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1
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Yang Z, Cao T, Yang K, Ren Z, Kan Q, Zhou Y. The effect and mechanism of CDK11 in promoting breast cancer cell proliferation, migration, and doxorubicin resistance by regulating EGFR. Panminerva Med 2024; 66:329-331. [PMID: 38127061 DOI: 10.23736/s0031-0808.23.04983-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023]
Affiliation(s)
- Zhe Yang
- Academy of Medical Science, Zhengzhou University, Zhengzhou, China
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory for Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Tianze Cao
- Academy of Medical Science, Zhengzhou University, Zhengzhou, China
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory for Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kaiqing Yang
- Academy of Medical Science, Zhengzhou University, Zhengzhou, China
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory for Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhe Ren
- Academy of Medical Science, Zhengzhou University, Zhengzhou, China
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory for Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Quancheng Kan
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China -
- Henan Key Laboratory for Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yubing Zhou
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory for Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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2
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Gujarathi R, Franses JW, Pillai A, Liao CY. Targeted therapies in hepatocellular carcinoma: past, present, and future. Front Oncol 2024; 14:1432423. [PMID: 39267840 PMCID: PMC11390354 DOI: 10.3389/fonc.2024.1432423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 08/13/2024] [Indexed: 09/15/2024] Open
Abstract
Targeted therapies are the mainstay of systemic therapies for patients with advanced, unresectable, or metastatic hepatocellular carcinoma. Several therapeutic targets, such as c-Met, TGF-β, and FGFR, have been evaluated in the past, though results from these clinical studies failed to show clinical benefit. However, these remain important targets for the future with novel targeted agents and strategies. The Wnt/β-catenin signaling pathway, c-Myc oncogene, GPC3, PPT1 are exciting novel targets, among others, currently undergoing evaluation. Through this review, we aim to provide an overview of previously evaluated and potentially novel therapeutic targets and explore their continued relevance in ongoing and future studies for HCC.
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Affiliation(s)
- Rushabh Gujarathi
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Joseph W Franses
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Anjana Pillai
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, University of Chicago, Chicago, IL, United States
| | - Chih-Yi Liao
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL, United States
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3
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Fujiwara A, Takemura K, Tanaka A, Matsumoto M, Katsuyama M, Okanoue T, Yamaguchi K, Itoh Y, Iwata K, Amagase K, Umemura A. Carfilzomib shows therapeutic potential for reduction of liver fibrosis by targeting hepatic stellate cell activation. Sci Rep 2024; 14:19288. [PMID: 39164386 PMCID: PMC11335859 DOI: 10.1038/s41598-024-70296-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 08/14/2024] [Indexed: 08/22/2024] Open
Abstract
Because hepatic stellate cells (HSCs) play a major role in fibrosis, we focused on HSCs as a potential target for the treatment of liver fibrosis. In this study, we attempted to identify drug candidates to inactivate HSCs and found that several proteasome inhibitors (PIs) reduced HSC viability. Our data showed that a second-generation PI, carfilzomib (CZM), suppressed the expression of fibrotic markers in primary murine HSCs at low concentrations of 5 or 10 nM. Since CZM was not toxic to HSCs up to a concentration of 12.5 nM, we examined its antifibrotic effects further. CZM achieved a clear reduction in liver fibrosis in the carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis without worsening of liver injury. Mechanistically, RNA sequence analysis of primary HSCs revealed that CZM inhibits mitosis in HSCs. In the CCl4-injured liver, amphiregulin, which is known to activate mitogenic signaling pathways and fibrogenic activity and is upregulated in murine and human metabolic dysfunction-associated steatohepatitis (MASH), was downregulated by CZM administration, leading to inhibition of mitosis in HSCs. Thus, CZM and next-generation PIs in development could be potential therapeutic agents for the treatment of liver fibrosis via inactivation of HSCs without liver injury.
