the initial recurrence event was significantly higher in the high-VSR group (39% vs. 18%; P = 0.025). The yearly transition probabilities, defined by a Markov model from postoperative R0 status to advanced disease or death (7.6% vs. 1.5%, P < 0.001) and early recurrence stage to advanced disease or death (15.4% vs. 2.8%, P = 0.004), were higher in the high-VSR group, suggesting that patients with a higher VSR are vulnerable to disease progression. CONCLUSION A high VSR was found to be an independent predictor of disease progression and poor prognosis for HCC patients with underlying liver cirrhosis having resection for HCC.
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Affiliation(s)
- Satoshi Okubo
- Hepato-Biliary-Pancreatic Surgery Division, Department of Gastroenterological surgery, Toranomon Hospital, Minatoku, Tokyo, Japan
| | - Junichi Shindoh
- Hepato-Biliary-Pancreatic Surgery Division, Department of Gastroenterological surgery, Toranomon Hospital, Minatoku, Tokyo, Japan.
- Okinaka Memorial Institute for Medical Disease, Tokyo, Japan.
| | - Yuta Kobayashi
- Hepato-Biliary-Pancreatic Surgery Division, Department of Gastroenterological surgery, Toranomon Hospital, Minatoku, Tokyo, Japan
| | - Ryosuke Umino
- Hepato-Biliary-Pancreatic Surgery Division, Department of Gastroenterological surgery, Toranomon Hospital, Minatoku, Tokyo, Japan
| | - Miho Akabane
- Hepato-Biliary-Pancreatic Surgery Division, Department of Gastroenterological surgery, Toranomon Hospital, Minatoku, Tokyo, Japan
| | - Kazutaka Kojima
- Hepato-Biliary-Pancreatic Surgery Division, Department of Gastroenterological surgery, Toranomon Hospital, Minatoku, Tokyo, Japan
| | - Masaji Hashimoto
- Hepato-Biliary-Pancreatic Surgery Division, Department of Gastroenterological surgery, Toranomon Hospital, Minatoku, Tokyo, Japan
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Lee SK, Lee SW, Jang JW, Bae SH, Choi JY, Yoon SK. Immunological Markers, Prognostic Factors and Challenges Following Curative Treatments for Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:10271. [PMID: 34638613 PMCID: PMC8508906 DOI: 10.3390/ijms221910271] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortalities worldwide. Patients with early-stage HCC are eligible for curative treatments, such as surgical resection, liver transplantation (LT) and percutaneous ablation. Although curative treatments provide excellent long-term survival, almost 70-80% of patients experience HCC recurrence after curative treatments. Tumor-related factors, including tumor size, number and differentiation, and underlying liver disease, are well-known risk factors for recurrence following curative therapies. Moreover, the tumor microenvironment (TME) also plays a key role in the recurrence of HCC. Many immunosuppressive mechanisms, such as an increase in regulatory T cells and myeloid-derived suppressor cells with a decrease in cytotoxic T cells, are implicated in HCC recurrence. These suppressive TMEs are also modulated by several factors and pathways, including mammalian target of rapamycin signaling, vascular endothelial growth factor, programmed cell death protein 1 and its ligand 1. Based on these mechanisms and the promising results of immune checkpoint blockers (ICBs) in advanced HCC, there have been several ongoing adjuvant studies using a single or combination of ICB following curative treatments in HCC. In this review, we strive to provide biologic and immunological markers, prognostic factors, and challenges associated with clinical outcomes after curative treatments, including resection, LT and ablation.
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Affiliation(s)
- Soon Kyu Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Sung Won Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Jeong Won Jang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Si Hyun Bae
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Jong Young Choi
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Seung Kew Yoon
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
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Indole hydrazide compound ZJQ-24 inhibits angiogenesis and induces apoptosis cell death through abrogation of AKT/mTOR pathway in hepatocellular carcinoma. Cell Death Dis 2020; 11:926. [PMID: 33116125 PMCID: PMC7595202 DOI: 10.1038/s41419-020-03108-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 09/27/2020] [Accepted: 09/30/2020] [Indexed: 12/24/2022]
Abstract
Angiogenesis and the activation of AKT/mTOR pathway are crucial for hepatocarcinoma development and progression, the activation of mTORC1/2 and relevant substrates have been confirmed in clinical hepatocarcinoma samples. Therefore, AKT/mTOR pathway represents the major targets for anti-cancer drugs development. Here, we investigated the anti-proliferative activity and mechanisms of ZJQ-24 in hepatocellular carcinoma, both in vivo and in vitro. A hepatocellular carcinoma xenograft model showed that ZJQ-24 significantly inhibited tumor growth with few side effects. MTT assays, flow cytometric analysis, Western blotting and immunohistochemistry identified that ZJQ-24 effectively suppressed hepatocellular carcinoma cell proliferation via G2/M phase arrest and caspase-dependent apoptosis but had no cytotoxic on normal cells. Furthermore, ZJQ-24 significantly blocked AKT/mTOR signaling by down-regulation of mTORC1 molecules, including phospho-p70S6K (Thr389) and phospho-4EBP-1 (Ser65, Thr37/46, Thr70) and phospho-AKT (Ser473) in HCC cells. It is very important that the ZJQ-24 did not induce the mTORC1-depdent PI3K/Akt feedback activation through JNK excitation. Moreover, ZJQ-24 inhibited the cap-dependent translation initiation by impairing the assembly of the eIF4E/eIF4G complex. Immunohistochemistry further confirmed ZJQ-24 inhibited the tumor growth through suppression of VEGF and AKT/mTOR pathways in vivo. Thus, the present study is the first to illustrate that ZJQ-24 triggers antiangiogenic activity and apoptosis via inhibiting the AKT/mTOR pathway in hepatocellular carcinoma cells, providing basic scientific evidence that ZJQ-24 shows great potential function as inhibitor of angiogenesis and tumor growth in hepatocellular carcinoma.
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11
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Dimri M, Satyanarayana A. Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12020491. [PMID: 32093152 PMCID: PMC7072513 DOI: 10.3390/cancers12020491] [Citation(s) in RCA: 207] [Impact Index Per Article: 41.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 02/14/2020] [Accepted: 02/18/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a complex biological process and is often diagnosed at advanced stages with no effective treatment options. With advances in tumor biology and molecular genetic profiling, several different signaling pathways and molecular mechanisms have been identified as responsible for initiating and promoting HCC. Targeting these critical pathways, which include the receptor tyrosine kinase pathways, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK), the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), the Wnt/β-catenin signaling pathway, the ubiquitin/proteasome degradation and the hedgehog signaling pathway has led to the identification of novel therapeutics for HCC treatment. In this review, we elaborated on our current understanding of the signaling pathways involved in the development and initiation of HCC and anticipate the potential targets for therapeutic drug development.
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12
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Casadei-Gardini A, Orsi G, Caputo F, Ercolani G. Developments in predictive biomarkers for hepatocellular carcinoma therapy. Expert Rev Anticancer Ther 2020; 20:63-74. [PMID: 31910040 DOI: 10.1080/14737140.2020.1712198] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and the third largest cause of cancer-relateddeaths worldwide. Potentially curative treatments (surgical resection, radiofrequency or liver transplantation) are only available for few patients, while transarterial chemoembolization (TACE) or systemic agents are the best treatments for intermediate and advanced stage disease. The identification of markers that allow us to choose the best treatment for the patient is urgent.Areas covered: In this review we summarize the potential biological markers to predict the efficacy of all treatment available in patients with HCC and discuss anew biomarker with ahigher potential of success in the next future.Expert opinion: HCC is aheterogeneous disease. Tumors are heterogeneous in terms of genetic alteration,with spatial heterogeneity in cellular density, necrosis and angiogenesis.This heterogeneity may affect prognosis and treatment. Tumor heterogeneity can be difficult to quantify with traditional imaging due to subjective assessment of images; the same for sampling biopsy, which evaluates only asmall part of the tumor. We think that combining multi-OMICSwith radiomics represents apromising strategy for evaluating tumor heterogenicity and for identifying biomarkers of response and prognosis.
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Affiliation(s)
- Andrea Casadei-Gardini
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Orsi
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Francesco Caputo
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Giorgio Ercolani
- General and Oncology Surgery, Morgagni-Pierantoni Hospital, Forli, Italy.,Department of Medical & Surgical Sciences-DIMEC, Alma Mater Studiorum-University of Bologna, Bologna, Italy
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13
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Shao YY, Liu TH, Hsu C, Lu LC, Shen YC, Lin ZZ, Cheng AL, Hsu CH. Early alpha-foetoprotein response associated with treatment efficacy of immune checkpoint inhibitors for advanced hepatocellular carcinoma. Liver Int 2019; 39:2184-2189. [PMID: 31400295 DOI: 10.1111/liv.14210] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 07/25/2019] [Accepted: 07/30/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Post-treatment decline in serum alpha-foetoprotein (AFP) levels has been shown to predict the treatment efficacy of antiangiogenic therapy for advanced hepatocellular carcinoma (HCC). We explored whether a decline in AFP levels was also associated with treatment outcomes of immune checkpoint inhibitors (ICIs) in patients with advanced HCC. METHODS We reviewed all patients who received ICI therapy for advanced HCC. AFP response was evaluated in patients with the pretreatment AFP level of >20 ng/mL. We defined early AFP response as a >20% decline in serum AFP levels within the first 4 weeks of treatment initiation relative to pretreatment levels. We then studied whether early AFP response was associated with treatment outcomes. RESULTS Sixty patients were enrolled in this study; 43 of them were evaluable for early AFP response. The objective response rate of early AFP responders was significantly higher than that of early AFP nonresponders (73% vs. 14%, P < .001). Early AFP responders, compared with early AFP nonresponders, exhibited significantly longer overall survival (OS) (median, 28.0 vs 11.2 months, P = .048) and progression-free survival (PFS) (median, 15.2 vs 2.7 months, P = .002). After adjusting for other clinicopathological variables and treatments, early AFP response remained an independent predictor for longer OS (hazard ratio [HR] = 0.089, 95% confidence interval [CI] = 0.018-0.441; P = .003) and PFS (HR = 0.128, 95% CI = 0.041-0.399; P < .001). CONCLUSION Early AFP response was associated with higher treatment efficacy of ICIs for advanced HCC. Additional validation studies are nonetheless warranted.
