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1
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Huang R, Ding J, Xie WF. Liver cancer. SINUSOIDAL CELLS IN LIVER DISEASES 2024:349-366. [DOI: 10.1016/b978-0-323-95262-0.00017-6] [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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2
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Is There a Place for Somatostatin Analogues for the Systemic Treatment of Hepatocellular Carcinoma in the Immunotherapy Era? LIVERS 2022. [DOI: 10.3390/livers2040024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Patients with advanced hepatocellular carcinoma (HCC) have a very limited survival rate even after the recent inclusion of kinase inhibitors or immune checkpoint inhibitors in the therapeutic armamentarium. A significant problem with the current proposed therapies is the considerable cost of treatment that may be a serious obstacle in low- and middle-income countries. Implementation of somatostatin analogues (SSAs) has the potential to overcome this obstacle, but due to some negative studies their extensive evaluation came to a halt. However, experimental evidence, both in vitro and in vivo, has revealed various mechanisms of the anti-tumor effects of these analogues, including inhibition of cancer cell proliferation and angiogenesis and induction of apoptosis. Favorable indirect effects such as inhibition of liver inflammation and fibrosis and influence on macrophage-mediated innate immunity have also been noted and are presented in this review. Furthermore, the clinical application of SSAs is both presented and compared with clinical trials of kinase and immune checkpoint inhibitors (ICIs). No direct trials have been performed to compare survival in the same cohort of patients, but the cost of treatment with SSAs is a fraction compared to the other modalities and with significantly less serious side effects. As in immunotherapy, patients with viral HCC (excluding alcoholics), as well as Barcelona stage B or C and Child A patients, are the best candidates, since they usually have a survival prospect of at least 6 months, necessary for optimum results. Reasons for treatment failures are also discussed and further research is proposed.
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3
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Dias Carvalho P, Martins F, Mendonça S, Ribeiro A, Machado AL, Carvalho J, Oliveira MJ, Velho S. Mutant KRAS modulates colorectal cancer cells invasive response to fibroblast‐secreted factors through the HGF/C‐MET axis. Int J Cancer 2022; 151:1810-1823. [DOI: 10.1002/ijc.34225] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 07/07/2022] [Accepted: 07/19/2022] [Indexed: 11/06/2022]
Affiliation(s)
- Patrícia Dias Carvalho
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
- ICBAS ‐ Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto Porto Portugal
| | - Flávia Martins
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
- Department of Pathology FMUP – Faculty of Medicine of the University of Porto Porto Portugal
| | - Susana Mendonça
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
- Department of Pathology FMUP – Faculty of Medicine of the University of Porto Porto Portugal
| | - Andreia Ribeiro
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
| | - Ana Luísa Machado
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
- Department of Pathology FMUP – Faculty of Medicine of the University of Porto Porto Portugal
- Ciências Químicas e das Biomoléculas, Centro de Investigação em Saúde e Ambiente, Escola Superior de Saúde do Porto, Instituto Politécnico do Porto Porto Portugal
| | - Joana Carvalho
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
| | - Maria José Oliveira
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- INEB – Institute of Biomedical Engineering, University of Porto Porto Portugal
| | - Sérgia Velho
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
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4
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Lam M, Reales-Calderon JA, Ow JR, Adriani G, Pavesi A. In vitro 3D liver tumor microenvironment models for immune cell therapy optimization. APL Bioeng 2021; 5:041502. [PMID: 34632251 PMCID: PMC8492081 DOI: 10.1063/5.0057773] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/03/2021] [Indexed: 12/24/2022] Open
Abstract
Despite diagnostic and therapeutic advances, liver cancer kills more than 18 million people every year worldwide, urging new strategies to model the disease and to improve the current therapeutic options. In vitro tumor models of human cancer continue to evolve, and they represent an important screening tool. However, there is a tremendous need to improve the physiological relevance and reliability of these in vitro models to fulfill today's research requirements for better understanding of cancer progression and treatment options at different stages of the disease. This review describes the hepatocellular carcinoma microenvironmental characteristics and illustrates the current immunotherapy strategy to fight the disease. Moreover, we present a recent collection of 2D and 3D in vitro liver cancer models and address the next generation of in vitro systems recapitulating the tumor microenvironment complexity in more detail.
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Affiliation(s)
- Maxine Lam
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (ASTAR), Singapore, Singapore
| | - Jose Antonio Reales-Calderon
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (ASTAR), Singapore, Singapore
| | - Jin Rong Ow
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (ASTAR), Singapore, Singapore
| | - Giulia Adriani
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Andrea Pavesi
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (ASTAR), Singapore, Singapore
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5
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Nishida N. Role of Oncogenic Pathways on the Cancer Immunosuppressive Microenvironment and Its Clinical Implications in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:3666. [PMID: 34359568 PMCID: PMC8345137 DOI: 10.3390/cancers13153666] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/19/2021] [Accepted: 07/19/2021] [Indexed: 12/11/2022] Open
Abstract
The tumor immune microenvironment, including hepatocellular carcinoma (HCC), is complex, consisting of crosstalk among tumor components such as the cancer cells, stromal cells and immune cells. It is conceivable that phenotypic changes in cancer cells by genetic and epigenetic alterations affect the cancer-stroma interaction and anti-cancer immunity through the expression of immune checkpoint molecules, growth factors, cytokines, chemokines and metabolites that may act on the immune system in tumors. Therefore, predicting the outcome of ICI therapy requires a thorough understanding of the oncogenic signaling pathways in cancer and how they affect tumor immune evasion. In this review, we have detailed how oncogenic signaling pathways can play a role in altering the condition of the cellular components of the tumor immune microenvironment such as tumor-associated macrophages, regulatory T cells and myeloid-derived suppressor cells. The RAS/MAPK, PI3K/Akt, Wnt/β-catenin and JAK/STAT pathways have all been implicated in anti-tumor immunity. We also found that factors that reflect the immune microenvironment of the tumor, including the status of oncogenic pathways such as the volume of tumor-infiltrating T cells, expression of the immune checkpoint protein PD-1 and its ligand PD-L1, and activation of the Wnt/β-catenin signaling pathway, predict a response to ICI therapy in HCC cases.
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Affiliation(s)
- Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511, Japan
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6
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Zheng N, Zhang S, Wu W, Zhang N, Wang J. Regulatory mechanisms and therapeutic targeting of vasculogenic mimicry in hepatocellular carcinoma. Pharmacol Res 2021; 166:105507. [PMID: 33610718 DOI: 10.1016/j.phrs.2021.105507] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 02/15/2021] [Accepted: 02/16/2021] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is a typical hyper-vascular solid tumor; aberrantly rich in tumor vascular network contributes to its malignancy. Conventional anti-angiogenic therapies seem promising but transitory and incomplete efficacy on HCC. Vasculogenic mimicry (VM) is one of functional microcirculation patterns independent of endothelial vessels which describes the plasticity of highly aggressive tumor cells to form vasculogenic-like networks providing sufficient blood supply for tumor growth and metastasis. As a pivotal alternative mechanism for tumor vascularization when tumor cells undergo lack of oxygen and nutrients, VM has an association with the malignant phenotype and poor clinical outcome for HCC, and may challenge the classic anti-angiogenic treatment of HCC. Current studies have contributed numerous findings illustrating the underlying molecular mechanisms and signaling pathways supporting VM in HCC. In this review, we summarize the correlation between epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and VM, the role of hypoxia and extracellular matrix remodeling in VM, the involvement of adjacent non-cancerous cells, cytokines and growth factors in VM, as well as the regulatory influence of non-coding RNAs on VM in HCC. Moreover, we discuss the clinical significance of VM in practice and the potential therapeutic strategies targeting VM for HCC. A better understanding of the mechanism underlying VM formation in HCC may optimize anti-angiogenic treatment modalities for HCC.
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Affiliation(s)
- Ning Zheng
- Department of Pharmacology, The School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, Fujian 350122, China
| | - Shaoqin Zhang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China
| | - Wenda Wu
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China
| | - Nan Zhang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China
| | - Jichuang Wang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China.
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Abstract
Chronic liver injury due to viral hepatitis, alcohol abuse, and metabolic disorders is a worldwide health concern. Insufficient treatment of chronic liver injury leads to fibrosis, causing liver dysfunction and carcinogenesis. Most cases of hepatocellular carcinoma (HCC) develop in the fibrotic liver. Pathological features of liver fibrosis include extracellular matrix (ECM) accumulation, mesenchymal cell activation, immune deregulation, and angiogenesis, all of which contribute to the precancerous environment, supporting tumor development. Among liver cells, hepatic stellate cells (HSCs) and macrophages play critical roles in fibrosis and HCC. These two cell types interplay and remodel the ECM and immune microenvironment in the fibrotic liver. Once HCC develops, HCC-derived factors influence HSCs and macrophages to switch to protumorigenic cell populations, cancer-associated fibroblasts and tumor-associated macrophages, respectively. This review aims to summarize currently available data on the roles of HSCs and macrophages in liver fibrosis and HCC, with a focus on their interaction.
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Affiliation(s)
- Michitaka Matsuda
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Ekihiro Seki
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
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Lang YD, Chen HY, Ho CM, Shih JH, Hsu EC, Shen R, Lee YC, Chen JW, Wu CY, Yeh HW, Chen RH, Jou YS. PSPC1-interchanged interactions with PTK6 and β-catenin synergize oncogenic subcellular translocations and tumor progression. Nat Commun 2019; 10:5716. [PMID: 31844057 PMCID: PMC6914800 DOI: 10.1038/s41467-019-13665-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 11/12/2019] [Indexed: 12/30/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to metastasis. Paraspeckle component 1 (PSPC1) upregulation has been identified as an HCC pro-metastatic activator associated with poor patient prognosis, but with a lack of targeting strategy. Here, we report that PSPC1, a nuclear substrate of PTK6, sequesters PTK6 in the nucleus and loses its metastasis driving capability. Conversely, PSPC1 upregulation or PSPC1-Y523F mutation promotes epithelial-mesenchymal transition, stemness, and metastasis via cytoplasmic translocation of active PTK6 and nuclear translocation of β-catenin, which interacts with PSPC1 to augment Wnt3a autocrine signaling. The aberrant nucleocytoplasmic shuttling of active PTK6/β-catenin is reversed by expressing the PSPC1 C-terminal interacting domain (PSPC1-CT131), thereby suppressing PSPC1/PTK6/β-catenin-activated metastasis to prolong the survival of HCC orthotopic mice. Thus, PSPC1 is the contextual determinant of the oncogenic switch of PTK6/β-catenin subcellular localizations, and PSPC1-CT131 functions as a dual inhibitor of PSPC1 and PTK6 with potential for improving cancer therapy. PSPC1 has a critical role in promoting EMT and metastasis. Here, the authors demonstrate that PSPC1 is the contextual determinant of the oncogenic switch of PTK6/β-catenin subcellular localizations to drive metastasis of hepatocellular carcinoma cells via a PSPC1/PTK6/β-catenin signaling.