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Affiliation(s)
- Ayana Fujiwara
- Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
- Laboratory of Pharmacology and Pharmacotherapeutics, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, 525-8577, Japan
| | - Keisuke Takemura
- Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Anna Tanaka
- Laboratory of Pharmacology and Pharmacotherapeutics, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, 525-8577, Japan
| | - Misaki Matsumoto
- Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
- Department of Clinical Pharmacology and Pharmacotherapy, Wakayama Medical University, Wakayama, Japan
| | - Masato Katsuyama
- Radioisotope Center, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Takeshi Okanoue
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka, Japan
| | - Kanji Yamaguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazumi Iwata
- Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Kikuko Amagase
- Laboratory of Pharmacology and Pharmacotherapeutics, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, 525-8577, Japan
| | - Atsushi Umemura
- Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
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4
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Gonzalez-Sanchez E, Vaquero J, Caballero-Diaz D, Grzelak J, Fusté NP, Bertran E, Amengual J, Garcia-Saez J, Martín-Mur B, Gut M, Esteve-Codina A, Alay A, Coulouarn C, Calero-Perez S, Valdecantos P, Valverde AM, Sánchez A, Herrera B, Fabregat I. The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche. J Pathol 2024; 263:482-495. [PMID: 38872438 DOI: 10.1002/path.6299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 03/19/2024] [Accepted: 04/25/2024] [Indexed: 06/15/2024]
Abstract
Liver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of pro-fibrotic factors are not well characterized. Epidermal growth factor receptor (EGFR) signaling in hepatocytes is essential for the regenerative processes of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Our group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes (ΔEGFR mice). Here, we have analyzed the response of WT and ΔEGFR mice to chronic treatment with carbon tetrachloride (CCl4), which induces a pro-inflammatory and fibrotic process in the liver. The results indicated that the hallmarks of liver fibrosis were attenuated in CCl4-treated ΔEGFR mice when compared with CCl4-treated WT mice, coinciding with a faster resolution of the fibrotic process and ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable increase in the population of M2 macrophages, more related to fibrosis resolution, as well as in the population of lymphocytes related to eradication of the damage. Transcriptome analysis of hepatocytes, and secretome studies of extracellular media from in vitro experiments, allowed us to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro-fibrotic and pro-inflammatory mediators; these have consequences for the deposition of extracellular matrix proteins, as well as for the immune microenvironment. Overall, our study uncovered novel mechanistic insights regarding EGFR kinase-dependent actions in hepatocytes that reveal its key role in chronic liver damage. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Grants
- EHDG1703 CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases
- CERCA Programme/Generalitat de Catalunya
- CIVP20A6593 Fundacion Ramon Areces
- PID2019-108651RJ-I00 Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- PID2021-122551OB-100 Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- PID-2021-122766OB-100 Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- RTC2019-007125-1 Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- RTI2018-094052-B-100 Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- RTI2018-094079-B-100 Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- RTI2018-099098-B-100 Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- RYC2021-034121-I Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- European Regional Development Fund
- Instituto de Salud Carlos III
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Affiliation(s)
- Ester Gonzalez-Sanchez
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
- Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- Department of Physiology and Pharmacology, Faculty of Pharmacy, University of Salamanca, Salamanca, Spain
| | - Javier Vaquero
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
- Centro de Investigación del Cancer and Instituto de Biología Molecular y Celular del Cancer, CSIC-Universidad de Salamanca, Salamanca, Spain
| | - Daniel Caballero-Diaz
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
| | - Jan Grzelak
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
| | - Noel P Fusté
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
| | - Esther Bertran
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
| | - Josep Amengual
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
| | - Juan Garcia-Saez
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
- Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Beatriz Martín-Mur
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Marta Gut
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
| | - Anna Esteve-Codina
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Ania Alay
- Unit of Bioinformatics for Precision Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain
- Preclinical and Experimental Research in Thoracic Tumors (PReTT), Oncobell Program, IDIBELL, L'Hospitalet de Llobregat, Spain
| | - Cedric Coulouarn
- Inserm, Univ Rennes, OSS (Oncogenesis, Stress, Signaling) UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France
| | - Silvia Calero-Perez
- Biomedical Research Institute Sols-Morreale, Spanish National Research Council and Autonomous University of Madrid (IIBM, CSIC-UAM), Madrid, Spain
- Biomedical Research Networking Center in Diabetes and Associated Metabolic Disorders (CIBERDEM); ISCIII, Madrid, Spain
| | - Pilar Valdecantos
- Biomedical Research Institute Sols-Morreale, Spanish National Research Council and Autonomous University of Madrid (IIBM, CSIC-UAM), Madrid, Spain
- Biomedical Research Networking Center in Diabetes and Associated Metabolic Disorders (CIBERDEM); ISCIII, Madrid, Spain