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Affiliation(s)
- Yu-Yun Shao
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei City, Taiwan.,National Taiwan University Cancer Center, Taipei City, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
| | - Tsung-Hao Liu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei City, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu City, Taiwan
| | - Chiun Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei City, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
| | - Li-Chun Lu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei City, Taiwan.,National Taiwan University Cancer Center, Taipei City, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
| | - Yin-Chung Shen
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei City, Taiwan.,National Taiwan University Cancer Center, Taipei City, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
| | - Zhong-Zhe Lin
- National Taiwan University Cancer Center, Taipei City, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan
| | - Ann-Lii Cheng
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei City, Taiwan.,National Taiwan University Cancer Center, Taipei City, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan
| | - Chih-Hung Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei City, Taiwan.,National Taiwan University Cancer Center, Taipei City, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
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14
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Moeini A, Torrecilla S, Tovar V, Montironi C, Andreu-Oller C, Peix J, Higuera M, Pfister D, Ramadori P, Pinyol R, Solé M, Heikenwälder M, Friedman SL, Sia D, Llovet JM. An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents. Gastroenterology 2019; 157:1383-1397.e11. [PMID: 31344396 PMCID: PMC6815707 DOI: 10.1053/j.gastro.2019.07.028] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 07/02/2019] [Accepted: 07/17/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Cirrhosis and chronic inflammation precede development of hepatocellular carcinoma (HCC) in approximately 80% of cases. We investigated immune-related gene expression patterns in liver tissues surrounding early-stage HCCs and chemopreventive agents that might alter these patterns to prevent liver tumorigenesis. METHODS We analyzed gene expression profiles of nontumor liver tissues from 392 patients with early-stage HCC (training set, N = 167 and validation set, N = 225) and liver tissue from patients with cirrhosis without HCC (N = 216, controls) to identify changes in expression of genes that regulate the immune response that could contribute to hepatocarcinogenesis. We defined 172 genes as markers for this deregulated immune response, which we called the immune-mediated cancer field (ICF). We analyzed the expression data of liver tissues from 216 patients with cirrhosis without HCC and investigated the association between this gene expression signature and development of HCC and outcomes of patients (median follow-up, 10 years). Human liver tissues were also analyzed by histology. C57BL/6J mice were given a single injection of diethylnitrosamine (DEN) followed by weekly doses of carbon tetrachloride to induce liver fibrosis and tumorigenesis. Mice were then orally given the multiple tyrosine inhibitor nintedanib or vehicle (controls); liver tissues were collected and histology, transcriptome, and protein analyses were performed. We also analyzed transcriptomes of liver tissues collected from mice on a choline-deficient high-fat diet, which developed chronic liver inflammation and tumors, orally given aspirin and clopidogrel or the anti-inflammatory agent sulindac vs mice on a chow (control) diet. RESULTS We found the ICF gene expression pattern in 50% of liver tissues from patients with cirrhosis without HCC and in 60% of nontumor liver tissues from patients with early-stage HCC. The liver tissues with the ICF gene expression pattern had 3 different features: increased numbers of effector T cells; increased expression of genes that suppress the immune response and activation of transforming growth factor β signaling; or expression of genes that promote inflammation and activation of interferon gamma signaling. Patients with cirrhosis and liver tissues with the immunosuppressive profile (10% of cases) had a higher risk of HCC (hazard ratio, 2.41; 95% confidence interval, 1.21-4.80). Mice with chemically induced fibrosis or diet-induced steatohepatitis given nintedanib or aspirin and clopidogrel down-regulated the ICF gene expression pattern in liver and developed fewer and smaller tumors than mice given vehicle. CONCLUSIONS We identified an immune-related gene expression pattern in liver tissues of patients with early-stage HCC, called the ICF, that is associated with risk of HCC development in patients with cirrhosis. Administration of nintedanib or aspirin and clopidogrel to mice with chronic liver inflammation caused loss of this gene expression pattern and development of fewer and smaller liver tumors. Agents that alter immune regulatory gene expression patterns associated with carcinogenesis might be tested as chemopreventive agents in patients with cirrhosis.
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MESH Headings
- Animals
- Anticarcinogenic Agents/pharmacology
- Aspirin/pharmacology
- Biomarkers, Tumor/genetics
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Case-Control Studies
- Cell Transformation, Neoplastic/drug effects
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/immunology
- Cell Transformation, Neoplastic/pathology
- Clopidogrel/pharmacology
- Diethylnitrosamine
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Gene Regulatory Networks
- Humans
- Indoles/pharmacology
- Liver Neoplasms/genetics
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms, Experimental/genetics
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/pathology
- Liver Neoplasms, Experimental/prevention & control
- Male
- Mice, Inbred C57BL
- Transcriptome
- Tumor Escape/genetics
- Tumor Microenvironment
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Affiliation(s)
- Agrin Moeini
- Liver Cancer Translational Research Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Liver Unit, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Sara Torrecilla
- Liver Cancer Translational Research Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Liver Unit, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Victoria Tovar
- Liver Cancer Translational Research Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Liver Unit, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Carla Montironi
- Liver Cancer Translational Research Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Liver Unit, Universitat de Barcelona, Barcelona, Catalonia, Spain; Mount Sinai Liver Cancer Program, Department of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Carmen Andreu-Oller
- Liver Cancer Translational Research Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Liver Unit, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Judit Peix
- Liver Cancer Translational Research Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Liver Unit, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Mónica Higuera
- Liver Cancer Translational Research Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Liver Unit, Universitat de Barcelona, Barcelona, Catalonia, Spain; Liver diseases, Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Dominik Pfister
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
| | - Pierluigi Ramadori
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
| | - Roser Pinyol
- Liver Cancer Translational Research Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Liver Unit, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Manel Solé
- Liver Cancer Translational Research Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Liver Unit, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
| | - Scott L Friedman
- Mount Sinai Liver Cancer Program, Department of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Daniela Sia
- Mount Sinai Liver Cancer Program, Department of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, USA.
| | - Josep M Llovet
- Liver Cancer Translational Research Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Liver Unit, Universitat de Barcelona, Barcelona, Catalonia, Spain; Mount Sinai Liver Cancer Program, Department of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, USA; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
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Ponomarev AV, Shubina IZ. Insights Into Mechanisms of Tumor and Immune System Interaction: Association With Wound Healing. Front Oncol 2019; 9:1115. [PMID: 31709183 PMCID: PMC6823879 DOI: 10.3389/fonc.2019.01115] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 10/07/2019] [Indexed: 12/14/2022] Open
Abstract
A large number of studies have presented a great deal of information about tumor and immune system interaction. Nevertheless, the problem of tumor evasion from the immune reaction is still difficult to resolve. Understanding the ways in which immunosuppressive tumor microenvironment develops and maintains its potential is of utmost importance to ensure the best use of the suppressed immune functions. The study presents a review covering the data on tumor-associated antigens, mechanisms of tumor evasion from the immune reactions, and search for common immunosuppressive processes of tumor growth and normal wound healing. The study discusses the important role of monocytes/macrophages in the regulation of immune system reactions. We suggest that the simultaneous actions of growth factors and pro-inflammatory cytokines may result in the suppression of the immune system. The study describes intracellular signaling molecules that take part in the regulation of the myeloid cell functions. If the hypothesis is proved correct, the indicated interaction of cytokines could be regarded as a prospective target for antitumor therapy.
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Affiliation(s)
| | - Irina Zh Shubina
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
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16
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Tanaka Y, Tateishi R, Koike K. Proteoglycans Are Attractive Biomarkers and Therapeutic Targets in Hepatocellular Carcinoma. Int J Mol Sci 2018; 19:3070. [PMID: 30297672 PMCID: PMC6213444 DOI: 10.3390/ijms19103070] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 10/03/2018] [Accepted: 10/04/2018] [Indexed: 12/11/2022] Open
Abstract
Proteoglycans, which consist of a protein core and glycosaminoglycan chains, are major components of the extracellular matrix and play physiological roles in maintaining tissue homeostasis. In the carcinogenic tissue microenvironment, proteoglycan expression changes dramatically. Altered proteoglycan expression on tumor and stromal cells affects cancer cell signaling pathways, which alters growth, migration, and angiogenesis and could facilitate tumorigenesis. This dysregulation of proteoglycans has been implicated in the pathogenesis of diseases such as hepatocellular carcinoma (HCC) and the underlying mechanism has been studied extensively. This review summarizes the current knowledge of the roles of proteoglycans in the genesis and progression of HCC. It focuses on well-investigated proteoglycans such as serglycin, syndecan-1, glypican 3, agrin, collagen XVIII/endostatin, versican, and decorin, with particular emphasis on the potential of these factors as biomarkers and therapeutic targets in HCC regarding the future perspective of precision medicine toward the "cure of HCC".