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Affiliation(s)
- Yaw-Dong Lang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - Hsin-Yi Chen
- Graduate Institute of Cancer Biology & Drug Discovery, College of Medical Science & Technology, Taipei Medical University, Taipei, 11031, Taiwan.,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan
| | - Chun-Ming Ho
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan.,Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsin-Chu, 30068, Taiwan.,Bioinformatics Program, Taiwan International Graduate Program, Institute of Information Science, Academia Sinica, Taipei, 11529, Taiwan
| | - Jou-Ho Shih
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - En-Chi Hsu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - Roger Shen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan.,Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, 11221, Taiwan
| | - Yu-Ching Lee
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Jyun-Wei Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - Cheng-Yen Wu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - Hsi-Wen Yeh
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - Ruey-Hwa Chen
- Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan
| | - Yuh-Shan Jou
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan. .,Bioinformatics Program, Taiwan International Graduate Program, Institute of Information Science, Academia Sinica, Taipei, 11529, Taiwan. .,Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, 11221, Taiwan.
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9
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Liao X, Bu Y, Chang F, Jia F, Song G, Xiao X, Zhang M, Ning P, Jia Q. Remodeling of hepatic stellate cells orchestrated the stroma-derived oxaliplatin-resistance through CCN3 paracrine in hepatocellular carcinoma. BMC Cancer 2019; 19:1192. [PMID: 31805888 PMCID: PMC6896671 DOI: 10.1186/s12885-019-6362-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 11/14/2019] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Hepatic stellate cells (HSCs) have a key role in fibrogenesis and in the filtrates of the hepatocellular carcinoma (HCC) stroma, in which they are remodeled and play a critical role in HCC progression. However, the precise role of HSCs trending, infiltration and paracrine in orchestrating the stroma-derived oxaliplatin-resistance in HCC is still vague. METHODS The chemo-resistant models were established to explore the correlation between HSC cells and the condition of chemoresistance. The HCC clinical samples were collected to confirm this phenomenon. Then, the relationship between secretory CCN3 from oxaliplatin-resistant HCC and the infiltration of HSCs in associated HCC microenvironment was evaluated. Finally, the role and mechanism of HSCs remodeling in the orchestration of oxaliplatin-resistant HCC were explored. RESULTS The increased infiltration of HSCs and collagen accumulation were found in the microenvironment of oxaliplatin-resistant HCC. The cDNA profiles of the oxaliplatin-resistant HCC was reanalyzed, and CCN3 was one of the significantly increased genes. In HCC clinical samples, the levels of CCN3 and α-SMA are positively correlated, and high expression of CCN3 and α-SMA are positively associated with malignant phenotype and poor prognosis. Then the enhanced abilities of migration and proliferation of HSCs, and elevation of the cytokines paracrine from HSCs relating to HCC malignancy were proved in vitro and in vivo, and which were related to CCN3-ERK signaling pathway activation. CONCLUSIONS HSCs remodeling are positively related to CCN3 paracrine in hepatocellular carcinoma, which orchestrated the stroma-derived resistance to chemotherapy in HCC.
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Affiliation(s)
- Xia Liao
- Department of Nutrition, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yang Bu
- Department of Hepatobiliary Surgery, General Hospital, Ningxia Medical University, Yinchuan, 750001, China
| | - Fan Chang
- Metabolite Research Center, Shaanxi Institute of Microbiology, Xi'an, 710043, China
| | - Fengan Jia
- Metabolite Research Center, Shaanxi Institute of Microbiology, Xi'an, 710043, China
| | - Ge Song
- Department of Nutrition, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xuelian Xiao
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, China
| | - Mei Zhang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, China
| | - Pengbo Ning
- School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, China
| | - Qingan Jia
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, China.
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10
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Scheau C, Badarau IA, Caruntu C, Mihai GL, Didilescu AC, Constantin C, Neagu M. Capsaicin: Effects on the Pathogenesis of Hepatocellular Carcinoma. Molecules 2019; 24:E2350. [PMID: 31247901 PMCID: PMC6651067 DOI: 10.3390/molecules24132350] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 06/21/2019] [Accepted: 06/24/2019] [Indexed: 12/22/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent cancers, and to date, there have been very few drugs available that can improve survival, the most well-known being sorafenib. The pathogenesis of HCC is complex, involving multiple processes including abnormal cell and tissue regeneration, angiogenesis, genomic instability, cellular proliferation, and signaling pathway alterations. Capsaicin is a substance that holds increasingly high interest and is studied as a therapeutic option in a wide array of diseases. Several studies have investigated capsaicin roles in various stages of HCC oncogenesis. This paper aims to thoroughly detail the available information on the individual effects of capsaicin on the cellular mechanisms and pathways involved in HCC development, as well as investigate their possible cooperation and interferences. The synergistic antitumor effects of capsaicin and sorafenib are also addressed.
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Affiliation(s)
- Cristian Scheau
- Department of Physiology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Ioana Anca Badarau
- Department of Physiology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania.
| | - Constantin Caruntu
- Department of Physiology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania.
- Department of Dermatology, Prof. N.C. Paulescu National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania.
| | - Gratiela Livia Mihai
- Department of Physiology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Andreea Cristiana Didilescu
- Department of Embryology, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Carolina Constantin
- Immunology Department, Victor Babes National Institute of Pathology, 050096 Bucharest, Romania
- Department of Pathology, Colentina University Hospital, 020125 Bucharest, Romania
| | - Monica Neagu
- Immunology Department, Victor Babes National Institute of Pathology, 050096 Bucharest, Romania
- Department of Pathology, Colentina University Hospital, 020125 Bucharest, Romania
- Faculty of Biology, University of Bucharest, 76201 Bucharest, Romania
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11
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Recent Insight into the Role of Fibrosis in Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinoma. Int J Mol Sci 2019; 20:ijms20071745. [PMID: 30970564 PMCID: PMC6480228 DOI: 10.3390/ijms20071745] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 03/20/2019] [Accepted: 03/23/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most widespread tumors in the world and its prognosis is poor because of lack of effective treatments. Epidemiological studies show that non-alcoholic steatohepatitis (NASH) and advanced fibrosis represent a relevant risk factors to the HCC development. However little is known of pathophysiological mechanisms linking liver fibrogenesis to HCC in NASH. Recent advances in scientific research allowed to discover some mechanisms that may represent potential therapeutic targets. These include the integrin signaling, hepatic stellate cells (HSCs) activation, Hedgehog signaling and alteration of immune system. In the near future, knowledge of fibrosis-dependent carcinogenic mechanisms, will help optimize antifibrotic therapies as an approach to prevent and treat HCC in patients with NASH and advanced fibrosis.
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12
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Makino Y, Hikita H, Kodama T, Shigekawa M, Yamada R, Sakamori R, Eguchi H, Morii E, Yokoi H, Mukoyama M, Hiroshi S, Tatsumi T, Takehara T. CTGF Mediates Tumor-Stroma Interactions between Hepatoma Cells and Hepatic Stellate Cells to Accelerate HCC Progression. Cancer Res 2018; 78:4902-4914. [PMID: 29967264 DOI: 10.1158/0008-5472.can-17-3844] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 04/16/2018] [Accepted: 06/26/2018] [Indexed: 11/16/2022]
Abstract
Connective tissue growth factor (CTGF) is a matricellular protein related to hepatic fibrosis. This study aims to clarify the roles of CTGF in hepatocellular carcinoma (HCC), which usually develops from fibrotic liver. CTGF was overexpressed in 93 human HCC compared with nontumorous tissues, primarily in tumor cells. Increased CTGF expression was associated with clinicopathologic malignancy of HCC. CTGF was upregulated in hepatoma cells in hepatocyte-specific Kras-mutated mice (Alb-Cre KrasLSL-G12D/+). Hepatocyte-specific knockout of CTGF in these mice (Alb-Cre KrasLSL-G12D/+ CTGFfl/fl) decreased liver tumor number and size. Hepatic stellate cells (HSC) were present in both human and murine liver tumors, and α-SMA expression, a marker of HSC activation, positively correlated with CTGF expression. Forced expression of CTGF did not affect growth of PLC/PRF/5 cells, a hepatoma cell line with little CTGF expression, but facilitated their growth in the presence of LX-2 cells, an HSC line. The growth of HepG2 cells, which express high levels of CTGF, was promoted by coculture with LX-2 cells compared with monoculture. Growth promotion by LX-2 cells was negated by an anti-CTGF antibody in both culture and xenografts. Coculturing LX-2 cells with HepG2 cells drove LX-2-derived production of IL6, which led to STAT-3 activation and proliferation of HepG2 cells. An anti-CTGF antibody reduced IL6 production in LX-2 cells and suppressed STAT-3 activation in HepG2 cells. In conclusion, our data identify tumor cell-derived CTGF as a keystone in the HCC microenvironment, activating nearby HSC that transmit progrowth signals to HCC cells, and this interaction is susceptible to inhibition by an anti-CTGF antibody.Significance: Protumor cross-talk between cancer cells and hepatic stellate cells presents an opportunity for therapeutic intervention against HCC.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/4902/F1.large.jpg Cancer Res; 78(17); 4902-14. ©2018 AACR.