| | - Angela M Valverde
- Biomedical Research Institute Sols-Morreale, Spanish National Research Council and Autonomous University of Madrid (IIBM, CSIC-UAM), Madrid, Spain
- Biomedical Research Networking Center in Diabetes and Associated Metabolic Disorders (CIBERDEM); ISCIII, Madrid, Spain
| | - Aránzazu Sánchez
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
- Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Blanca Herrera
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
- Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Isabel Fabregat
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
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Zhou XQ, Li YP, Dang SS. Precision targeting in hepatocellular carcinoma: Exploring ligand-receptor mediated nanotherapy. World J Hepatol 2024; 16:164-176. [PMID: 38495282 PMCID: PMC10941735 DOI: 10.4254/wjh.v16.i2.164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/10/2024] [Accepted: 01/18/2024] [Indexed: 02/27/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and poses a major challenge to global health due to its high morbidity and mortality. Conventional chemotherapy is usually targeted to patients with intermediate to advanced stages, but it is often ineffective and suffers from problems such as multidrug resistance, rapid drug clearance, nonspecific targeting, high side effects, and low drug accumulation in tumor cells. In response to these limitations, recent advances in nanoparticle-mediated targeted drug delivery technologies have emerged as breakthrough approaches for the treatment of HCC. This review focuses on recent advances in nanoparticle-based targeted drug delivery systems, with special attention to various receptors overexpressed on HCC cells. These receptors are key to enhancing the specificity and efficacy of nanoparticle delivery and represent a new paradigm for actively targeting and combating HCC. We comprehensively summarize the current understanding of these receptors, their role in nanoparticle targeting, and the impact of such targeted therapies on HCC. By gaining a deeper understanding of the receptor-mediated mechanisms of these innovative therapies, more effective and precise treatment of HCC can be achieved.
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Affiliation(s)
- Xia-Qing Zhou
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Ya-Ping Li
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Shuang-Suo Dang
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
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Lazzaro A, Hartshorn KL. A Comprehensive Narrative Review on the History, Current Landscape, and Future Directions of Hepatocellular Carcinoma (HCC) Systemic Therapy. Cancers (Basel) 2023; 15:cancers15092506. [PMID: 37173972 PMCID: PMC10177076 DOI: 10.3390/cancers15092506] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 04/18/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
We provide a comprehensive review of current approved systemic treatment strategies for advanced hepatocellular carcinoma (HCC), starting with the phase III clinical trial of sorafenib which was the first to definitively show a survival benefit. After this trial, there was an initial period of little progress. However, in recent years, an explosion of new agents and combinations of agents has resulted in a markedly improved outlook for patients. We then provide the authors' current approach to therapy, i.e., "How We Treat HCC". Promising future directions and important gaps in therapy that persist are finally reviewed. HCC is a highly prevalent cancer worldwide and the incidence is growing due not only to alcoholism, hepatitis B and C, but also to steatohepatitis. HCC, like renal cell carcinoma and melanoma, is a cancer largely resistant to chemotherapy but the advent of anti-angiogenic, targeted and immune therapies have improved survival for all of these cancers. We hope this review will heighten interest in the field of HCC therapies, provide a clear outline of the current data and strategy for treatment, and sensitize readers to new developments that are likely to emerge in the near future.
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Affiliation(s)
- Alexander Lazzaro
- Department of Medicine, Boston Medical Center, Boston, MA 02118, USA
| | - Kevan L Hartshorn
- Section of Hematology Oncology, Boston University Chobanian and Avedisian School of Medicine, Boston Medical Center, Boston, MA 02118, USA
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7
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Poojari R, Mohanty B, Kadwad V, Suryawanshi D, Chaudhari P, Khade B, Srivastava R, Gupta S, Panda D. Combinatorial cetuximab targeted polymeric nanocomplexes reduce PRC1 level and abrogate growth of metastatic hepatocellular carcinoma in vivo with efficient radionuclide uptake. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2022; 41:102529. [PMID: 35104671 DOI: 10.1016/j.nano.2022.102529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 12/27/2021] [Accepted: 01/16/2022] [Indexed: 06/14/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most aggressive form of cancer with poor drug responses. Developing an effective drug treatment remains a major unmet clinical need for HCC. We report a comprehensive study of combinatorial Cetuximab (Cet) targeted polymeric poly(D, L-lactide-co-glycolide)-b-poly(ethylene glycol) nanocomplexes delivery of Combretastatin A4 (CA4) and 2-Methoxyestradiol (2ME) (Cet-PLGA-b-PEG-CA4 NP + Cet-PLGA-b-PEG-2ME NP) against metastatic HCC in SCID mice. 125I-Cet-PLGA-b-PEG NP showed potent accumulation and retention in HCC tumors with longer circulation time up to 48 h (18 ± 1.0% ID/g, P < .0001). Combinatorial treatment with targeted polymeric nanocomplexes presented significant tumor growth inhibition (85%, P < .0001) than the free drug combinatorial counterpart, effectively inhibited orthotopic HCC and prevented lung metastasis. Combinatorial nanocomplexes treatment significantly blocked PRC1, a novel target of therapeutic response against HCC. Thus, the combinatorial cetuximab-targeted polymeric nanocomplexes possess superior antitumor activity against metastatic HCC and provide supports for the clinical translation ahead.