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Affiliation(s)
- Yasuo Tanaka
- Graduate School of Medicine, Department of Gastroenterology, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
| | - Ryosuke Tateishi
- Graduate School of Medicine, Department of Gastroenterology, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
| | - Kazuhiko Koike
- Graduate School of Medicine, Department of Gastroenterology, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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17
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A Phase I Study of Combination Therapy with Sorafenib and 5-Fluorouracil in Patients with Advanced Hepatocellular Carcinoma. Drugs R D 2018; 17:381-388. [PMID: 28573606 PMCID: PMC5629128 DOI: 10.1007/s40268-017-0187-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background and aims Sorafenib is the first molecular targeted drug approved for the treatment of advanced hepatocellular carcinoma (HCC) and is a potent small molecule inhibitor of multiple kinases. Combination therapy with sorafenib and other cytotoxic agents for HCC may result in additive anticancer activity. The purpose of this phase I study was to investigate the safety and tolerability of combination therapy with sorafenib and 5-fluorouracil (5-FU) and to determine the optimum dose of 5-FU for a phase II trial. Methods This phase I study used a conventional 3 + 3 dose-escalation design. The primary endpoint was to determine the maximum tolerated dose (MTD) of 5-FU in combination with sorafenib and to determine the recommended dosage (RD) for phase II. The secondary endpoints evaluated were toxicity and the tumor response rate. All patients received 800 mg of sorafenib daily and three different dosages of 5-FU (250, 350, and 450 mg/m2/day) for 20 days by intravenous infusion in 1 month as one cycle. Results Twelve patients with advanced HCC were evaluated. The MTD of 5-FU in combination with sorafenib was 450 mg/m2/day, and 350 mg/m2/day was selected as the RD for a phase II study. Thrombocytopenia, stomatitis, and hand-foot skin reaction were observed as grade 3 adverse events. Nine patients achieved stable disease (75%), and three patients (25%) were judged to have progressive disease. The disease control rate was 75%. Conclusions Combination therapy with sorafenib and 5-FU appears to be well tolerated and may have the potential to be an option for advanced HCC.
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18
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Chen Y, Zhong W, Chen B, Yang C, Zhou S, Liu J. Effect of curcumin on vascular endothelial growth factor in hypoxic HepG2 cells via the insulin-like growth factor 1 receptor signaling pathway. Exp Ther Med 2018; 15:2922-2928. [PMID: 29599831 PMCID: PMC5867490 DOI: 10.3892/etm.2018.5783] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 12/08/2017] [Indexed: 12/13/2022] Open
Abstract
To investigate the anti-angiogenic effect and underlying molecular mechanisms of curcumin on HepG2 cells under hypoxic conditions, insulin-like growth factor 1 receptor (IGF-1R) knockout HepG2 cells were constructed using a clustered regularly interspaced short palindromic repeats/Cas9 genome-editing system. Hypoxic conditions were generated using cobalt chloride (CoCl2). An MTT assay was performed to measure the effects of curcumin on cell viability in hypoxia-induced IGF-1R knockout HepG2 cells, while western blot analysis was used to detect the expression of IGF-1R, phosphorylated (p)-protein kinase B (Akt), p-extracellular signal-regulated kinases (Erk)1/2, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). The results revealed that CoCl2 at low concentrations (50 and 100 µM) had no significant inhibitory effects on IGF-1R knockout HepG2 cells. However, with increasing concentrations of CoCl2 and treatment time, cell viability decreased and was significantly reduced at 150, 200 and 400 µM compared with the control group (P<0.05). The expression of HIF-1α and VEGF were significantly increased when the cells were treated with 150 or 200 µM CoCl2 compared with the control (P<0.05). With the increase of CoCl2 concentration or the treatment time, the expression of HIF-1α and VEGF were upregulated gradually. Additionally, curcumin significantly inhibited the expression of p-Akt, p-Erk1/2, HIF-1α and VEGF in hypoxia-induced IGF-1R knockout HepG2 cells. In conclusion, the findings of the present study suggest that curcumin may serve a pivotal role in tumor suppression via the inhibition of IGF-1R-mediated angiogenesis under hypoxic conditions.
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Affiliation(s)
- Yihui Chen
- Department of General Surgery, The 175th Hospital of PLA, Affiliated Southeast Hospital of Xiamen University, Zhangzhou, Fujian 363000, P.R. China
| | - Wei Zhong
- Department of General Surgery, The 175th Hospital of PLA, Affiliated Southeast Hospital of Xiamen University, Zhangzhou, Fujian 363000, P.R. China
| | - Baohua Chen
- Department of General Surgery, The 184th Hospital of PLA, Yingtan, Jiangxi 335000, P.R. China
| | - Chuanyu Yang
- Department of General Surgery, The 175th Hospital of PLA, Affiliated Southeast Hospital of Xiamen University, Zhangzhou, Fujian 363000, P.R. China
| | - Song Zhou
- Department of General Surgery, The 175th Hospital of PLA, Affiliated Southeast Hospital of Xiamen University, Zhangzhou, Fujian 363000, P.R. China
| | - Jing Liu
- Department of General Surgery, The 175th Hospital of PLA, Affiliated Southeast Hospital of Xiamen University, Zhangzhou, Fujian 363000, P.R. China
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19
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Prenner S, Kulik L. Hepatocellular Carcinoma. ZAKIM AND BOYER'S HEPATOLOGY 2018:668-692.e9. [DOI: 10.1016/b978-0-323-37591-7.00046-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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20
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Herzog J, Ehrlich SM, Pfitzer L, Liebl J, Fröhlich T, Arnold GJ, Mikulits W, Haider C, Vollmar AM, Zahler S. Cyclin-dependent kinase 5 stabilizes hypoxia-inducible factor-1α: a novel approach for inhibiting angiogenesis in hepatocellular carcinoma. Oncotarget 2017; 7:27108-21. [PMID: 27027353 PMCID: PMC5053636 DOI: 10.18632/oncotarget.8342] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 03/16/2016] [Indexed: 01/25/2023] Open
Abstract
We recently introduced CDK5 as target in HCC, regulating DNA damage response. Based on this and on our previous knowledge about vascular effects of CDK5, we investigated the role of CDK5 in angiogenesis in HCC, one of the most vascularized tumors. We put a special focus on the transcription factor HIF-1α, a master regulator of tumor angiogenesis. The interaction of CDK5 with HIF-1α was tested by Western blot, PCR, reporter gene assay, immunohistochemistry, kinase assay, co-immunoprecipitation, mass spectrometry, and mutation studies. In vivo, different murine HCC models, were either induced by diethylnitrosamine or subcutaneous injection of HUH7 or HepG2 cells. The correlation of vascular density and CDK5 was assessed by immunostaining of a microarray of liver tissues from HCC patients. Inhibition of CDK5 in endothelial or HCC cells reduced HIF-1α levels in vitro and in vivo, and transcription of HIF-1α target genes (VEGFA, VEGFR1, EphrinA1). Mass spectrometry and site directed mutagenesis revealed a stabilizing phosphorylation of HIF-1α at Ser687 by CDK5. Vascular density was decreased in murine HCC models by CDK5 inhibition. In conclusion, inhibiting CDK5 is a multi-modal systemic approach to treat HCC, hitting angiogenesis, as well as the tumor cells themselves.
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Affiliation(s)
- Julia Herzog
- Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany
| | - Sandra M Ehrlich
- Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany
| | - Lisa Pfitzer
- Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany
| | - Johanna Liebl
- Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany
| | - Thomas Fröhlich
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center Munich, University of Munich, Munich, Germany
| | - Georg J Arnold
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center Munich, University of Munich, Munich, Germany
| | - Wolfgang Mikulits
- Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Christine Haider
- Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Angelika M Vollmar
- Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany
| | - Stefan Zahler
- Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany
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Current Status and Future Prospects of Biomarkers in the Diagnosis of Hepatocellular Carcinoma. Int J Biol Markers 2017; 32:e361-e369. [PMID: 28967065 DOI: 10.5301/ijbm.5000299] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2017] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) has one of the highest death rates of any cancer in the world, and its incidence is increasing worldwide. Early-stage diagnosis of HCC is thus crucial for medical treatment. Detection of tumor biomarkers is one of the main methods for the early diagnosis of HCC. At present, α-fetoprotein (AFP) is the most practical serum biomarker for HCC diagnosis. However, the diagnostic accuracy of HCC with serum AFP exhibits both sensitivity and specificity far below satisfaction, especially with small sizes of HCC. As a result, the discovery of new biomarkers and/or their combination to enhance both the sensitivity and specificity for laboratory diagnosis of HCC is a crucial goal. With the development of new technology and advances in research, a number of new and specific biomarkers of HCC have been discovered. These biomarkers and their applications for the diagnosis, treatment monitoring and prognosis prediction of HCC, are reviewed in this article.
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22
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Novikova MV, Khromova NV, Kopnin PB. Components of the Hepatocellular Carcinoma Microenvironment and Their Role in Tumor Progression. BIOCHEMISTRY (MOSCOW) 2017; 82:861-873. [PMID: 28941454 DOI: 10.1134/s0006297917080016] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This review summarizes recently published data on the mechanisms of tumor cell interaction with the tumor microenvironment. Tumor stroma influences the processes of hepatocarcinogenesis, epithelial-to-mesenchymal transition, invasion, and metastasis. The tumor microenvironment includes both cellular and noncellular components. Main cellular components of hepatocellular carcinoma (HCC) stroma are tumor-associated fibroblasts, hepatic stellate cells, immune cells, and endothelial cells that produce extracellular components of tumor microenvironment such as extracellular matrix, various proteins, proteolytic enzymes, growth factors, and cytokines. The noncellular components of the stroma modulate signaling pathways in tumor cells and stimulate invasion and metastasis. The tumor microenvironment composition and organization can serve as prognostic factors in HCC pathogenesis. Current approaches in HCC targeted therapy are aimed at creating efficient strategies for interrupting tumor interactions with the stroma. Recent data on the composition and role of the microenvironment in HCC pathogenesis, as well as new developments in antitumor drug design are discussed.
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Affiliation(s)
- M V Novikova
- Blokhin Russian Cancer Research Center, Ministry of Health of Russia, Moscow, 115478, Russia.