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Affiliation(s)
- Yuki Makino
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Minoru Shigekawa
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Ryoko Yamada
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Eiichi Morii
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hideki Yokoi
- Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Masashi Mukoyama
- Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | | | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
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13
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14
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Harris WP, Wong KM, Saha S, Dika IE, Abou-Alfa GK. Biomarker-Driven and Molecular Targeted Therapies for Hepatobiliary Cancers. Semin Oncol 2018; 45:116-123. [PMID: 30348531 DOI: 10.1053/j.seminoncol.2018.03.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 03/07/2018] [Indexed: 12/18/2022]
Abstract
The recent accumulation of molecular profiling data for primary hepatobiliary malignancies, including hepatocellular carcinoma and biliary tract cancers, has led to a proliferation of promising therapeutic investigations in recent years. Treatment with pathway-specific targeted inhibitors and immunotherapeutic agents have demonstrated promising early clinical results. Key molecular alterations in common hepatobiliary cancers and ongoing interventional clinical trials of molecularly targeted systemic agents focusing on hepatocellular carcinoma and biliary tract cancer are reviewed.
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Affiliation(s)
- William P Harris
- Department of Medicine, Division of Medical Oncology, University of Washington, Seattle WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle WA
| | - Kit Man Wong
- Department of Medicine, Division of Medical Oncology, University of Washington, Seattle WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle WA
| | - Supriya Saha
- Department of Medicine, Division of Medical Oncology, University of Washington, Seattle WA; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle WA
| | - Imane El Dika
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ghassan K Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Medical College at Cornell University, New York, NY.
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15
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Endostatin Stimulates Proliferation and Migration of Myofibroblasts Isolated from Myocardial Infarction Model Rats. Int J Mol Sci 2018; 19:ijms19030741. [PMID: 29509663 PMCID: PMC5877602 DOI: 10.3390/ijms19030741] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 02/24/2018] [Accepted: 03/01/2018] [Indexed: 02/06/2023] Open
Abstract
Myofibroblasts contribute to the healing of infarcted areas after myocardial infarction through proliferation, migration, and production of extracellular matrix (ECM). Expression of endostatin, a cleaved fragment of type XVIII collagen, increases in the heart tissue of an experimental myocardial infarction model. In the present study, we examined the effect of endostatin on the function of myofibroblasts derived from an infarcted area. The myocardial infarction model was created by ligating the left anterior descending artery in rats. Two weeks after the operation, α-smooth muscle actin (α-SMA)-positive myofibroblasts were isolated from the infarcted area. Endostatin significantly increased the proliferation and migration of myofibroblasts in vitro. On the other hand, endostatin had no effect on the production of type I collagen, a major ECM protein produced by myofibroblasts. Endostatin activated Akt and extracellular signal-regulated kinase (ERK), and the pharmacological inhibition of these signaling pathways suppressed the endostatin-induced proliferation and migration. A knockdown of the COL18A1 gene in the myocardial infarction model rats using small interference RNA (siRNA) worsened the cardiac function concomitant with wall thinning and decreased the α-SMA-positive myofibroblasts and scar formation compared with that of control siRNA-injected rats. In summary, we demonstrated for the first time that endostatin might be an important factor in the healing process after myocardial infarction through the activation of myofibroblasts.
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16
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Liu J, Dang H, Wang XW. The significance of intertumor and intratumor heterogeneity in liver cancer. Exp Mol Med 2018; 50:e416. [PMID: 29303512 PMCID: PMC5992990 DOI: 10.1038/emm.2017.165] [Citation(s) in RCA: 158] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 05/11/2017] [Indexed: 02/06/2023] Open
Abstract
Genomic analyses of primary liver cancer samples reveal a complex mutational landscape with vast intertumor and intratumor heterogeneity. Different primary liver tumors and subclones within each tumor display striking molecular and biological variations. Consequently, tumor molecular heterogeneity contributes to drug resistance and tumor relapse following therapy, which poses a substantial obstruction to improving outcomes of patients with liver cancer. There is an urgent need to the compositional and functional understanding of tumor heterogeneity. In this review, we summarize genomic and non-genomic diversities, which include stemness and microenvironmental causes of the functional heterogeneity of the primary liver cancer ecosystem. We discuss the importance and intricacy of intratumor heterogeneity in the context of cancer cell evolution. We also discuss methodologies applicable to determine intratumor heterogeneity and highlight the best-fit patient-derived in vivo and in vitro models to recapture the functional heterogeneity of primary liver cancer with the aim to improve future therapeutic strategies.
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Affiliation(s)
- Jinping Liu
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Hien Dang
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Xin Wei Wang
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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17
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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: 70] [Impact Index Per Article: 8.8] [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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18
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Yoo SY, Jeong SN, Kang DH, Heo J. Evolutionary cancer-favoring engineered vaccinia virus for metastatic hepatocellular carcinoma. Oncotarget 2017; 8:71489-71499. [PMID: 29069721 PMCID: PMC5641064 DOI: 10.18632/oncotarget.17288] [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] [Received: 12/08/2016] [Accepted: 04/11/2017] [Indexed: 12/31/2022] Open
Abstract
Engineered vaccinia virus-based therapy shows promising results in patients with advanced hepatocellular carcinoma, although a strategic virus design for the metastatic liver and the study of its efficacy in treating the cancer has not been well assessed. In this paper, we proposed a simple and strategic virus design for targeting metastatic hepatocellular carcinoma. We developed an evolutionary cancer-favoring engineered vaccinia virus (CVV, which is produced by repeated selective replication in cancerous tissues and then deleting viral thymidine kinase genes) and investigated its therapeutic effects on metastatic liver cancer. The expression of the cell surface marker, CD44, which is associated with cancer stem cells, seems to be correlated with the cells’ metastatic characteristics; cellular migration, epithelial-mesenchymal transition (EMT) expression and liver tumorigenicity. The highly metastatic and tumorigenic Sk-Hep-1 cell line was selected and injected directly onto the liver tissue to develop a liver-to-colon metastasis model. In an animal study, the subjects were treated with sorafenib, CVV, or sorafenib with CVV. Metastatic regions were interestingly rare in the CVV-treated groups (i.e., CVV or sorafenib with CVV) whereas metastatic regions existed in the sorafenib-treated group. From results, we concluded that our simple strategy of developing a cancer-favoring virus can successfully eradicate metastatic liver cancer cells, provided that our CVV can be a promising therapeutic virus that targets metastatic liver cancer.
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Affiliation(s)
- So Young Yoo
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 609-735, Republic of Korea.,Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 626-770, Republic of Korea.,Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Busan 602-739, Republic of Korea
| | - Su-Nam Jeong
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 609-735, Republic of Korea
| | - Dae Hwan Kang
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 626-770, Republic of Korea.,Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Busan 602-739, Republic of Korea
| | - Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Busan 602-739, Republic of Korea
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19
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Affo S, Yu LX, Schwabe RF. The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2016; 12:153-186. [PMID: 27959632 DOI: 10.1146/annurev-pathol-052016-100322] [Citation(s) in RCA: 482] [Impact Index Per Article: 53.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Liver cancer is the second leading cause of cancer mortality worldwide, causing more than 700,000 deaths annually. Because of the wide landscape of genomic alterations and limited therapeutic success of targeting tumor cells, a recent focus has been on better understanding and possibly targeting the microenvironment in which liver tumors develop. A unique feature of liver cancer is its close association with liver fibrosis. More than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers, suggesting an important role of liver fibrosis in the premalignant environment (PME) of the liver. Cholangiocarcinoma (CCA), in contrast, is characterized by a strong desmoplasia that typically occurs in response to the tumor, suggesting a key role of cancer-associated fibroblasts (CAFs) and fibrosis in its tumor microenvironment (TME). Here, we discuss the functional contributions of myofibroblasts, CAFs, and fibrosis to the development of HCC and CCA in the hepatic PME and TME, focusing on myofibroblast- and extracellular matrix-associated growth factors, fibrosis-associated immunosuppressive pathways, as well as mechanosensitive signaling cascades that are activated by increased tissue stiffness. Better understanding of the role of myofibroblasts in HCC and CCA development and progression may provide the basis to target these cells for tumor prevention or therapy.
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Affiliation(s)
- Silvia Affo
- Department of Medicine, Columbia University, New York, NY 10032;
| | - Le-Xing Yu
- Department of Medicine, Columbia University, New York, NY 10032;
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York, NY 10032;
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20
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Chen G, Nakamura I, Dhanasekaran R, Iguchi E, Tolosa EJ, Romecin PA, Vera RE, Almada LL, Miamen AG, Chaiteerakij R, Zhou M, Asiedu MK, Moser CD, Han S, Hu C, Banini BA, Oseini AM, Chen Y, Fang Y, Yang D, Shaleh HM, Wang S, Wu D, Song T, Lee JS, Thorgeirsson SS, Chevet E, Shah VH, Fernandez-Zapico ME, Roberts LR. Transcriptional Induction of Periostin by a Sulfatase 2-TGFβ1-SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma. Cancer Res 2016; 77:632-645. [PMID: 27872089 DOI: 10.1158/0008-5472.can-15-2556] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 10/07/2016] [Accepted: 10/27/2016] [Indexed: 12/15/2022]
Abstract
Existing antiangiogenic approaches to treat metastatic hepatocellular carcinoma (HCC) are weakly effectual, prompting further study of tumor angiogenesis in this disease setting. Here, we report a novel role for sulfatase 2 (SULF2) in driving HCC angiogenesis. Sulf2-deficient mice (Sulf2 KO) exhibited resistance to diethylnitrosamine-induced HCC and did not develop metastases like wild-type mice (Sulf2 WT). The smaller and less numerous tumors formed in Sulf2 KO mice exhibited a markedly lower microvascular density. In human HCC cells, SULF2 overexpression increased endothelial proliferation, adhesion, chemotaxis, and tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of αvβ3/5 integrins, as an effector protein in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo The TGFβ1/SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical HCC specimens, elevated levels of SULF2 correlated with increased microvascular density, POSTN levels, and relatively poorer patient survival. Together, our findings define an important axis controlling angiogenesis in HCC and a mechanistic foundation for rational drug development. Cancer Res; 77(3); 632-45. ©2016 AACR.