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Affiliation(s)
- Radhika Poojari
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India.
| | - Bhabani Mohanty
- Comparative Oncology and Small Animal Imaging Facility, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Vijay Kadwad
- Radiopharmaceuticals Production, Board of Radiation and Isotope Technology (BRIT), Navi Mumbai, India
| | | | - Pradip Chaudhari
- Comparative Oncology and Small Animal Imaging Facility, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India; Homi Bhabha National Institute (HBNI), Training School Complex, Anushakti Nagar, Mumbai, India
| | - Bharat Khade
- Epigenetics and Chromatin Biology Group, ACTREC-TMC, Navi Mumbai, India
| | - Rohit Srivastava
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
| | - Sanjay Gupta
- Epigenetics and Chromatin Biology Group, ACTREC-TMC, Navi Mumbai, India; Homi Bhabha National Institute (HBNI), Training School Complex, Anushakti Nagar, Mumbai, India
| | - Dulal Panda
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India.
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Zheng P, Huang Z, Tong DC, Zhou Q, Tian S, Chen BW, Ning DM, Guo YM, Zhu WH, Long Y, Xiao W, Deng Z, Lei YC, Tian XF. Frankincense myrrh attenuates hepatocellular carcinoma by regulating tumor blood vessel development through multiple epidermal growth factor receptor-mediated signaling pathways. World J Gastrointest Oncol 2022; 14:450-477. [PMID: 35317323 PMCID: PMC8919004 DOI: 10.4251/wjgo.v14.i2.450] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 11/19/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In traditional Chinese medicine (TCM), frankincense and myrrh are the main components of the antitumor drug Xihuang Pill. These compounds show anticancer activity in other biological systems. However, whether frankincense and/or myrrh can inhibit the occurrence of hepatocellular carcinoma (HCC) is unknown, and the potential molecular mechanism(s) has not yet been determined.
AIM To predict and determine latent anti-HCC therapeutic targets and molecular mechanisms of frankincense and myrrh in vivo.
METHODS In the present study, which was based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (http://tcmspw.com/tcmsp.php), Universal Protein database (http://www.uniprot.org), GeneCards: The Human Gene Database (http://www.genecards.org/) and Comparative Toxicogenomics Database (http://www.ctdbase.org/), the efficacy of and mechanism by which frankincense and myrrh act as anti-HCC compounds were predicted. The core prediction targets were screened by molecular docking. In vivo, SMMC-7721 human liver cancer cells were transplanted as xenografts into nude mice to establish a subcutaneous tumor model, and two doses of frankincense plus myrrh or one dose of an EGFR inhibitor was administered to these mice continuously for 14 d. The tumors were collected and evaluated: the tumor volume and growth rate were gauged to evaluate tumor growth; hematoxylin-eosin staining was performed to estimate histopathological changes; immunofluorescence (IF) was performed to detect the expression of CD31, α-SMA and collagen IV; transmission electron microscopy (TEM) was conducted to observe the morphological structure of vascular cells; enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of secreted HIF-1α and TNF-α; reverse transcription-polymerase chain reaction (RT-qPCR) was performed to measure the mRNA expression of HIF-1α, TNF-α, VEGF and MMP-9; and Western blot (WB) was performed to determine the levels of proteins expressed in the EGFR-mediated PI3K/Akt and MAPK signaling pathways.