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23
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Elsonbaty SM, Zahran WE, Moawed FS. Gamma-irradiated β-glucan modulates signaling molecular targets of hepatocellular carcinoma in rats. Tumour Biol 2017; 39:1010428317708703. [PMID: 28810822 DOI: 10.1177/1010428317708703] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
β-glucans are one of the most abundant forms of polysaccharides known as biological response modifiers which influence host's biological response and stimulate immune system. Accordingly, this study was initiated to evaluate irradiated β-glucan as a modulator for cellular signaling growth factors involved in the pathogenesis of hepatocellular carcinoma in rats. Hepatocellular carcinoma was induced with 20 mg diethylnitrosamine/kg BW. Rats received daily by gastric gavage 65 mg irradiated β-glucan/kg BW. It was found that treatment of rats with diethylnitrosamine induced hepatic injury and caused significant increase in liver injury markers with a concomitant significant increase in both hepatic oxidative and inflammatory indices: alpha-fetoprotein, interferon gamma, and interleukin 6 in comparison with normal and irradiated β-glucan-treated groups. Western immunoblotting showed a significant increase in the signaling growth factors: extracellular signal-regulated kinase 1 and phosphoinositide 3-kinase proteins in a diethylnitrosamine-treated group while both preventive and therapeutic irradiated β-glucan treatments recorded significant improvement versus diethylnitrosamine group via the modulation of growth factors that encounters hepatic toxicity. The transcript levels of vascular endothelial growth factor A and inducible nitric oxide synthase genes were significantly higher in the diethylnitrosamine-treated group in comparison with controls. Preventive and therapeutic treatments with irradiated β-glucan demonstrated that the transcript level of these genes was significantly decreased which demonstrates the protective effect of β-glucan. Histological investigations revealed that diethylnitrosamine treatment affects the hepatic architecture throughout the significant severe appearance of inflammatory cell infiltration in the portal area and congestion in the portal vein in association with severe degeneration and dysplasia in hepatocytes all over hepatic parenchyma. The severity of hepatic architecture changes was significantly decreased with both β-glucan therapeutic and preventive treatments. In conclusion, irradiated β-glucan modulated signal growth factors, vascular endothelial growth factor A, extracellular signal-regulated kinase 1, and phosphatidylinositol-3-kinase, which contributed to experimental hepatocarcinogenesis.
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Affiliation(s)
- Sawsan M Elsonbaty
- 1 National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
| | - Walid E Zahran
- 2 Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Fatma Sm Moawed
- 1 National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
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24
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Guo H, Tsung K. Tumor reductive therapies and antitumor immunity. Oncotarget 2017; 8:55736-55749. [PMID: 28903456 PMCID: PMC5589695 DOI: 10.18632/oncotarget.18469] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 05/03/2017] [Indexed: 12/29/2022] Open
Abstract
Tumor reductive therapy is to reduce tumor burden through direct killing of tumor cells. So far, there is no report on the connection between antitumor immunity and tumor reductive therapies. In the last few years, a new category of cancer treatment, immunotherapy, emerged and they are categorized separately from classic cytotoxic treatments (chemo and radiation therapy). The most prominent examples include cellular therapies (LAK and CAR-T) and immune checkpoint inhibitors (anti-PD-1 and CTLA-4). Recent advances in clinical immunotherapy and our understanding of the mechanism behind them revealed that these therapies have a closer relationship with classic cancer treatments than we thought. In many cases, the effectiveness of classic therapies is heavily influenced by the status of the underlying antitumor-immunity. On the other hand, immunotherapies have shown better outcome when combined with tumor reductive therapies, not only due to the combined effects of tumor killing by each therapy but also because of a synergy between the two. Many clinical observations can be explained once we start to look at these classic therapies from an immunity standpoint. We have seen their direct effect on tumor antigen in vivo that they impact antitumor immunity more than we have realized. In turn, antitumor immunity contributes to tumor control and destruction as well. This review will take the immunological view of the classic therapies and summarize historical as well as recent findings in animal and clinical studies to make the argument that most of the cancer treatments exert their ultimate efficacy through antitumor immunity.
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Affiliation(s)
- Huiqin Guo
- Department of Thoracic Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Kangla Tsung
- Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
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25
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Wang Y, Takeishi K, Li Z, Cervantes-Alvarez E, Collin de l'Hortet A, Guzman-Lepe J, Cui X, Zhu J. Microenvironment of a tumor-organoid system enhances hepatocellular carcinoma malignancy-related hallmarks. Organogenesis 2017; 13:83-94. [PMID: 28548903 DOI: 10.1080/15476278.2017.1322243] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Organ-like microenviroment and 3-dimensional (3D) cell culture conformations have been suggested as promising approaches to mimic in a micro-scale a whole organ cellular functions and interactions present in vivo. We have used this approach to examine biologic features of hepatocellular carcinoma (HCC) cells. In this study, we demonstrate that hepatocellular carcinoma (HCC) cells, fibroblasts, endothelial cells and extracellular matrix can generate organoid-like spheroids that enhanced numerous features of human HCC observed in vivo. We show that the addition of non-parenchymal cells such as fibroblast and endothelial cells is required for spheroid formation as well as the maintenance of the tissue-like structure. Furthermore, HCC cells cultured as spheroids with non-parenchymal cells express more neo-angiogenesis-related markers (VEGFR2, VEGF, HIF-α), tumor-related inflammatory factors (CXCR4, CXCL12, TNF-α) and molecules-related to induced epithelial-mesenchymal transition (TGFβ, Vimentin, MMP9) compared with organoids containing only HCC cells. These results demonstrate the importance of non-parenchymal cells in the cellular composition of HCC organoids. The novelty of the multicellular-based organotypic culture system strongly supports the integration of this approach in a high throughput approach to identified patient-specific HCC malignancy and accurate anti-tumor therapy screening after surgery.
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Affiliation(s)
- Yang Wang
- a Department of Hepatobiliary Surgery , Peking University People's Hospital , Beijing , China.,b Department of Pathology , University of Pittsburgh , Pittsburgh , PA , USA
| | - Kazuki Takeishi
- b Department of Pathology , University of Pittsburgh , Pittsburgh , PA , USA.,c Department of Surgery and Science , Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan
| | - Zhao Li
- a Department of Hepatobiliary Surgery , Peking University People's Hospital , Beijing , China
| | - Eduardo Cervantes-Alvarez
- b Department of Pathology , University of Pittsburgh , Pittsburgh , PA , USA.,d PECEM, Facultad de Medicina , Universidad Nacional Autónoma de México , Mexico City , México
| | | | - Jorge Guzman-Lepe
- b Department of Pathology , University of Pittsburgh , Pittsburgh , PA , USA
| | - Xiao Cui
- a Department of Hepatobiliary Surgery , Peking University People's Hospital , Beijing , China
| | - Jiye Zhu
- a Department of Hepatobiliary Surgery , Peking University People's Hospital , Beijing , China
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26
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Wang G, Gao X, Gu G, Shao Z, Li M, Wang P, Yang J, Cai X, Li Y. Polyethylene glycol-poly(ε-benzyloxycarbonyl-l-lysine)-conjugated VEGF siRNA for antiangiogenic gene therapy in hepatocellular carcinoma. Int J Nanomedicine 2017; 12:3591-3603. [PMID: 28533682 PMCID: PMC5431695 DOI: 10.2147/ijn.s131078] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
A polyethylene glycol-poly(ε-benzyloxycarbonyl-l-lysine) (PEG-SS-PLL) block copolymer based on a disulfide-linked, novel biodegradable catiomer bearing a PEG-sheddable shell was developed to avoid "PEG dilemma" in nanoparticle intracellular tracking of PEG-PLL where PEG was nondegradable. However, PEG-SS-PLL catiomers have not been used to deliver small interfering VEGF RNA (siVEGF) in antiangiogenesis gene therapy. In this study, we aimed to investigate whether this novel biodegradable catiomer can deliver siVEGF into cancer cells and at the same time have an antitumor effect in a xenograft mouse model. It was found that PEG-SS-PLL efficiently delivered siVEGF with negligible cytotoxicity, and significantly decreased the expression of VEGF at both the messenger-RNA and protein levels both in vitro and in vivo, and thus tumor growth was inhibited. Our findings demonstrated that PEG-SS-PLL/siVEGF could potentially be applied to antiangiogenesis gene therapy for hepatocellular carcinoma.
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Affiliation(s)
- Gangmin Wang
- Department of Urology, Huashan Hospital, Fudan University
| | - XiaoLong Gao
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai
| | - GuoJun Gu
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai
| | - ZhiHong Shao
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai
| | - MingHua Li
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai
| | - PeiJun Wang
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai
| | - JianRong Yang
- Department of Hepatobiliary Surgery, Third People's Hospital of Guangxi Zhuang Autonomous Region, Nanning
| | - XiaoJun Cai
- Institute for Advanced Materials and Nano Biomedicine, School of Material Science and Engineering, Tongji University, Shanghai, People's Republic of China
| | - YongYong Li
- Institute for Advanced Materials and Nano Biomedicine, School of Material Science and Engineering, Tongji University, Shanghai, People's Republic of China
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27
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Liu F, Luo L, Wei Y, Wang W, Wen T, Yang J, Xu M, Li B. Association of VEGFA polymorphisms with susceptibility and clinical outcome of hepatocellular carcinoma in a Chinese Han population. Oncotarget 2017; 8:16488-16497. [PMID: 28147320 PMCID: PMC5369979 DOI: 10.18632/oncotarget.14870] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 01/16/2017] [Indexed: 02/05/2023] Open
Abstract
Vascular endothelial growth factor A (VEGFA) is an important angiogenesis regulator, which plays an important role in angiogenesis and progression of tumor, including hepatocellular carcinoma (HCC). We aimed at determining whether single nucleotide polymorphisms of VEGFA gene influence the development and clinical outcomes of HCC. We analyzed four potential functional polymorphisms (936C/T, 634G/C, 1612G/A, 2578C/A) of VEGFA gene in 476 HCC patients and 526 controls using matrix-assisted laser desorption ionization time-of-flight mass spectrometry method. Serum VEGF levels were measured by enzyme-linked immunosorbent assay. The Kaplan-Meier methods with log-rank test and Cox regression models were used to compare survival of resected HCC patients according to the genotype. We found that only the VEGFA 2578C/A polymorphism was significantly associated with decreased risk of HCC (AA/AC vs. CC; adjusted OR = 0.69, 95% CI = 0.51-0.93). Furthermore, the 2578C/A polymorphism was associated with significantly decreased postoperative recurrence (AA/AC vs. CC, adjusted OR = 0.51; 95% CI, 0.29-0.88) and improved overall survival (AA/AC vs. CC, adjusted HR = 0.27, 95% CI = 0.13-0.52) of resected HCC patients. In addition, the VEGF serum levels in HCC patients were significantly higher than those in healthy controls, although no significant association between VEGFA genotype and serum levels of VEGF was observed. These results suggest that the VEGFA 2578 C/A polymorphism may play a potential role in the development and clinical outcome of HCC among Chinese Han population.