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Affiliation(s)
- Gang Chen
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Ikuo Nakamura
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Renumathy Dhanasekaran
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.,Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California
| | - Eriko Iguchi
- Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Ezequiel J Tolosa
- Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Paola A Romecin
- Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Renzo E Vera
- Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Luciana L Almada
- Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Alexander G Miamen
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Roongruedee Chaiteerakij
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.,Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Mengtao Zhou
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Michael K Asiedu
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Catherine D Moser
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Shaoshan Han
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Chunling Hu
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Bubu A Banini
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Abdul M Oseini
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Yichun Chen
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Yong Fang
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Dongye Yang
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Hassan M Shaleh
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Shaoqing Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.,Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California
| | - Dehai Wu
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Tao Song
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Ju-Seog Lee
- Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas
| | - Snorri S Thorgeirsson
- Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, Maryland
| | - Eric Chevet
- INSERM U1242, Chemistry, Oncogenesis Stress Signaling, Université Rennes 1, and Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Martin E Fernandez-Zapico
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.,Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
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21
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Bu Y, Jia QA, Ren ZG, Xue TC, Zhang QB, Zhang KZ, Zhang QB, You Y, Tian H, Qin LX, Tang ZY. The herbal compound Songyou Yin (SYY) inhibits hepatocellular carcinoma growth and improves survival in models of chronic fibrosis via paracrine inhibition of activated hepatic stellate cells. Oncotarget 2016; 6:40068-80. [PMID: 26517671 PMCID: PMC4741880 DOI: 10.18632/oncotarget.5313] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 10/09/2015] [Indexed: 01/27/2023] Open
Abstract
Chronic fibrosis is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathological progression of hepatic fibrosis has been linked to cellular processes that promote tumor growth and metastasis. Several recent studies have highlighted the cross-talk between tumor cells and activated hepatic stellate cells (aHSCs) in HCC. The herbal compound Songyou Yin (SYY) is known to attenuate hepatoma cell invasion and metastasis via down-regulation of cytokine secretion by aHSCs. However the underlying mechanism of SYY treatment in reversal of hepatic fibrosis and metastasis of liver cancers is not known. In the current study, a nude mouse model with liver fibrosis bearing orthotopic xenograft was established and we found that SYY could reduce associated fibrosis, inhibit tumor growth and improve survival. In the subcutaneous tumor model with fibrosis, we found that SYY could inhibit liver cancer. In vitro, hepatoma cells incubated with conditioned media (CM) from SYY treated aHSCs showed reduced proliferation, decrease in colony formation and invasive potential. SYY treated group showed altered gene expression, with 1205 genes up-regulated and 1323 genes down-regulated. Gene cluster analysis indicated that phosphatidylinositol-3-kinase (PI3K) was one of the key genes altered in the expression profiles. PI3K related markers were all significantly down-regulated. ELISA also indicated decreased secretion of cytokines which were regulated by PI3K/AKT signaling after SYY treatment in the hepatic stellate cell line, LX2. These data clearly demonstrate that SYY therapy inhibits HCC invasive and metastatic potential and improves survival in nude mice models with chronic fibrosis background via inhibition of cytokine secretion by activated hepatic stellate cells.
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Affiliation(s)
- Yang Bu
- Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750001, China.,Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Qing-An Jia
- Cancer Center, Institutes of Biomedical Sciences, General Surgery, Huashan Hospital, Fudan University, Shanghai 200032, China
| | - Zheng-Gang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Tong-Chun Xue
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Quan-Bao Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Ke-Zhi Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Qiang-Bo Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Yang You
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Hui Tian
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Lun-Xiu Qin
- Cancer Center, Institutes of Biomedical Sciences, General Surgery, Huashan Hospital, Fudan University, Shanghai 200032, China
| | - Zhao-You Tang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
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22
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Abstract
Advanced hepatocellular carcinoma (HCC) is a serious therapeutic challenge and targeted therapies only provide a modest benefit in terms of overall survival. Novel approaches are urgently needed for the treatment of this prevalent malignancy. Evidence demonstrating the antigenicity of tumour cells, the discovery that immune checkpoint molecules have an essential role in immune evasion of tumour cells, and the impressive clinical results achieved by blocking these inhibitory receptors, are revolutionizing cancer immunotherapy. Here, we review the data on HCC immunogenicity, the mechanisms for HCC immune subversion and the different immunotherapies that have been tested to treat HCC. Taking into account the multiplicity of hyperadditive immunosuppressive forces acting within the HCC microenvironment, a combinatorial approach is advised. Strategies include combinations of systemic immunomodulation and gene therapy, cell therapy or virotherapy.
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23
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Liao BY, Wang Z, Hu J, Liu WF, Shen ZZ, Zhang X, Yu L, Fan J, Zhou J. PI-88 inhibits postoperative recurrence of hepatocellular carcinoma via disrupting the surge of heparanase after liver resection. Tumour Biol 2015; 37:2987-98. [PMID: 26415733 DOI: 10.1007/s13277-015-4085-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 09/13/2015] [Indexed: 01/27/2023] Open
Abstract
Phosphomannopentaose sulfate (PI-88), an effective inhibitor of heparanase (HPSE), exhibited anti-recurrence and anti-metastasis activity in preliminary clinical trials of hepatocellular carcinoma (HCC); however, the underlying mechanisms remain uncertain. Our aim was to reveal the mechanism by which PI-88 inhibits recurrence and intrahepatic metastasis. A tissue microarray containing samples from 352 HCC patients was used to determine HPSE expression. We performed enzyme-linked immunosorbent assay (ELISA) to detect plasma levels of HPSE in 40 HCC patients. We also used quantitative polymerase chain reaction, western blot analysis, and immunohistochemical staining to assess HPSE expression of HCC cell lines and tissues. The in vitro effects of PI-88 were examined by cell proliferation and migration assays. In vivo PI-88 activity was assessed using murine orthotopic HCC models. Intratumoral HPSE was an independent prognostic marker for postsurgical overall survival (P = 0.001) and time to recurrence (P < 0.001) of HCC patients with hepatectomy. Elevated levels of HPSE were detected both in postsurgical plasma of HCC patients and an orthotopic mouse model after hepatectomy. PI-88 inhibited tumor recurrence and metastasis after liver resection in the mouse model. In vitro expression of HPSE was up-regulated by overexpression of early growth response 1 (EGR1), which is induced after hepatectomy. Up-regulation of HPSE enhanced the sensitivity of HCC cells to PI-88 and the inhibitive effect of PI-88 on cell proliferation and migration. Our data show that PI-88 effectively inhibits postoperative recurrence and intrahepatic metastasis of HCC, providing an experimental basis for the clinical application of PI-88 in HCC patients who have undergone hepatectomy.
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Affiliation(s)
- Bo-Yi Liao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China
| | - Zheng Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China
| | - Jie Hu
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China
| | - Wei-Feng Liu
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China
| | - Zao-Zhuo Shen
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China
| | - Xin Zhang
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China
| | - Lei Yu
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China
| | - Jia Fan
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China. .,Institute of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China.
| | - Jian Zhou
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China. .,Institute of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China.
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24
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Phan LM, Fuentes-Mattei E, Wu W, Velazquez-Torres G, Sircar K, Wood CG, Hai T, Jimenez C, Cote GJ, Ozsari L, Hofmann MC, Zheng S, Verhaak R, Pagliaro L, Cortez MA, Lee MH, Yeung SCJ, Habra MA. Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma. Cancer Res 2015; 75:4131-42. [PMID: 26282167 DOI: 10.1158/0008-5472.can-14-3707] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Accepted: 07/06/2015] [Indexed: 12/24/2022]
Abstract
Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in adrenocortical carcinoma has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of adrenocortical carcinoma. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human adrenocortical carcinoma samples was positively associated with cancer-related biologic processes, including proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of adrenocortical carcinoma cells with exogenous HGF resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA-mediated knockdown or pharmacologic inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance, further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in adrenocortical carcinoma growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer.
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Affiliation(s)
- Liem M Phan
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Enrique Fuentes-Mattei
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Weixin Wu
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Guermarie Velazquez-Torres
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kanishka Sircar
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Christopher G Wood
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tao Hai
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Camilo Jimenez
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gilbert J Cote
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Levent Ozsari
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Marie-Claude Hofmann
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Siyuan Zheng
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Roeland Verhaak
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lance Pagliaro
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Maria Angelica Cortez
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mong-Hong Lee
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sai-Ching J Yeung
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mouhammed Amir Habra
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Zhao L, Wu Y, Xie XD, Chu YF, Li JQ, Zheng L. c-Met identifies a population of matrix metalloproteinase 9-producing monocytes in peritumoural stroma of hepatocellular carcinoma. J Pathol 2015; 237:319-29. [PMID: 26108200 DOI: 10.1002/path.4578] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 04/23/2015] [Accepted: 06/19/2015] [Indexed: 12/17/2022]
Abstract
Macrophages (Mϕ) are prominent components of solid tumours and exhibit distinct phenotypes in different microenvironments. Previously, we found that tumours could alter the normal developmental process of Mϕ to trigger transient activation of monocytes in the peritumoural stroma of human hepatocellular carcinoma (HCC). In the present study, we showed that a fraction of monocytes in the peritumoural stroma, but not in HCC cancer nests, expressed surface c-Met molecules. Monocytes exposed to tumours strongly expressed c-Met proteins with kinetics similar to their activation status, and significant correlations were found between c-Met levels and HLA-DR expression on tumour-infiltrating monocytes. NF-κB-mediated autocrine TNF-α stimulated the expression of c-Met on activated monocytes, and by interacting with its ligand hepatocyte growth factor (HGF), c-Met increased the motility and matrix metalloproteinase (MMP) 9-producing capacity of tumour-associated monocytes. The intensity of c-Met expression on tumour-infiltrating monocytes was associated with high mortality and reduced survival of patients with HCC. Therefore, the expression of c-Met on activated monocytes/Mϕ may represent a novel mechanism by which a tumour actively and precisely regulates the distribution and functions of these cells to facilitate disease progression.