RESULTS The results of the network pharmacology analysis showed that there were 35 active components in the frankincense and myrrh extracts targeting 151 key targets. The molecular docking analysis showed that both boswellic acid and stigmasterol showed strong affinity for the targets, with the greatest affinity for EGFR. Frankincense and myrrh treatment may play a role in the treatment of HCC by regulating hypoxia responses and vascular system-related pathological processes, such as cytokine-receptor binding, and pathways, such as those involving serine/threonine protein kinase complexes and MAPK, HIF-1 and ErbB signaling cascades. The animal experiment results were verified. First, we found that, through frankincense and/or myrrh treatment, the volume of subcutaneously transplanted HCC tumors was significantly reduced, and the pathological morphology was attenuated. Then, IF and TEM showed that frankincense and/or myrrh treatment reduced CD31 and collagen IV expression, increased the coverage of perivascular cells, tightened the connection between cells, and improved the shape of blood vessels. In addition, ELISA, RT-qPCR and WB analyses showed that frankincense and/or myrrh treatment inhibited the levels of hypoxia-inducible factors, inflammatory factors and angiogenesis-related factors, namely, HIF-1α, TNF-α, VEGF and MMP-9. Furthermore, mechanistic experiments illustrated that the effect of frankincense plus myrrh treatment was similar to that of an EGFR inhibitor with regard to controlling EGFR activation, thereby inhibiting the phosphorylation activity of its downstream targets: the PI3K/Akt and MAPK (ERK, p38 and JNK) pathways.
CONCLUSION In summary, frankincense and myrrh treatment targets tumor blood vessels to exert anti-HCC effects via EGFR-activated PI3K/Akt and MAPK signaling pathways, highlighting the potential of this dual TCM compound as an anti-HCC candidate.
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Affiliation(s)
- Piao Zheng
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
- Department of Integrated Traditional Chinese and Western Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Zhen Huang
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Dong-Chang Tong
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Qing Zhou
- The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha 410021, Hunan Province, China
| | - Sha Tian
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Bo-Wei Chen
- The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha 410021, Hunan Province, China
| | - Di-Min Ning
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Yin-Mei Guo
- Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Wen-Hao Zhu
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Yan Long
- The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha 410021, Hunan Province, China
| | - Wei Xiao
- Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Zhe Deng
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Yi-Chen Lei
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Xue-Fei Tian
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
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9
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Théret N, Bouezzeddine F, Azar F, Diab-Assaf M, Legagneux V. ADAM and ADAMTS Proteins, New Players in the Regulation of Hepatocellular Carcinoma Microenvironment. Cancers (Basel) 2021; 13:cancers13071563. [PMID: 33805340 PMCID: PMC8037375 DOI: 10.3390/cancers13071563] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Members of the adamalysin family are multi-domain proteins involved in many cancer-related functions. In this review, we will examine the literature on the involvement of adamalysins in hepatocellular carcinoma progression and their importance in the tumor microenvironment where they regulate the inflammatory response and the epithelial–mesenchymal transition. We complete this review with an analysis of adamalysin expression in a large cohort of patients with hepatocellular carcinoma from The Cancer Genome Atlas (TCGA) database. These original results give a new insight into the involvement of all adamalysins in the primary liver cancer. Abstract The tumor microenvironment plays a major role in tumor growth, invasion and resistance to chemotherapy, however understanding how all actors from microenvironment interact together remains a complex issue. The tumor microenvironment is classically represented as three closely connected components including the stromal cells such as immune cells, fibroblasts, adipocytes and endothelial cells, the extracellular matrix (ECM) and the cytokine/growth factors. Within this space, proteins of the adamalysin family (ADAM for a disintegrin and metalloproteinase; ADAMTS for ADAM with thrombospondin motifs; ADAMTSL for ADAMTS-like) play critical roles by modulating cell–cell and cell–ECM communication. During last decade, the implication of adamalysins in the development of hepatocellular carcinoma (HCC) has been supported by numerous studies however the functional characterization of most of them remain unsettled. In the present review we propose both an overview of the literature and a meta-analysis of adamalysins expression in HCC using data generated by The Cancer Genome Atlas (TCGA) Research Network.
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Affiliation(s)
- Nathalie Théret
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en santé, Environnement et Travail)-UMR_S1085, University of Rennes 1, 35000 Rennes, France; (F.A.); (V.L.)
- Correspondence:
| | - Fidaa Bouezzeddine
- Molecular Cancer and Pharmaceutical Biology Laboratory, Faculty of Sciences II, Lebanese University Fanar, 1500 Beirut, Lebanon; (F.B.); (M.D.-A.)
| | - Fida Azar
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en santé, Environnement et Travail)-UMR_S1085, University of Rennes 1, 35000 Rennes, France; (F.A.); (V.L.)
| | - Mona Diab-Assaf
- Molecular Cancer and Pharmaceutical Biology Laboratory, Faculty of Sciences II, Lebanese University Fanar, 1500 Beirut, Lebanon; (F.B.); (M.D.-A.)
| | - Vincent Legagneux
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en santé, Environnement et Travail)-UMR_S1085, University of Rennes 1, 35000 Rennes, France; (F.A.); (V.L.)