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Affiliation(s)
- Fei Liu
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Limei Luo
- Department of Clinical Immunological Laboratory, West China Hospital, Sichuan University, 610041, China
| | - Yonggang Wei
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Wentao Wang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Tianfu Wen
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Jiayin Yang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Mingqing Xu
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Bo Li
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
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28
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Tumor Microenvironment, a Paradigm in Hepatocellular Carcinoma Progression and Therapy. Int J Mol Sci 2017. [PMID: 28216578 DOI: 10.3390/ijms18020405.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most lethal and prevalent cancers in the human population. Different etiological factors such as hepatitis B and C virus, alcohol and diabetes cause liver injury followed by inflammation, necrosis and hepatocytes proliferation. Continuous cycles of this destructive-regenerative process culminates in liver cirrhosis which is characterized by regenerating nodules that progress to dysplastic nodules and ultimately HCC. Despite its significance, there is only an elemental understanding of the pathogenetic mechanisms, and there are only limited therapeutic options. Therefore, the study of the involved molecular mechanisms can open a new insight to define more effective treatment strategies. A variety of alterations have been reported in HCC patients, particularly the cancer-associated microenvironment components including immune cells, fibroblast cells, endothelial cells and extracellular matrix can support the neoplastic cells to proliferate, growth and invade. This review summarizes the current state of knowledge and highlights the principal challenges that are relevant to controlling this milieu.
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29
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Tahmasebi Birgani M, Carloni V. Tumor Microenvironment, a Paradigm in Hepatocellular Carcinoma Progression and Therapy. Int J Mol Sci 2017; 18:ijms18020405. [PMID: 28216578 PMCID: PMC5343939 DOI: 10.3390/ijms18020405] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 02/02/2017] [Accepted: 02/08/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most lethal and prevalent cancers in the human population. Different etiological factors such as hepatitis B and C virus, alcohol and diabetes cause liver injury followed by inflammation, necrosis and hepatocytes proliferation. Continuous cycles of this destructive–regenerative process culminates in liver cirrhosis which is characterized by regenerating nodules that progress to dysplastic nodules and ultimately HCC. Despite its significance, there is only an elemental understanding of the pathogenetic mechanisms, and there are only limited therapeutic options. Therefore, the study of the involved molecular mechanisms can open a new insight to define more effective treatment strategies. A variety of alterations have been reported in HCC patients, particularly the cancer-associated microenvironment components including immune cells, fibroblast cells, endothelial cells and extracellular matrix can support the neoplastic cells to proliferate, growth and invade. This review summarizes the current state of knowledge and highlights the principal challenges that are relevant to controlling this milieu.
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Affiliation(s)
- Maryam Tahmasebi Birgani
- Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 63461, Iran.
| | - Vinicio Carloni
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, Florence 50134, Italy.
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30
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Yang S, Liu G. Targeting the Ras/Raf/MEK/ERK pathway in hepatocellular carcinoma. Oncol Lett 2017; 13:1041-1047. [PMID: 28454211 DOI: 10.3892/ol.2017.5557] [Citation(s) in RCA: 158] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Accepted: 09/28/2016] [Indexed: 12/12/2022] Open
Abstract
Although the biological basis of hepatocellular carcinoma (HCC) remains unclear, effective treatments and improvement of the survival rate remain worthwhile research goals. Abnormal protein signaling pathways contributing to uncontrolled cell proliferation, differentiation, survival and apoptosis are biomarkers of the carcinogenic process. Certain mutated components or overexpression of the rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway are increasingly being studied in HCC carcinogenesis. The present review addresses the effect of the Ras/Raf/MEK/ERK signaling pathway on the pathogenesis of HCC, and provides an update on the preclinical and clinical development of various inhibitors targeting this core signaling pathway, which include various Ras inhibitors, Raf inhibitors and MEK inhibitors for HCC.
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Affiliation(s)
- Sufang Yang
- Department of Pharmacy, The First Affiliated Hospital of Shantou University Medical Collage, Shantou, Guangdong 515041, P.R. China
| | - Guohua Liu
- Department of Pharmacy, The First Affiliated Hospital of Shantou University Medical Collage, Shantou, Guangdong 515041, P.R. China
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31
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Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J Gastroenterol 2017; 52:512-519. [PMID: 27704266 PMCID: PMC5357473 DOI: 10.1007/s00535-016-1263-4] [Citation(s) in RCA: 265] [Impact Index Per Article: 33.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 09/06/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Lenvatinib is an oral inhibitor of vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor alpha, RET, and KIT. This phase 2, single-arm, open-label multicenter study evaluated lenvatinib in advanced hepatocellular carcinoma (HCC). METHODS Patients with histologically/clinically confirmed advanced HCC who did not qualify for surgical resection or local therapies received lenvatinib at a dosage of 12 mg once daily (QD) in 28-day cycles. The primary efficacy endpoint was time to progression (TTP) per modified Response Evaluation Criteria in Solid Tumors v1.1; secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR), and overall survival (OS). RESULTS Between July 2010 and June 2011, 46 patients received lenvatinib at sites across Japan and Korea. The median TTP, as determined by independent radiological review, was 7.4 months [95 % confidence interval (CI): 5.5-9.4]. Seventeen patients (37 %) had partial response and 19 patients (41 %) had stable disease (ORR: 37 %; DCR: 78 %). Median OS was 18.7 months (95 % CI: 12.7-25.1). The most common any-grade adverse events (AEs) were hypertension (76 %), palmar-plantar erythrodysesthesia syndrome (65 %), decreased appetite (61 %), and proteinuria (61 %). Dose reductions and discontinuations due to AEs occurred in 34 (74 %) and 10 patients (22 %), respectively. Median body weight was lower in patients with an early (<30 days) dose withdrawal or reduction than in those without. CONCLUSIONS Lenvatinib 12-mg QD showed clinical activity and acceptable toxicity profiles in patients with advanced HCC, but early dose modification was necessary in patients with lower body weight. Further development of lenvatinib in HCC should consider dose modification by body weight. TRIAL REGISTRATION ID: www.ClinicalTrials.gov NCT00946153.
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32
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Sukharamwala P, Hennessey D, Wood T, Singh S, Ryan C, Rosemurgy A. Molecular profiles in foregut oncology. Cancer Genet 2016; 209:537-553. [PMID: 27887938 DOI: 10.1016/j.cancergen.2016.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 09/30/2015] [Accepted: 09/19/2016] [Indexed: 02/07/2023]
Abstract
Oncology is and will continue to evolve resulting from a better understanding of the biology and intrinsic genetic profile of each cancer. Tumor biomarkers and targeted therapies are the new face of precision medicine, so it is essential for all physicians caring for cancer patients to understand and assist patients in understanding the role and importance of such markers and strategies to target them. This review was initiated in an attempt to identify, characterize, and discuss literature supporting clinically relevant molecular markers and interventions. The efficacy of targeting specific markers will be examined with data from clinical trials focusing on treatments for esophageal, gastric, liver, gallbladder, biliary tract, and pancreatic cancers.
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Affiliation(s)
| | - Daniel Hennessey
- Florida Hospital Tampa, 3000 Medical Park Drive Suite 310, Tampa, FL 33613, USA
| | - Thomas Wood
- Florida Hospital Tampa, 3000 Medical Park Drive Suite 310, Tampa, FL 33613, USA
| | - Shelly Singh
- Florida Hospital Tampa, 3000 Medical Park Drive Suite 310, Tampa, FL 33613, USA
| | - Carrie Ryan
- Florida Hospital Tampa, 3000 Medical Park Drive Suite 310, Tampa, FL 33613, USA
| | - Alexander Rosemurgy
- Florida Hospital Tampa, 3000 Medical Park Drive Suite 310, Tampa, FL 33613, USA.
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33
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Chauhan R, Lahiri N. Tissue- and Serum-Associated Biomarkers of Hepatocellular Carcinoma. BIOMARKERS IN CANCER 2016; 8:37-55. [PMID: 27398029 PMCID: PMC4933537 DOI: 10.4137/bic.s34413] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 03/15/2016] [Accepted: 03/27/2016] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC), one of the leading causes of cancer deaths in the world, is offering a challenge to human beings, with the current modes of treatment being a palliative approach. Lack of proper curative or preventive treatment methods encouraged extensive research around the world with an aim to detect a vaccine or therapeutic target biomolecule that could lead to development of a drug or vaccine against HCC. Biomarkers or biological disease markers have emerged as a potential tool as drug/vaccine targets, as they can accurately diagnose, predict, and even prevent the diseases. Biomarker expression in tissue, serum, plasma, or urine can detect tumor in very early stages of its development and monitor the cancer progression and also the effect of therapeutic interventions. Biomarker discoveries are driven by advanced techniques, such as proteomics, transcriptomics, whole genome sequencing, micro- and micro-RNA arrays, and translational clinics. In this review, an overview of the potential of tissue- and serum-associated HCC biomarkers as diagnostic, prognostic, and therapeutic targets for drug development is presented. In addition, we highlight recently developed micro-RNA, long noncoding RNA biomarkers, and single-nucleotide changes, which may be used independently or as complementary biomarkers. These active investigations going on around the world aimed at conquering HCC might show a bright light in the near future.