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Affiliation(s)
- Lan Zhao
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China.,State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, PR China
| | - Yan Wu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Xu-Dong Xie
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Yi-Fan Chu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Jin-Qing Li
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, PR China
| | - Limin Zheng
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China.,State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, PR China
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26
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Rozenblum N, Zeira E, Bulvik B, Gourevitch S, Yotvat H, Galun E, Goldberg SN. Radiofrequency Ablation: Inflammatory Changes in the Periablative Zone Can Induce Global Organ Effects, including Liver Regeneration. Radiology 2015; 276:416-25. [DOI: 10.1148/radiol.15141918] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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27
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Steinway SN, Dang H, You H, Rountree CB, Ding W. The EGFR/ErbB3 Pathway Acts as a Compensatory Survival Mechanism upon c-Met Inhibition in Human c-Met+ Hepatocellular Carcinoma. PLoS One 2015; 10:e0128159. [PMID: 26000702 PMCID: PMC4441360 DOI: 10.1371/journal.pone.0128159] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 04/22/2015] [Indexed: 12/22/2022] Open
Abstract
Background c-Met, a high-affinity receptor for Hepatocyte Growth Factor (HGF), plays a critical role in tumor growth, invasion, and metastasis. Hepatocellular carcinoma (HCC) patients with activated HGF/c-Met signaling have a significantly worse prognosis. Targeted therapies using c-Met tyrosine kinase inhibitors are currently in clinical trials for HCC, although receptor tyrosine kinase inhibition in other cancers has demonstrated early success. Unfortunately, therapeutic effect is frequently not durable due to acquired resistance. Methods We utilized the human MHCC97-H c-Met positive (c-Met+) HCC cell line to explore the compensatory survival mechanisms that are acquired after c-Met inhibition. MHCC97-H cells with stable c-Met knockdown (MHCC97-H c-Met KD cells) were generated using a c-Met shRNA vector with puromycin selection and stably transfected scrambled shRNA as a control. Gene expression profiling was conducted, and protein expression was analyzed to characterize MHCC97-H cells after blockade of the c-Met oncogene. A high-throughput siRNA screen was performed to find putative compensatory survival proteins, which could drive HCC growth in the absence of c-Met. Findings from this screen were validated through subsequent analyses. Results We have previously demonstrated that treatment of MHCC97-H cells with a c-Met inhibitor, PHA665752, results in stasis of tumor growth in vivo. MHCC97-H c-Met KD cells demonstrate slower growth kinetics, similar to c-Met inhibitor treated tumors. Using gene expression profiling and siRNA screening against 873 kinases and phosphatases, we identified ErbB3 and TGF-α as compensatory survival factors that are upregulated after c-Met inhibition. Suppressing these factors in c-Met KD MHCC97-H cells suppresses tumor growth in vitro. In addition, we found that the PI3K/Akt signaling pathway serves as a negative feedback signal responsible for the ErbB3 upregulation after c-Met inhibition. Furthermore, in vitro studies demonstrate that combination therapy with PHA665752 and Gefitinib (an EGFR inhibitor) significantly reduced cell viability and increased apoptosis compared with either PHA665752 or Gefitinib treatment alone. Conclusion c-Met inhibition monotherapy is not sufficient to eliminate c-Met+ HCC tumor growth. Inhibition of both c-Met and EGFR oncogenic pathways provides superior suppression of HCC tumor growth. Thus, combination of c-Met and EGFR inhibition may represent a superior therapeutic regimen for c-Met+ HCC.
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Affiliation(s)
- Steven N. Steinway
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
| | - Hien Dang
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
| | - Hanning You
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
| | - C. Bart Rountree
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
| | - Wei Ding
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
- * E-mail:
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28
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Wang XY, Pei Y, Xie M, Jin ZH, Xiao YS, Wang Y, Zhang LN, Li Y, Huang WH. An artificial blood vessel implanted three-dimensional microsystem for modeling transvascular migration of tumor cells. LAB ON A CHIP 2015; 15:1178-87. [PMID: 25565271 DOI: 10.1039/c4lc00973h] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Reproducing a tumor microenvironment consisting of blood vessels and tumor cells for modeling tumor invasion in vitro is particularly challenging. Here, we report an artificial blood vessel implanted 3D microfluidic system for reproducing transvascular migration of tumor cells. The transparent, porous and elastic artificial blood vessels are obtained by constructing polysaccharide cellulose-based microtubes using a chitosan sacrificial template, and possess excellent cytocompatibility, permeability, and mechanical characteristics. The artificial blood vessels are then fully implanted into the collagen matrix to reconstruct the 3D microsystem for modeling transvascular migration of tumor cells. Well-defined simulated vascular lumens were obtained by proliferation of the human umbilical vein endothelial cells (HUVECs) lining the artificial blood vessels, which enables us to reproduce structures and functions of blood vessels and replicate various hemodynamic parameters. Based on this model, the adhesion and transvascular migration of tumor cells across the artificial blood vessel have been well reproduced.
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Affiliation(s)
- Xue-Ying Wang
- Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, China.
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29
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Wang X, Liu H, Zhang Z, Liu Y, Li Y, Gui J, Chu Y. High-level expression and characterization of bioactive human truncated variant of hepatocyte growth factor in Escherichia coli. World J Microbiol Biotechnol 2014; 30:2851-9. [PMID: 25118831 DOI: 10.1007/s11274-014-1711-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Accepted: 07/25/2014] [Indexed: 02/05/2023]
Abstract
Hepatocyte growth factor (HGF) is an effective anti-fibrotic factor because of its bioactivity in inhibiting fibrosis-related proteins in the development of hepatic fibrosis. However, high-level production of bioactive mature form HGF is difficult because of its complex structure. Here, we report a non-fusion protein expression system to obtain truncated variant of N-terminal hairpin and first kringle domains of HGF (tvNK1) in Escherichia coli to determine its anti-fibrotic effects on hepatic stellate cells (HSCs). Under the selected conditions of cultivation and isopropyl-β-D-1-thiogalactopyranoside induction, the expression level of tvNK1 accounted for approximately 65 % of the total cellular protein and 50 % of fusion protein in the supernatant of whole cell lysates. The recombinant protein could be purified in one step with Ni(2+)-affinity chromatograph. Finally, about 65 mg recombinant tvNK1 was obtained from 1 l fermentation culture with no <95 % purity. In vitro, the final purified tvNK1 was shown to inhibit the proliferation of HSCs and decrease the mRNA and protein expression levels of fibrosis-related COL1A1 and α-smooth muscle actin genes.
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Affiliation(s)
- Xiaohua Wang
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, 157011, People's Republic of China
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30
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Mikuriya Y, Tashiro H, Kuroda S, Nambu J, Kobayashi T, Amano H, Tanaka Y, Ohdan H. Fatty liver creates a pro-metastatic microenvironment for hepatocellular carcinoma through activation of hepatic stellate cells. Int J Cancer 2014; 136:E3-13. [PMID: 25053237 DOI: 10.1002/ijc.29096] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2013] [Accepted: 07/10/2014] [Indexed: 12/29/2022]
Abstract
Fatty liver (FL) is associated with development of hepatocellular carcinoma (HCC). However, whether FL itself promotes the progression of HCC is unclear. We recently found that hepatic stellate cells (HSCs) were prominently activated in the steatotic liver. Here, we investigated whether steatotic livers promote HCC progression and whether HSCs of steatotic liver are associated with HCC progression. We implanted rat HCC cells into diet-induced steatotic livers in rats via portal vein injection. Thereafter, HSCs and HCC cells were co-implanted subcutaneously into nude rats. Migration and proliferation of HCC cells were measured, and activation of ERK and Akt in these cells was determined by western blotting. Chemokines secreted from HSCs and HCC cells were also evaluated by ELISA. Steatotic livers significantly promoted HCC metastasis compared with non-steatotic livers. Additionally, co-implantation of HCC cells with HSCs from steatotic livers produced significantly larger tumors in recipient rats as compared to those induced by HCC cells co-implanted with HSCs from normal livers (NLs). HSCs isolated from steatotic livers, compared with HSCs isolated from NLs, secreted greater amounts of interleukin-1α, vascular endothelial growth factor, and transforming growth factor-β. These cytokines may enhance the proliferation and migration of HCC cells by increasing the phosphorylation of ERK and Akt in HCC cells. Moreover, we noted that the Rho-kinase inhibitor deactivated activated HSCs and attenuated HCC progression. In conclusion, the rat steatotic liver microenvironment favors HCC metastasis, and this effect appears to be promoted by activated HSCs in the steatotic liver.
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Affiliation(s)
- Yoshihiro Mikuriya
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Japan
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31
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Wang ZM, Zhou LY, Liu BB, Jia QA, Dong YY, Xia YH, Ye SL. Rat hepatic stellate cells alter the gene expression profile and promote the growth, migration and invasion of hepatocellular carcinoma cells. Mol Med Rep 2014; 10:1725-33. [PMID: 25109274 PMCID: PMC4148379 DOI: 10.3892/mmr.2014.2435] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 11/15/2013] [Indexed: 01/27/2023] Open
Abstract
The aim of the present study was to examine the effects of activated hepatic stellate cells (HSCs) and their paracrine secretions, on hepatocellular cancer cell growth and gene expression in vitro and in vivo. Differentially expressed genes in McA-RH7777 hepatocellular carcinoma (HCC) cells following non-contact co-culture with activated stellate cells, were identified by a cDNA microarray. The effect of the co-injection of HCC cells and activated HSCs on tumor size in rats was also investigated. Non-contact co-culture altered the expression of 573 HCC genes by >2-fold of the control levels. Among the six selected genes, ELISA revealed increased protein levels of hepatic growth factor, matrix metalloproteinase-2 (MMP-2) and −9 (MMP-9). Incubation of HCC cells with medium conditioned by activated HSCs significantly increased the proliferation rate (P<0.001), migration rate and the number of invasive HCC cells (P=0.001). Co-injection of HCC cells and activated HSCs into rats significantly increased the weight of the resulting HCC tumors (P<0.01). The paracrine activity of activated HSCs markedly altered the gene expression profile of HCC cells and affected their growth, migration and invasiveness. The results from the present study indicate that the interaction between the activated HSCs and HCC has an important role in the development of HCC.