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Affiliation(s)
- Ranjit Chauhan
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.; Department of Biology, University of Winnipeg, Winnipeg, Manitoba, Canada
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34
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Kim JU, Shariff MIF, Crossey MME, Gomez-Romero M, Holmes E, Cox IJ, Fye HKS, Njie R, Taylor-Robinson SD. Hepatocellular carcinoma: Review of disease and tumor biomarkers. World J Hepatol 2016; 8:471-484. [PMID: 27057305 PMCID: PMC4820639 DOI: 10.4254/wjh.v8.i10.471] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 03/02/2016] [Accepted: 03/16/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy and now the second commonest global cause of cancer death. HCC tumorigenesis is relatively silent and patients experience late symptomatic presentation. As the option for curative treatments is limited to early stage cancers, diagnosis in non-symptomatic individuals is crucial. International guidelines advise regular surveillance of high-risk populations but the current tools lack sufficient sensitivity for early stage tumors on the background of a cirrhotic nodular liver. A number of novel biomarkers have now been suggested in the literature, which may reinforce the current surveillance methods. In addition, recent metabonomic and proteomic discoveries have established specific metabolite expressions in HCC, according to Warburg’s phenomenon of altered energy metabolism. With clinical validation, a simple and non-invasive test from the serum or urine may be performed to diagnose HCC, particularly benefiting low resource regions where the burden of HCC is highest.
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35
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Qiu Y, Yu H, Shi X, Xu K, Tang Q, Liang B, Hu S, Bao Y, Xu J, Cai J, Peng W, Cao Q, Yin P. microRNA-497 inhibits invasion and metastasis of colorectal cancer cells by targeting vascular endothelial growth factor-A. Cell Prolif 2016; 49:69-78. [PMID: 26840372 DOI: 10.1111/cpr.12237] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 09/29/2015] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES microRNAs (miRNAs), are non-coding RNAs that regulate gene expression, and are involved in tumour development. The aim of this study was to investigate microRNA-497 (miR-497) expression and its role in development of colorectal cancer (CRC). MATERIALS AND METHODS RT-PCR was performed to detect expression of miR-497 in CRC cell lines (HCT8, LOVO, Ls-174, HCT116 and HT29) and in clinical cancer specimens. To further understand its role, we restored expression of miR-497 in the HCT116 cell line by transfection with miR-497 mimics or inhibitors. Effects of miR-497 on cell proliferation, migration and invasion of targets were also determined both in vitro and in vivo. RESULTS miR-497 expression decreased in 34 CRC tissues compared to non-tumour tissues and in tumour cell lines. Overexpression of miR-497 did not inhibit cancer cell growth but suppressed metastasis and invasion both in vitro and in vivo. Vascular endothelial growth factor-A (VEGF-A) was confirmed to be a target of miR-497. Furthermore, we found overexpression of miR-497 altered expression of key molecules of the VEGF-A/ERK/MMP-9 signalling pathway. CONCLUSIONS Thus our results provide evidence that miR-497 might function as a metastasis suppressor in CRC. Targeting miR-497 may provide a strategy for blocking its metastasis.
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Affiliation(s)
- Yanyan Qiu
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Hui Yu
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Xiaojing Shi
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Ke Xu
- Cancer Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Qingfeng Tang
- Cancer Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Bo Liang
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Songjiao Hu
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Yijie Bao
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Jianhua Xu
- Cancer Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Jie Cai
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Wen Peng
- Department of Kidney, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Qin Cao
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Peihao Yin
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.,Cancer Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
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36
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Kojima-Yuasa A, Huang X, Matsui-Yuasa I. Synergistic Anticancer Activities of Natural Substances in Human Hepatocellular Carcinoma. Diseases 2015; 3:260-281. [PMID: 28943624 PMCID: PMC5548258 DOI: 10.3390/diseases3040260] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 10/11/2015] [Accepted: 10/13/2015] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is highly resistant to currently available chemotherapeutic agents. The clinical outcome of HCC treatment remains unsatisfactory. Therefore, new effective and well-tolerated therapy strategies are needed. Natural products are excellent sources for the development of new medications for disease treatment. Recently, we and other researchers have suggested that the combined effect of natural products may improve the effect of chemotherapy treatments against the proliferation of cancer cells. In addition, many combination treatments with natural products augmented intracellular reactive oxygen species (ROS). In this review we will demonstrate the synergistic anticancer effects of a combination of natural products with chemotherapeutic agents or natural products against human HCC and provide new insight into the development of novel combination therapies against HCC.
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Affiliation(s)
- Akiko Kojima-Yuasa
- Department of Food and Human Health Sciences, Graduate School of Human Life Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan.
| | - Xuedan Huang
- Department of Pharmacognosy, School of Pharmacy, Kitasato University, 5-9-1 Shirogane, Minato-ku, Tokyo 108-8641, Japan.
| | - Isao Matsui-Yuasa
- Department of Food and Human Health Sciences, Graduate School of Human Life Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan.
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37
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Loaiza-Bonilla A, Furth EE, Morrissette JJD. Next-generation sequencing and personalized genomic medicine in hepatobiliary malignancies. Hepat Oncol 2015; 2:359-370. [PMID: 30191018 PMCID: PMC6095428 DOI: 10.2217/hep.15.20] [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
Liver cancer is a heterogeneous group of tumors characterized by significant molecular and genomic heterogeneity. The advent of powerful genomic technologies has allowed detection of recurrent somatic alterations in liver cancer, including mutations, copy number alterations as well as changes in transcriptomes and epigenomes, with the potential to translate these data into clinically relevant predictive and prognostic factors. In this review, we discuss recent advances in the application of high-throughput genomic technologies in liver cancer and the integration of such cancer genome profiling data, highlighting specific relevant subgroups and explain how this knowledge can be used in translational clinical research, 'basket trials', molecular tumor boards, targeted therapy and for personalized genomic medicine applications.
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Affiliation(s)
- Arturo Loaiza-Bonilla
- Abramson Cancer Center, Perelman Center for Advanced Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Emma E Furth
- Department of Pathology & Laboratory Medicine, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - Jennifer JD Morrissette
- Department of Pathology & Laboratory Medicine, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA
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AGK enhances angiogenesis and inhibits apoptosis via activation of the NF-κB signaling pathway in hepatocellular carcinoma. Oncotarget 2015; 5:12057-69. [PMID: 25474138 PMCID: PMC4323001 DOI: 10.18632/oncotarget.2666] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Accepted: 10/28/2014] [Indexed: 01/14/2023] Open
Abstract
High levels of angiogenesis and resistance to apoptosis are major clinical features of hepatocellular carcinoma (HCC), a lethal disease with a high incidence worldwide. However, the precise mechanisms underlying these malignant properties remain unclear. Here, we demonstrated that acylglycerol kinase (AGK) is markedly overexpressed in HCC cell lines and clinical tissues. Immunohistochemical analysis of 245 clinical HCC specimens revealed patients with high levels of AGK expression had poorer overall survival compared to patients with low AGK expression. Furthermore, overexpressing AGK significantly enhanced angiogenesis and inhibited apoptosis in vitro and promoted the tumorigenicity of HCC cells in vivo; silencing endogenous AGK had the opposite effects. Importantly, AGK enhanced angiogenesis and inhibited apoptosis in HCC in part via activation of NF-κB signaling. Our findings provide new evidence that AGK plays an important role in promoting angiogenesis and providing resistance to apoptosis, thus AGK may represent a novel therapeutic target for HCC.
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Lee KA, Ahn JY, Lee SH, Singh Sekhon S, Kim DG, Min J, Kim YH. Aptamer-based Sandwich Assay and its Clinical Outlooks for Detecting Lipocalin-2 in Hepatocellular Carcinoma (HCC). Sci Rep 2015; 5:10897. [PMID: 26039737 PMCID: PMC4454046 DOI: 10.1038/srep10897] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 04/20/2015] [Indexed: 01/15/2023] Open
Abstract
We validated a single-stranded, DNA aptamer-based, diagnostic method capable of detecting Lipocalin-2 (LCN2), a biomarker from clinically relevant hepatocellular carcinoma (HCC) patient serum, in the sandwich assay format. Nine aptamers (LCN2_apta1 to LCN2_apta9) for LCN2 were screened with SELEX processes, and a sandwich pair (LCN2_apta2 and LCN2_apta4) was finally chosen using surface plasmon resonance (SPR) and dot blotting analysis. The result of the proposed aptamer sandwich construction shows that LCN2 was sensitively detected in the concentration range of 2.5–500 ng mL−1 with a limit of detection of 0.6 ng mL−1. Quantitative measurement tests in HCC patients were run on straight serum and were compared with the performance of the conventional antibody-based ELISA kit. The aptamer sandwich assay demonstrated an excellent dynamic range for LCN2 at clinically relevant serum levels, covering sub-nanogram per mL concentrations. The new approach offers a simple and robust method for detecting serum biomarkers that have low and moderate abundance. It consists of functionalization, hybridization and signal read-out, and no dilution is required. The results of the study demonstrate the capability of the aptamer sandwich assay platform for diagnosing HCC and its potential applicability to the point-of-care testing (POCT) system.