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Affiliation(s)
- Zhi-Ming Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Le-Yuan Zhou
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Bin-Bin Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Qin-An Jia
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Yin-Ying Dong
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Yun-Hong Xia
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Sheng-Long Ye
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
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O'Connor JW, Gomez EW. Biomechanics of TGFβ-induced epithelial-mesenchymal transition: implications for fibrosis and cancer. Clin Transl Med 2014; 3:23. [PMID: 25097726 PMCID: PMC4114144 DOI: 10.1186/2001-1326-3-23] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 07/02/2014] [Indexed: 12/18/2022] Open
Abstract
Fibrosis, a disease that results in loss of organ function, contributes to a significant number of deaths worldwide and sustained fibrotic activation has been suggested to increase the risk of developing cancer in a variety of tissues. Fibrogenesis and tumor progression are regulated in part through the activation and activity of myofibroblasts. Increasing evidence links myofibroblasts found within fibrotic lesions and the tumor microenvironment to a process termed epithelial-mesenchymal transition (EMT), a phenotypic change in which epithelial cells acquire mesenchymal characteristics. EMT can be stimulated by soluble signals, including transforming growth factor (TGF)-β, and recent studies have identified a role for mechanical cues in directing EMT. In this review, we describe the role that EMT plays in fibrogenesis and in the progression of cancer, with particular emphasis placed on biophysical signaling mechanisms that control the EMT program. We further describe specific TGFβ-induced intracellular signaling cascades that are affected by cell- and tissue-level mechanics. Finally, we highlight the implications of mechanical induction of EMT on the development of treatments and targeted intervention strategies for fibrosis and cancer.
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Affiliation(s)
- Joseph W O'Connor
- Department of Chemical Engineering, The Pennsylvania State University, 204 Fenske Laboratory, 16802 University Park, PA, USA
| | - Esther W Gomez
- Department of Chemical Engineering, The Pennsylvania State University, 204 Fenske Laboratory, 16802 University Park, PA, USA ; Department of Biomedical Engineering, The Pennsylvania State University, 16802 University Park, PA, USA
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Han S, Han L, Yao Y, Sun H, Zan X, Liu Q. Activated hepatic stellate cells promote hepatocellular carcinoma cell migration and invasion via the activation of FAK-MMP9 signaling. Oncol Rep 2013; 31:641-8. [PMID: 24284889 DOI: 10.3892/or.2013.2872] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 09/06/2013] [Indexed: 11/06/2022] Open
Abstract
Activated hepatic stellate cells (HSCs) are the major subtype of stromal cells in the liver tumor microenvironment which can promote the growth and migration of hepatocellular carcinoma (HCC) cells. However, the underlying mechanisms by which activated HSCs exert their oncogenic effects are not fully understood to date. In the present study, we investigated the number of activated HSCs and its clinicopathological significance in HCC and uncovered its correlation with focal adhesion kinase (FAK)-MMP9 signaling. A higher number of activated HSCs was associated with tumor invasion of the portal vein, advanced TNM stage and poorer tumor differentiation. The number of activated HSCs was positively correlated with the expression levels of p-FAK and MMP9 in HCC. Furthermore, we studied the effects of activated HSCs on the migration and invasion of HCC cells in vitro. Conditioned medium (CM) from activated HSCs or co-culture with activated HSCs significantly induced the migration and invasion of HCC cells. In addition, activation of FAK-MMP9 signaling in HCC was demonstrated in the presence of activated HSC-CM and of co-culture. Inhibition of FAK-MMP9 signaling in HCC cells with FAK short hairpin RNA (shRNA) abrogated the effects of activated HSCs on HCC cells. Taken together, our data suggest that activated HSCs in the tumor microenvironment promote HCC cell migration and invasion via activation of FAK-MMP9 signaling.
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Affiliation(s)
- Shaoshan Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of the College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Lei Han
- Department of Immunology and Pathogenic Biology, College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Yingmin Yao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of the College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Hao Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of the College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Xianfeng Zan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of the College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Qingguang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of the College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China
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Sun B, Zhang X, Cheng X, Zhang Y, Chen L, Shi L, Liu Z, Qian H, Wu M, Yin Z. Intratumoral hepatic stellate cells as a poor prognostic marker and a new treatment target for hepatocellular carcinoma. PLoS One 2013; 8:e80212. [PMID: 24278260 PMCID: PMC3835887 DOI: 10.1371/journal.pone.0080212] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Accepted: 09/30/2013] [Indexed: 12/29/2022] Open
Abstract
Hepatic stellate cells (HSCs), a specialized stromal cytotype in the liver, have been demonstrated to actively contribute to hepatocellular carcinoma (HCC) development. However, the previous studies were performed using HSC cell lines, and the prognostic value of intratumoral HSCs (tHSCs) was unclear. Here we isolated tHSCs from fresh human HCC tissues, and analyzed the abilities of tHSCs to promote HCC progression by using in vitro assays for cell viability, migration and invasion as well as epithelial-mesenchymal transition (EMT) phenotype. 252 HCC patients who underwent hepatectomy were enrolled for analysis of tHSCs and E-cadherin expression in tumor tissues, and 55 HCC patients for analysis of tHSCs in tumor tissues and circulating tumor cells (CTCs) in blood. Prognostic factors were then identified. The results showed that coculture of tHSCs with HCC cells had a stronger effect on HCC cell viability, migration and invasion, accompanied with the acquisition of epithelial-mesenchymal transition (EMT) phenotype. In vivo cotransplantation of HCC cells with tHSCs into nude mice more efficiently promoted tumor formation and growth. Icaritin, a known apoptosis inducer of HSCs, was demonstrated to effectively inhibit tHSC proliferation in vitro and tHSC-induced HCC-promoting effects in vivo. Clinical evidence indicated that tHSCs were rich in 45% of the HCC specimens, tHSC-rich subtypes were negatively correlated either with E-cadherin expression in tumor tissues (r = -0.256, p < 0.001) or with preoperative CTCs in blood (r = -0.287, p = 0.033), and were significantly correlated with tumor size (p = 0.027), TNM staging (p = 0.018), and vascular invasion (p = 0.008). Overall and recurrence-free survival rates of tHSC-rich patients were significantly worse than those for tHSC-poor patients. Multivariate analysis revealed tHSC-rich as an independent factor for overall and recurrence-free survival. In conclusion, tHSCs provide a promising prognostic biomarker and a new treatment target for HCC.
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Affiliation(s)
- Bin Sun
- Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xiaofeng Zhang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xianshuo Cheng
- Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yu Zhang
- Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lei Chen
- Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lehua Shi
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhenyu Liu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Haihua Qian
- Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Mengchao Wu
- Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhengfeng Yin
- Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- * E-mail:
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The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat Rev 2013; 40:558-66. [PMID: 24176790 DOI: 10.1016/j.ctrv.2013.10.001] [Citation(s) in RCA: 333] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Accepted: 10/06/2013] [Indexed: 12/14/2022]
Abstract
Non-small cell lung cancer (NSCLC) accounts for >80% of lung cancer cases and currently has an overall five-year survival rate of only 15%. Patients presenting with advanced stage NSCLC die within 18-months of diagnosis. Metastatic spread accounts for >70% of these deaths. Thus elucidation of the mechanistic basis of NSCLC-metastasis has potential to impact on patient quality of life and survival. Research on NSCLC metastasis has recently expanded to include non-cancer cell components of tumors-the stromal cellular compartment and extra-cellular matrix components comprising the tumor-microenvironment. Metastasis (from initial primary tumor growth through angiogenesis, intravasation, survival in the bloodstream, extravasation and metastatic growth) is an inefficient process and few released cancer cells complete the entire process. Micro-environmental interactions assist each of these steps and discovery of the mechanisms by which tumor cells co-operate with the micro-environment are uncovering key molecules providing either biomarkers or potential drug targets. The major sites of NSCLC metastasis are brain, bone, adrenal gland and the liver. The mechanistic basis of this tissue-tropism is beginning to be elucidated offering the potential to target stromal components of these tissues thus targeting therapy to the tissues affected. This review covers the principal steps involved in tumor metastasis. The role of cell-cell interactions, ECM remodeling and autocrine/paracrine signaling interactions between tumor cells and the surrounding stroma is discussed. The mechanistic basis of lung cancer metastasis to specific organs is also described. The signaling mechanisms outlined have potential to act as future drug targets minimizing lung cancer metastatic spread and morbidity.
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Arana S, Alves VAF, Sabino M, Tabata YA, Nonogaki S, Zaidan-Dagli ML, Hernandez-Blazquez FJ. Immunohistochemical evidence for myofibroblast-like cells associated with liver injury induced by aflatoxin B1 in rainbow trout (Oncorhynchus mykiss). J Comp Pathol 2013; 150:258-65. [PMID: 24016778 DOI: 10.1016/j.jcpa.2013.07.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Revised: 04/24/2013] [Accepted: 07/06/2013] [Indexed: 12/22/2022]
Abstract
In mammalian species, profibrogenic cells are activated to become myofibroblasts in response to liver damage. Few studies have examined hepatic myofibroblasts and their role in liver damage in teleosts. The aim of the present study was to investigate the involvement of myofibroblast-like cells in rainbow trout (Oncorhynchus mykiss) with hepatic damage induced by aflatoxin B1 (AFB1). Histopathological and immunohistochemical analyses characterized alterations in the liver stroma during the carcinogenic process. Anti-human α-smooth muscle actin (SMA) and anti-human desmin primary antibodies were used in immunohistochemistry. Only the anti-SMA reagent labelled cells in trout liver. In the livers of control fish, only smooth muscle in blood vessels and around bile ducts was labelled. In the livers from AFB1-treated fish, SMA-positive cells were present in the stroma surrounding neoplastic lesions and in areas of desmoplastic reaction. These observations indicate that in teleosts, as in mammals, the myofibroblast-like cell is involved in fibrosis associated with liver injury. Chronic liver injury induced in trout by aflatoxin may provide a useful model system for study of the evolution of such mechanisms.
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Affiliation(s)
- S Arana
- Department of Histology and Embryology, Institute of Biology, University of Campinas (UNICAMP), CP: 6109, CEP: 13083-970 Campinas, São Paulo, Brazil.
| | - V A F Alves
- Department of Pathology, School of Medicine, São Paulo University, São Paulo
| | - M Sabino
- Adolfo Lutz Institute, São Paulo, Brazil
| | - Y A Tabata
- Estação Experimental de Salmonicultura Dr. Ascânio de Faria, APTA, Secretaria de Agricultura e Abastecimento de São Paulo, São Paulo, Brazil
| | - S Nonogaki
- Adolfo Lutz Institute, São Paulo, Brazil
| | - M-L Zaidan-Dagli
- Department of Pathology, School of Veterinary Medicine and Animal Sciences, São Paulo University, São Paulo, Brazil
| | - F J Hernandez-Blazquez
- Department of Surgery, School of Veterinary Medicine and Animal Science, São Paulo University, São Paulo, Brazil
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Wang H, Chen L. Tumor microenviroment and hepatocellular carcinoma metastasis. J Gastroenterol Hepatol 2013; 28 Suppl 1:43-8. [PMID: 23855295 DOI: 10.1111/jgh.12091] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/06/2013] [Indexed: 12/16/2022]
Abstract
The cross talk between tumor cells and the surrounding peritumoral stroma has been extensively studied as a dynamic system involving the processes of hepatocarcinogenesis, tumor invasion, and metastasis in recent few decades. Besides hepatocytes, liver tumor microenvironments are generally classified into cellular and noncellular components, including hepatic stellate cells, fibroblasts, immune, endothelial, mesenchymal stem cells, together with growth factors, cytokines, extracellular matrix, hormone as well as viruses et al. The noncellular components manipulate hepatocellular carcinoma invasion and metastasis by facilitating epithelial-mesenchymal transition, increasing proteolytic activity of matrix metalloproteinases, and regulating antitumor immunity, etc. Because the main cause of death in hepatocellular carcinoma patients is tumor progression with metastasis, a better understanding of the interplay between hepatocytes and their environment during tumor metastasis may be helpful for the discovery of novel molecular targets.
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Affiliation(s)
- Hongyang Wang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
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38
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Association of tumor-associated fibroblasts with progression of hepatocellular carcinoma. Med Oncol 2013; 30:593. [PMID: 23794251 DOI: 10.1007/s12032-013-0593-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 04/25/2013] [Indexed: 12/12/2022]
Abstract
Interaction between tumor and stromal cells plays an important role in cancer progression. The aim of this study was to explore the effects of tumor-associated fibroblasts on regulation of hepatocellular carcinoma (HCC) progression. Sixty-five cases of HCC and the corresponding normal liver tissues were recruited for immunohistochemical assessment of α-smooth muscle actin (α-SMA) expression, a biomarker for activated fibroblasts. Clinicopathological data were also collected from HCC patients for association with α-SMA expression. Primary cell culture of fibroblasts from HCC tissues was used to generate conditioned medium for testing the effect on regulation of HCC cell migration capacity in the transwell cell migration assay. α-SMA protein was expressed in 84.0 % (21 out 25 cases) of the fibroblasts from the metastatic HCCs, 45 % (18/40) from HCCs without metastasis, and 19.2 % (5/26) from normal liver tissues, difference of which was statistically significant (P < 0.01). The expression of α-SMA protein in HCC tissues was associated with tumor thrombosis, poor pathology grade, advanced clinical stages, and lymph node metastasis. The conditioned medium from the primary cultured fibroblasts with α-SMA expression significantly promoted the migration capacity of HCC Hep3B cells compared to the heat-inactivated conditioned medium. The data from the current study demonstrated that expression of α-SMA protein in HCC fibroblasts associated with tumor metastasis and advanced clinical stages and that the conditioned medium from α-SMA-positive fibroblasts enhanced HCC cell migration. This study indicates that α-SMA protein might serve as a biomarker to predict HCC progression.
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39
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Dong HH, Xiang S, Liang HF, Li CH, Zhang ZW, Chen XP. The niche of hepatic cancer stem cell and cancer recurrence. Med Hypotheses 2013; 80:666-8. [DOI: 10.1016/j.mehy.2013.01.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Revised: 01/16/2013] [Accepted: 01/18/2013] [Indexed: 12/17/2022]
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Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 2013; 144:512-27. [PMID: 23313965 PMCID: PMC3578068 DOI: 10.1053/j.gastro.2013.01.002] [Citation(s) in RCA: 583] [Impact Index Per Article: 48.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Revised: 12/03/2012] [Accepted: 01/07/2013] [Indexed: 12/02/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver tumor and the third greatest cause of cancer-related death worldwide, and its incidence is increasing. Despite the significant improvement in management of HCC over the past 30 years, there are no effective chemoprevention strategies, and only one systemic therapy has been approved for patients with advanced tumors. This drug, sorafenib, acts on tumor cells and the stroma. HCC develops from chronically damaged tissue that contains large amounts of inflammation and fibrosis, which also promote tumor progression and resistance to therapy. Increasing our understanding of how stromal components interact with cancer cells and the signaling pathways involved could help identify new therapeutic and chemopreventive targets.
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Affiliation(s)
| | - Sara Toffanin
- Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York, USA
- Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, IRCSS Foundation, Milan, Italy
| | - Scott L. Friedman
- Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York, USA
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Tisch Cancer Institute), Mount Sinai School of Medicine, New York, New York, USA
| | - Josep M. Llovet
- Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York, USA
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Tisch Cancer Institute), Mount Sinai School of Medicine, New York, New York, USA
- HCC Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Liver Unit and Pathology Department. Hospital Clinic, Barcelona, Catalonia, Spain
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain
- University of Barcelona, Catalonia, Spain
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41
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Gao JJ, Inagaki Y, Xue X, Qu XJ, Tang W. c-Met: A potential therapeutic target for hepatocellular carcinoma. Drug Discov Ther 2012; 5:2-11. [PMID: 22466090 DOI: 10.5582/ddt.2011.v5.1.2] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The approval of receptor tyrosine kinase (RTK) targeted agent sorafenib as the first effective drug for the systemic treatment of advanced hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. A better understanding of HCC pathogenesis will lead to development of novel targeted treatments. As a typical member of the RTK family, c-Met represents an intriguing target for cancer therapy. The c-Met signaling pathway has been shown to be deregulated and to correlate with poor prognosis in a number of major human cancers. This review discusses the possibility of c-Met as a target in HCC treatment from the following respects: i) c-Met expression and activation profile in HCC, ii) relationship between c-Met and clinicopathologic state and prognosis of HCC, iii) role of c-Met signaling activity in HCC genesis and progression, and iv) strategy of c-Met pathway targeting therapy in HCC treatment.
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Affiliation(s)
- J J Gao
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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42
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Michaud NR, Jani JP, Hillerman S, Tsaparikos KE, Barbacci-Tobin EG, Knauth E, Putz H, Campbell M, Karam GA, Chrunyk B, Gebhard DF, Green LL, Xu JJ, Dunn MC, Coskran TM, Lapointe JM, Cohen BD, Coleman KG, Bedian V, Vincent P, Kajiji S, Steyn SJ, Borzillo GV, Los G. Biochemical and pharmacological characterization of human c-Met neutralizing monoclonal antibody CE-355621. MAbs 2012; 4:710-23. [PMID: 23007574 DOI: 10.4161/mabs.22160] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The c-Met proto-oncogene is a multifunctional receptor tyrosine kinase that is stimulated by its ligand, hepatocyte growth factor (HGF), to induce cell growth, motility and morphogenesis. Dysregulation of c-Met function, through mutational activation or overexpression, has been observed in many types of cancer and is thought to contribute to tumor growth and metastasis by affecting mitogenesis, invasion, and angiogenesis. We identified human monoclonal antibodies that bind to the extracellular domain of c-Met and inhibit tumor growth by interfering with ligand-dependent c-Met activation. We identified antibodies representing four independent epitope classes that inhibited both ligand binding and ligand-dependent activation of c-Met in A549 cells. In cells, the antibodies antagonized c-Met function by blocking receptor activation and by subsequently inducing downregulation of the receptor, translating to phenotypic effects in soft agar growth and tubular morphogenesis assays. Further characterization of the antibodies in vivo revealed significant inhibition of c-Met activity (≥ 80% lasting for 72-96 h) in excised tumors corresponded to tumor growth inhibition in multiple xenograft tumor models. Several of the antibodies identified inhibited the growth of tumors engineered to overexpress human HGF and human c-Met (S114 NIH 3T3) when grown subcutaneously in athymic mice. Furthermore, lead candidate antibody CE-355621 inhibited the growth of U87MG human glioblastoma and GTL-16 gastric xenografts by up to 98%. The findings support published pre-clinical and clinical data indicating that targeting c-Met with human monoclonal antibodies is a promising therapeutic approach for the treatment of cancer.
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Affiliation(s)
- Neil R Michaud
- Pfizer Global Research and Development, Groton, CT, USA.
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43
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Status and Development of The Tumor Microenvironment in Hepatocellular Carcinoma*. PROG BIOCHEM BIOPHYS 2012. [DOI: 10.3724/sp.j.1206.2011.00383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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44
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Wu SD, Ma YS, Fang Y, Liu LL, Fu D, Shen XZ. Role of the microenvironment in hepatocellular carcinoma development and progression. Cancer Treat Rev 2012; 38:218-25. [DOI: 10.1016/j.ctrv.2011.06.010] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2011] [Revised: 06/22/2011] [Accepted: 06/27/2011] [Indexed: 02/07/2023]
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Otranto M, Sarrazy V, Bonté F, Hinz B, Gabbiani G, Desmoulière A. The role of the myofibroblast in tumor stroma remodeling. Cell Adh Migr 2012; 6:203-19. [PMID: 22568985 PMCID: PMC3427235 DOI: 10.4161/cam.20377] [Citation(s) in RCA: 191] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Since its first description in wound granulation tissue, the myofibroblast has been recognized to be a key actor in the epithelial-mesenchymal cross-talk that plays a crucial role in many physiological and pathological situations, such as regulation of prostate development, ventilation-perfusion in lung alveoli or organ fibrosis. The presence of myofibroblasts in the stroma reaction to epithelial tumors is well established and many data are accumulating which suggest that the stroma compartment is an active participant in tumor onset and/or evolution. In this review we summarize the evidence in favor of this concept, the main mechanisms that regulate myofibroblast differentiation and function, as well as the biophysical and biochemical factors possibly involved in epithelial-stroma interactions, using liver carcinoma as main model, in view of achieving a better understanding of tumor progression mechanisms and of tools directed toward stroma as eventual therapeutic target.