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Affiliation(s)
- Kyeong-Ah Lee
- Department of Microbiology, Chungbuk National University, 1 Chungdae-Ro, Seowon-Gu, Cheongju 362-763, South Korea
| | - Ji-Young Ahn
- Department of Microbiology, Chungbuk National University, 1 Chungdae-Ro, Seowon-Gu, Cheongju 362-763, South Korea
| | - Sang-Hee Lee
- Department of Microbiology, Chungbuk National University, 1 Chungdae-Ro, Seowon-Gu, Cheongju 362-763, South Korea
| | - Simranjeet Singh Sekhon
- Department of Microbiology, Chungbuk National University, 1 Chungdae-Ro, Seowon-Gu, Cheongju 362-763, South Korea
| | - Dae-Ghon Kim
- Division of Gastroenterology and Hepatology, Research Institute of Clinical Medicine, Department of Internal Medicine, Chonbuk National University, Medical School and Hospital, Jeonju, 561-756, South Korea
| | - Jiho Min
- Graduate School of Semiconductor and Chemical Engineering, Chonbuk National University, 567 Baekje-daero, Deokjin-Gu, Jeonju, 561-756, South Korea
| | - Yang-Hoon Kim
- Department of Microbiology, Chungbuk National University, 1 Chungdae-Ro, Seowon-Gu, Cheongju 362-763, South Korea
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40
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Pan XY, Peng L, Han ZQ, Yin GQ, Song YK, Huang J. Hirudin promotes angiogenesis by modulating the cross-talk between p38 MAPK and ERK in rat ischemic skin flap tissue. Tissue Cell 2015; 47:301-10. [DOI: 10.1016/j.tice.2015.04.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Revised: 03/24/2015] [Accepted: 04/03/2015] [Indexed: 02/03/2023]
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HWANG SANGYOUN, HEO KYU, KIM JOONSEOK, IM JUNGWOO, LEE SUNMI, CHO MONG, KANG DAEHWAN, HEO JEONG, LEE JUNWOO, CHOI CHEOLWON, YANG KWANGMO. Emodin attenuates radioresistance induced by hypoxia in HepG2 cells via the enhancement of PARP1 cleavage and inhibition of JMJD2B. Oncol Rep 2015; 33:1691-8. [DOI: 10.3892/or.2015.3744] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Accepted: 12/08/2014] [Indexed: 11/06/2022] Open
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Muto J, Shirabe K, Sugimachi K, Maehara Y. Review of angiogenesis in hepatocellular carcinoma. Hepatol Res 2015; 45:1-9. [PMID: 24533487 DOI: 10.1111/hepr.12310] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Revised: 01/27/2014] [Accepted: 02/03/2014] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma (HCC) is a hypervascular tumor, and its vascularity is unique and greatly different from peripheral parenchyma of liver. Afferent and efferent vessels of HCC lesions come to differ as the lesion develops. The characteristic of the flow regulates the common style of metastasis. The portal tract of the HCC lesion is the first site of the intrahepatic metastasis, because cancer cells roll into the portal vein via efferent flow. On microscopic observation, HCC displays marked vascular abnormalities, arteriogenesis and capillarization. Arteriogenesis is defined as the growth of functional collateral arteries covered with smooth muscle cells from pre-existing arteries. Sinusoidal capillarization involves the transformation of fenestrated hepatic sinusoids into continuous capillaries. Several angiogenic factors have been reported, and some of them are studied as prognostic factors or target molecules of chemotherapeutic reagents. However, the mechanism of neovascularization during HCC development is still unclear. This review discusses the characteristics of angiogenesis in HCC and known angiogenic factors of HCC.
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Affiliation(s)
- Jun Muto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Zhang W, Kim R, Quintini C, Hashimoto K, Fujiki M, Diago T, Eghtesad B, Miller C, Fung J, Tan A, Menon KVN, Aucejo F. Prognostic role of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma undergoing liver transplantation. Liver Transpl 2015; 21:101-11. [PMID: 25283528 DOI: 10.1002/lt.24013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 09/04/2014] [Accepted: 09/29/2014] [Indexed: 12/21/2022]
Abstract
Vascular endothelial growth factor (VEGF) is pivotal in the development of hepatocellular carcinoma (HCC). Studies have demonstrated the prognostic value of circulating VEGF levels in patients undergoing liver resection or locoregional therapy (LRT) for HCC. We investigated the significance of preoperative plasma VEGF levels in patients with HCC undergoing liver transplantation (LT) at a Western transplant center. Pre-LT plasma VEGF levels were measured with an enzyme-linked immunoassay for 164 patients with HCC undergoing LT. The preoperative plasma VEGF level was correlated with clinicopathological variables and overall and recurrence-free post-LT survival. A higher pre-LT plasma VEGF level was significantly associated with pre-LT LRT (P = 0.01), multiple tumors (P = 0.02), a total tumor diameter ≥ 5 cm (P = 0.01), bilobar tumor distribution (P = 0.03), tumor vascular invasion (VI; P < 0.001), and HCC beyond the Milan criteria (P < 0.001). Patients with a plasma VEGF level > 44 pg/mL had significantly worse overall and disease-free survival than those with VEGF levels ≤ 44 pg/mL (P = 0.04 and P = 0.02, respectively). In a multivariate analysis, a plasma VEGF level > 44 pg/mL was independently associated with tumor VI (P < 0.001) and recurrence-free survival (hazard ratio = 2.12, 95% confidence interval = 1.08-4.14, P = 0.03). In conclusion, in patients with chronic end-stage liver disease and HCC, a pre-LT plasma VEGF level > 44 pg/mL may be a predictor of tumor VI and recurrence-free post-LT survival.
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Affiliation(s)
- Wei Zhang
- Hepatobiliary & Liver Transplant Surgery; Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Tsang CM, Cheung KCP, Cheung YC, Man K, Lui VWY, Tsao SW, Feng Y. Berberine suppresses Id-1 expression and inhibits the growth and development of lung metastases in hepatocellular carcinoma. Biochim Biophys Acta Mol Basis Dis 2014; 1852:541-51. [PMID: 25496992 DOI: 10.1016/j.bbadis.2014.12.004] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 11/27/2014] [Accepted: 12/03/2014] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is an invasive cancer with a high rate of recurrence and metastasis. Agents with anti-proliferative as well as anti-metastatic activity will be ideal for effective treatment. Here, we demonstrated that berberine, an isoquinoline alkaloid, harbored potent anti-metastatic and anti-proliferative activities in vivo. Using an orthotopic model of HCC (MHCC-97L), which spontaneously develops lung metastases (one of the most common sites of HCC metastasis), we found that berberine treatment (10mg/kg/2days) significantly reduced lung metastasis from the liver tumors by ~85% (quantitated by bioluminescence emitted from lung metastases). Histological examination also confirmed the reduced incidence and number of lung metastases in berberine-treated mice. Furthermore, berberine effectively suppressed extra-tumor invasion of the primary HCC implant into the surrounding normal liver tissue, illustrating its potent anti-metastatic action in vivo. Consistent with previous reports in other cancer, berberine's anti-tumor activity was accompanied by suppression of cellular proliferation, invasiveness and HIF-1α/VEGF signaling. Strikingly, further mechanistic investigation revealed that berberine exerted profound inhibitory effect on the expression of Id-1, which is a key regulator for HCC development and metastasis. Berberine could suppress the transcription level of Id-1 through inhibiting its promotor activity. Specific downregulation of Id-1 by knocking down its RNA transcripts in HCC cells inhibited cellular growth, invasion and VEGF secretion, demonstrating the functional relevance of Id-1 downregulation induced by berberine. Lastly, berberine's anti-proliferative and anti-invasive activities could be partially rescued by Id-1 overexpression in HCC models, revealing a novel anti-cancer/anti-invasive mechanism of berberine via Id-1 suppression.
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Affiliation(s)
- Chi Man Tsang
- Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Kenneth Chat Pan Cheung
- Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yuk Chun Cheung
- Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Kwan Man
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Vivian Wai-Yan Lui
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Sai Wah Tsao
- Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
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Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, Kudo M, Kang YK, Chen PJ, Toh HC, Gorbunova V, Eskens FALM, Qian J, McKee MD, Ricker JL, Carlson DM, El-Nowiem S. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 2014; 33:172-9. [PMID: 25488963 DOI: 10.1200/jco.2013.54.3298] [Citation(s) in RCA: 480] [Impact Index Per Article: 43.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE This open-label phase III trial evaluated efficacy and tolerability of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC) without prior systemic therapy. PATIENTS AND METHODS Patients were randomly assigned in a 1:1 ratio to linifanib 17.5 mg once daily or sorafenib 400 mg twice daily. Patients were stratified by region (Outside Asia, Japan, and rest of Asia), Eastern Cooperative Oncology Group performance score (ECOG PS; 0 or 1), vascular invasion or extrahepatic spread (yes or no), and hepatitis B virus (HBV) infection (yes or no). The primary end point of the study was overall survival (OS). Secondary end points were time to progression (TTP) and objective response rate (ORR) per RECIST v1.1. RESULTS We randomly assigned 1,035 patients (median age, 60 years; Asian, 66.6%; ECOG PS 0, 65.2%; HBV, 49.1%; vascular invasion or extrahepatic spread, 70.1%). Median OS was 9.1 months on the linifanib arm (95% CI, 8.1 to 10.2) and 9.8 months on the sorafenib arm (95% CI, 8.3 to 11.0; hazard ratio [HR], 1.046; 95% CI, 0.896 to 1.221). For prespecified stratification subgroups, OS HRs ranged from 0.793 to 1.119 and the 95% CI contained 1.0. Median TTP was 5.4 months on the linifanib arm (95% CI, 4.2 to 5.6) and 4.0 months on the sorafenib arm (95% CI, 2.8 to 4.2; HR, 0.759; 95% CI, 0.643 to 0.895; P = .001). Best response rate was 13.0% on the linifanib arm versus 6.9% on the sorafenib arm. Grade 3/4 adverse events (AEs); serious AEs; and AEs leading to discontinuation, dose interruption, and reduction were more frequent with linifanib (all P < .001). CONCLUSION Linifanib and sorafenib had similar OS in advanced HCC. Predefined superiority and noninferiority OS boundaries were not met for linifanib and the study failed to meet the primary end point. TTP and ORR favored linifanib; safety results favored sorafenib.
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Affiliation(s)
- Calin Cainap
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt.
| | - Shukui Qin
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
| | - Wen-Tsung Huang
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
| | - Ik Joo Chung
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
| | - Hongming Pan
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
| | - Ying Cheng
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
| | - Masatoshi Kudo
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
| | - Yoon-Koo Kang
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
| | - Pei-Jer Chen
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
| | - Han-Chong Toh
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
| | - Vera Gorbunova
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
| | - Ferry A L M Eskens
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
| | - Jiang Qian
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
| | - Mark D McKee
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
| | - Justin L Ricker
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
| | - Dawn M Carlson
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
| | - Saied El-Nowiem
- Calin Cainap, Institute of Oncology, Cluj-Napoca, Romania; Shukui Qin, Chinese People's Liberation Army Cancer Center, Bayi Hospital, Beijing; Hongming Pan, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou; Ying Cheng, Tumor Hospital of Jilin Province, Changchun, People's Republic of China; Wen-Tsung Huang, Chi Mei Medical Center, Liouying; Pei-Jer Chen, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Ik Joo Chung, Chonnam National University, Hwasun Hospital, Hwasun, Jeollonam-do; Yoon-Koo Kang, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; Masatoshi Kudo, Kinki University, Osaka, Japan; Han-Chong Toh, National Cancer Centre, Singapore, Singapore; Vera Gorbunova, Russian Academy of Medical Sciences, Moscow, Russia; Ferry A.L.M. Eskens, Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, AbbVie, North Chicago, IL; Saied El-Nowiem, Alexandria University, Alexandria, Egypt
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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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Fornaro L, Vivaldi C, Caparello C, Sacco R, Rotella V, Musettini G, Luchi S, Baldini EE, Falcone A, Masi G. Dissecting signaling pathways in hepatocellular carcinoma: new perspectives in medical therapy. Future Oncol 2014; 10:285-304. [PMID: 24490614 DOI: 10.2217/fon.13.181] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Prognosis of patients with advanced hepatocellular carcinoma (HCC) is poor and is largely influenced by associated liver comorbidities. Moreover, effective treatment alternatives are limited; with the exception of the multitargeted inhibitor sorafenib, established options in the treatment of advanced HCC no longer amenable with ablative or locoregional procedures are lacking. In light of the limited efficacy of chemotherapy in this setting, great efforts have been made in the definition of targetable molecular pathways with a central role in the progression of HCC. Targeting angiogenesis, growth factor receptors, intracellular transduction pathways, or mechanisms of gene-expression regulation represents the main way to improve patient outcome. At the same time, identifying clinical and biological factors, which may help selecting patients with higher chances of benefit, is essential in order to hasten drug development and maximize treatment efficacy.
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Affiliation(s)
- Lorenzo Fornaro
- Division of Medical Oncology, Ospedale Campo di Marte, Azienda USL2 Lucca, Lucca, Italy
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48
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Urbaczek AC, Ribeiro LCDA, Ximenes VF, Afonso A, Nogueira CT, Generoso WC, Alberice JV, Rudnicki M, Ferrer R, da Fonseca LM, da Costa PI. Inflammatory response of endothelial cells to hepatitis C virus recombinant envelope glycoprotein 2 protein exposure. Mem Inst Oswaldo Cruz 2014; 109:748-56. [PMID: 25317702 PMCID: PMC4238766 DOI: 10.1590/0074-0276140090] [Citation(s) in RCA: 10] [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: 03/11/2014] [Accepted: 07/29/2014] [Indexed: 12/12/2022] Open
Abstract
The hepatitis C virus (HCV) encodes approximately 10 different structural and non-structural proteins, including the envelope glycoprotein 2 (E2). HCV proteins, especially the envelope proteins, bind to cell receptors and can damage tissues. Endothelial inflammation is the most important determinant of fibrosis progression and, consequently, cirrhosis. The aim of this study was to evaluate and compare the inflammatory response of endothelial cells to two recombinant forms of the HCV E2 protein produced in different expression systems (Escherichia coli and Pichia pastoris). We observed the induction of cell death and the production of nitric oxide, hydrogen peroxide, interleukin-8 and vascular endothelial growth factor A in human umbilical vein endothelial cells (HUVECs) stimulated by the two recombinant E2 proteins. The E2-induced apoptosis of HUVECs was confirmed using the molecular marker PARP. The apoptosis rescue observed when the antioxidant N-acetylcysteine was used suggests that reactive oxygen species are involved in E2-induced apoptosis. We propose that these proteins are involved in the chronic inflammation caused by HCV.
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Affiliation(s)
- Ana Carolina Urbaczek
- Laboratório de Imunologia Clínica, Departamento de Análises Clínicas,
Escola de Ciências Farmacêuticas, Bauru, SP, Brasil
| | | | - Valdecir Farias Ximenes
- Departamento de Química, Faculdade de Ciências, Universidade Estadual
Paulista Julio de Mesquita Filho, Bauru, SP, Brasil
| | - Ana Afonso
- Departamento de Parasitologia Médica, Unidade de Parasitologia Médica e
Microbiologia, Instituto de Higiene e Medicina Tropcal, Universidade Nova de Lisboa,
Lisboa, Portugal
- Departamento de Morfologia e Patologia, Universidade Federal de São
Carlos, São Carlos, SP, Brasil
- Grupo de Bioanalítica, Microfabricações e Separações, Departamento de
Química e Física Molecular, Instituto de Química de São Carlos, Universidade de São
Paulo, São Carlos, SP, Brasil
| | - Camila Tita Nogueira
- Laboratório de Imunologia Clínica, Departamento de Análises Clínicas,
Escola de Ciências Farmacêuticas, Bauru, SP, Brasil
| | - Wesley Cardoso Generoso
- Departamento de Genética e Evolução, Universidade Federal de São
Carlos, São Carlos, SP, Brasil
| | - Juliana Vieira Alberice
- Grupo de Bioanalítica, Microfabricações e Separações, Departamento de
Química e Física Molecular, Instituto de Química de São Carlos, Universidade de São
Paulo, São Carlos, SP, Brasil
| | - Martina Rudnicki
- Escola de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo,
SP, Brasil
| | - Renila Ferrer
- Escola de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo,
SP, Brasil
| | - Luiz Marcos da Fonseca
- Laboratório de Imunologia Clínica, Departamento de Análises Clínicas,
Escola de Ciências Farmacêuticas, Bauru, SP, Brasil
| | - Paulo Inácio da Costa
- Laboratório de Imunologia Clínica, Departamento de Análises Clínicas,
Escola de Ciências Farmacêuticas, Bauru, SP, Brasil
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Hayano K, Yoshida H, Zhu AX, Sahani DV. Fractal analysis of contrast-enhanced CT images to predict survival of patients with hepatocellular carcinoma treated with sunitinib. Dig Dis Sci 2014; 59:1996-2003. [PMID: 24563237 DOI: 10.1007/s10620-014-3064-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Accepted: 02/05/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Intratumoral heterogeneity is a well-recognized feature of malignancy. AIMS To assess the heterogeneity of tumor using fractal analysis of contrast-enhanced computed tomography (CE-CT) images for predicting survival of hepatocellular carcinoma (HCC) patients treated with sunitinib. METHODS The patient cohort comprised 23 patients (19 men, 4 women; mean age 61.5 years) with HCC who underwent CE-CT at baseline and after one cycle of sunitinib. Arterial-phase (AP) and portal-phase (PP) CE-CT images were analyzed using a plugin software for ImageJ (NIH, Bethesda, MD). A differential box-counting method was employed to calculate the fractal dimension (FD) of the tumor. Tumor FD, density, and size were compared with survival. RESULTS Median progression-free survival (PFS) was 4.43 months. Patients were grouped into a favorable PFS (PFS >4.43 months; 9 patients) and an unfavorable PFS group (PFS ≤ 4.43; 13 patients). The baseline FD on both the AP and PP images was lower in the favorable PFS group than in the unfavorable PFS group (both P = 0.03). There was a significant difference in the change of the FD on the AP image between the favorable and unfavorable PFS groups (P = 0.02). Tumor density and size showed no significant correlations with PFS. In the Kaplan-Meier analysis, patients with tumors showing lower FD on the AP image at baseline showed longer PFS (P = 0.002). Patients with tumors showing a greater reduction in the FD on the PP image after one cycle of the therapy showed longer overall survival (P = 0.002). CONCLUSION The FD of the tumor on CE-CT images may be a useful biomarker for HCC patients treated with sunitinib.
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Affiliation(s)
- Koichi Hayano
- Division of Abdominal Imaging and Intervention, Department of Radiology, Massachusetts General Hospital, 55 Fruit Street, White 270, Boston, MA, 02114, USA,
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50
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Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Worldwide progressive population aging demands consensus development for decision making when treating elderly patients. Age itself might not be a critical determinant for the selection of a therapeutic option. In the past few years, the mechanisms of hepato-carcinogenesis have been elucidated, and the involvement of a number of pathways, including angiogenesis, aberrant signal transduction, and dysregulated cell cycle control, have been demonstrated, leading to evaluation of the activity and toxicity of some of the new molecularly targeted agents. Sorafenib was demonstrated to significantly increase the survival of patients with advanced HCC in two prospective, randomized, placebo-controlled trials. Subsequently, a number of retrospective or prospective studies have indicated that the effectiveness of sorafenib therapy in the treatment of HCC is similar in elderly and non-elderly patients. The aim of this review is to describe the impact of age on the effects of sorafenib-targeted therapy in patients with HCC, and the next treatment options with new targeted agents (everolimus, tivantinib, linifanib, etc.).
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