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Affiliation(s)
- Marcela Otranto
- Department of Physiology, Faculty of Pharmacy, University of Limoges, Limoges, France
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46
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Liao R, Sun TW, Yi Y, Wu H, Li YW, Wang JX, Zhou J, Shi YH, Cheng YF, Qiu SJ, Fan J. Expression of TREM-1 in hepatic stellate cells and prognostic value in hepatitis B-related hepatocellular carcinoma. Cancer Sci 2012; 103:984-92. [PMID: 22417086 DOI: 10.1111/j.1349-7006.2012.02273.x] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Revised: 03/05/2012] [Accepted: 03/07/2012] [Indexed: 12/31/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a typical inflammation-related malignancy characterized by high postoperative recurrence and metastasis. Although several inflammatory cells and inflammatory signatures have been linked to poor prognosis, the inflammation-associated molecular mechanisms of HCC development and progression are largely unknown. Here we show that triggering receptor expressed in myeloid cells (TREM)-1, a transmembrane receptor expressing in myeloid cells, was also expressed in tumor-activated hepatic stellate cells (HSCs) and associated with the aggressive behavior of HCC cells. Enzyme-linked immunosorbent assay was used to measure the expression levels of soluble TREM-1 (sTREM-1) in activated hepatic stellate cells supernatant and 92 preoperative and postoperative plasmas of patients with malignancy and/or benign liver tumor/disease, respectively. Expression levels of TREM-1 were assessed by immunohistochemistry in tissue microarray from 240 patients with HCC. As a result, increased secretion of sTREM-1 from activated HSCs was observed after co-culture with HCC cell lines (P < 0.001), and conditioned medium collected from activated HSCs/cancer associated myofibroblasts (CAMFs) with or without agonist/inhibitor of TREM-1 significantly changed the migratory ability of HCC cells. The levels of sTREM-1 were significantly higher in patients with HCC than those with benign liver tumors (P < 0.005). Peritumoral density of TREM-1 was shown to be an independent prognosis predictor according to univariate (P < 0.001 for both overall survival and time to recurrence) and multivariate analysis (P = 0.008 for overall survival; P = 0.005 for time to recurrence). Thus, these observations suggest that TREM-1 is related to the aggressive tumor behavior and has potential value as a prognostic factor for HCC.
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Affiliation(s)
- Rui Liao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
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Lin XD, Chen SQ, Qi YL, Zhu JW, Tang Y, Lin JY. Overexpression of thrombospondin-1 in stromal myofibroblasts is associated with tumor growth and nodal metastasis in gastric carcinoma. J Surg Oncol 2012; 106:94-100. [DOI: 10.1002/jso.23037] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2011] [Accepted: 12/18/2011] [Indexed: 12/23/2022]
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48
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You H, Ding W, Dang H, Jiang Y, Rountree CB. c-Met represents a potential therapeutic target for personalized treatment in hepatocellular carcinoma. Hepatology 2011; 54:879-89. [PMID: 21618573 PMCID: PMC3181384 DOI: 10.1002/hep.24450] [Citation(s) in RCA: 163] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2011] [Accepted: 05/15/2011] [Indexed: 12/12/2022]
Abstract
UNLABELLED c-Met, a high-affinity receptor for hepatocyte growth factor (HGF), plays a critical role in cancer growth, invasion, and metastasis. Hepatocellular carcinoma (HCC) patients with an active HGF/c-Met signaling pathway have a significantly worse prognosis. Although targeting the HGF/c-Met pathway has been proposed for the treatment of multiple cancers, the effect of c-Met inhibition in HCC remains unclear. The human HCC cell lines Huh7, Hep3B, MHCC97-L, and MHCC97-H were used in this study to investigate the effect of c-Met inhibition using the small molecule selective c-Met tyrosine kinase inhibitor PHA665752. MHCC97-L and MHCC97-H cells demonstrate a mesenchymal phenotype with decreased expression of E-cadherin and increased expression of c-Met, fibronectin, and Zeb2 compared with Huh7 and Hep3B cells, which have an epithelial phenotype. PHA665752 treatment blocked phosphorylation of c-Met and downstream phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase/Erk pathways, inhibited cell proliferation, and induced apoptosis in c-Met-positive MHCC97-L and MHCC97-H cells. In xenograft models, administration of PHA665752 significantly inhibited c-Met-positive MHCC97-L and MHCC97-H tumor growth, and PHA665752-treated tumors demonstrated marked reduction of both c-Met phosphorylation and cell proliferation. c-Met-negative Huh7 and Hep3B cells were not affected by c-Met inhibitor treatment in vitro or in vivo. In addition, c-Met-positive MHCC97-L and MHCC97-H cells demonstrated cancer stem cell-like characteristics, such as resistance to chemotherapy, tumor sphere formation, and increased expression of CD44 and ABCG2, and PHA665752 treatment suppressed tumor sphere formation and inhibited CD44 expression. CONCLUSION c-Met represents a potential target of personalized treatment for HCC with an active HGF/c-Met pathway.
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Affiliation(s)
- Hanning You
- Department of Pediatrics and Pharmacology, The Pennsylvania State University, College of Medicine, Hershey PA 17033, Division of Nephrology, Department of Medicine, The Pennsylvania State University, College of Medicine, Hershey PA 17033
| | - Wei Ding
- Department of Pediatrics and Pharmacology, The Pennsylvania State University, College of Medicine, Hershey PA 17033
| | - Hien Dang
- Department of Pediatrics and Pharmacology, The Pennsylvania State University, College of Medicine, Hershey PA 17033
| | - Yixing Jiang
- Penn State Hershey Cancer Institute, The Pennsylvania State University, College of Medicine, Hershey PA 17033
| | - C. Bart Rountree
- Department of Pediatrics and Pharmacology, The Pennsylvania State University, College of Medicine, Hershey PA 17033, Penn State Hershey Cancer Institute, The Pennsylvania State University, College of Medicine, Hershey PA 17033,Corresponding Author: C. Bart Rountree, M.D., Department of Pediatrics and Pharmacology, The Pennsylvania State University, College of Medicine, 500 University Drive, H085, Hershey PA 17033, 717-531-5901 voice, 717-531-0653 fax,
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Ji Z, Long H, Hu Y, Qiu X, Chen X, Li Z, Fan D, Ma B, Fan Q. Expression of MDR1, HIF-1α and MRP1 in sacral chordoma and chordoma cell line CM-319. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2010; 29:158. [PMID: 21143841 PMCID: PMC3017037 DOI: 10.1186/1756-9966-29-158] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2010] [Accepted: 12/08/2010] [Indexed: 01/01/2023]
Abstract
Background Chordoma was a typically slow-growing tumor. The therapeutic approach to chordoma had traditionally relied mainly on surgical therapy. And the main reason for therapeutic failure was resistance to chemotherapy and radiotherapy. However the refractory mechanism was not clear. The aim of this study was to investigate the expression of three genes (MDR1, HIF-1α and MRP1) associated with resistance to chemotherapy and radiotherapy in chordoma and chordoma cell line CM-319. Materials and methods Using immunohistochemical techniques, the expression of MDR1, HIF-1α and MRP1 was investigated in 50 chordoma specimen. Using RT-PCR and Western blot, the expression of MDR1, HIF-1α and MRP1 was investigated in chordoma and chordoma cell line CM-319. Results Expression of MDR1, HIF-1α and MRP1 was observed in 10%, 80% and 74% of all cases, respectively. Expression of MRP1 was correlated with HIF-1α. On the other hand, expression of MDR1 was not correlated with the expression of HIF-1α or MRP1. The expression of HIF-1α and MRP1 was observed, but MDR1 was not observed in chordoma and CM-319. Conclusion Expression of HIF-1α and MRP1 was observed in most chordoma specimen and CM-319 cell line; expression of HIF-1α correlated with MRP1. HIF-1α and MRP1 may play a role in the multidrug resistance of chordoma to chemotherapy.
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Affiliation(s)
- Zhengang Ji
- Department of Orthopedic Surgery, Orthopedics Oncology Institute of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, 710038, P.R. China
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Xu D, Matsuo Y, Ma J, Koide S, Ochi N, Yasuda A, Funahashi H, Okada Y, Takeyama H. Cancer cell-derived IL-1α promotes HGF secretion by stromal cells and enhances metastatic potential in pancreatic cancer cells. J Surg Oncol 2010; 102:469-77. [PMID: 20872950 DOI: 10.1002/jso.21530] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND AND OBJECTIVES Interleukin (IL)-1α and hepatocyte growth factor (HGF) play an important role in pancreatic cancer proliferation, angiogenesis, and invasiveness. The aim of this study was to investigate the cooperative role of HGF and IL-1α in metastatic processes promoted by interactions between pancreatic cancer cells and stromal cells. METHODS Expression of IL-1α and HGF mRNA and protein was determined by RT-PCR and ELISA. The effect of HGF on metastatic potential was evaluated by proliferation, invasion, and angiogenesis assays using an in vitro system consisting of co-cultured tumor cells and stromal cells. RESULTS IL-1α expression was closely correlated with metastatic potential, and cancer cell-derived IL-1α significantly promoted HGF expression by fibroblasts (P < 0.01). HGF not only enhanced the invasiveness and proliferation of pancreatic cancer cells, but also enhanced migration and proliferation of human umbilical vein endothelial cells (HUVECs). HGF significantly enhanced HUVEC tube formation (P < 0.01). Furthermore, the high liver-metastatic pancreatic cancer cell line (BxPC-3), which secretes IL-1α, significantly enhanced HUVEC tube formation compared with the low liver-metastatic cell line (Capan-2), which does not produce IL-1α (P < 0.01). CONCLUSION Autocrine IL-1α and paracrine HGF co-enhance the metastatic potential of pancreatic cancer cells via both IL-1α and HGF signaling pathways.
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Affiliation(s)
- Donghui Xu
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science, Mizuhoku, Nagoya, Japan
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