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10
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Yang F, Xu W, Pei Y. Amphiregulin induces interleukin-8 production and cell proliferation in lung epithelial cells through PI3K-Akt/ ERK pathways. EUR J INFLAMM 2021. [DOI: 10.1177/2058739221998202] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Amphiregulin (AR), belongs to the epidermal growth factor (EGF) family, is able to induce a series of pathological and physiological responses by binding and activating epidermal growth factor receptor (EGFR). Interleukin-8 (IL-8) or CXCL8, a pro-inflammatory chemokine, has been suggested to be involved in tumor cell proliferation and inflammatory microenvironment via transactivation of the EGFR. However, whether there is a crosstalk between AR with IL-8 during inflammatory response remain to be fully understood. The current study was designed to investigate the possible mechanism of the interactions between AR and IL-8 production in human lung epithelial cells in vitro. Lung epithelial A549 cells were stimulated with lipopolysaccharide (LPS) to generate ALI model. LPS-induced AR and IL-8 production by A549 cells was measured by real-time PCR, Western Blot, and ELISA. The AR neutralizing antibody, PI3K specific inhibitor LY294002, JNK specific inhibitor SP60012, ERK specific inhibitor PD98089, and p38 inhibitor SB203580 were used to investigate the role of these signal pathways in LPS-induced cell proliferation, AR and IL-8 expression. LPS could induce AR through PI3K/Akt and ERK signal pathways. Furthermore, LPS induced AR promoted the production of IL-8 requires activation of EGFR, PI3K/Akt, and ERK signal pathways. The neutralizing antibody to AR prevented production of IL-8 induced by LPS. Treatment with Erlotinib, PI3K inhibitors, ERK inhibitor significantly inhibited AR-induced IL-8 production and cell proliferation. Our data indicate that a distinct role of EGFR–PI3K–Akt/ERK pathway as a bridge of interaction between AR and IL-8 production, as one of potential mechanisms to regulate inflammation and cell proliferation in human lung epithelial cells.
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Affiliation(s)
- Fangfang Yang
- Respiratory and Critical Care Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China
| | - Wei Xu
- Respiratory and Critical Care Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China
| | - Yanli Pei
- Respiratory and Critical Care Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China
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11
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Elbadawy M, Yamanaka M, Goto Y, Hayashi K, Tsunedomi R, Hazama S, Nagano H, Yoshida T, Shibutani M, Ichikawa R, Nakahara J, Omatsu T, Mizutani T, Katayama Y, Shinohara Y, Abugomaa A, Kaneda M, Yamawaki H, Usui T, Sasaki K. Efficacy of primary liver organoid culture from different stages of non-alcoholic steatohepatitis (NASH) mouse model. Biomaterials 2020; 237:119823. [PMID: 32044522 DOI: 10.1016/j.biomaterials.2020.119823] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 01/21/2020] [Accepted: 01/24/2020] [Indexed: 12/12/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is associated with liver fibrosis and cirrhosis, which eventually leads to hepatocellular carcinoma. Although several animal models were developed to understand the mechanisms of NASH pathogenesis and progression, it remains obscure. A 3D organoid culture system can recapitulate organ structures and maintain gene expression profiles of original tissues. We therefore tried to generate liver organoids from different degrees [defined as mild (NASH A), moderate (NASH B) and severe (NASH C)] of methionine- and choline-deficient diet-induced NASH model mice and analyzed the difference of their architecture, cell components, organoid-forming efficacy, and gene expression profiles. Organoids from each stage of NASH model mice were successfully generated. Interestingly, epithelial-mesenchymal transition was observed in NASH C organoids. Expression of Collagen I and an activated hepatic stellite cell marker, α-sma was upregulated in the liver organoids from NASH B and C mice. The analysis of RNA sequencing revealed that several novel genes were upregulated in all NASH liver organoids. These results suggest that our generated liver organoids from different stages of NASH diseased mice might become a useful tool for in vitro studies of the molecular mechanism of NASH development and also for identifying novel biomarkers for early diagnosis of NASH disease.
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Affiliation(s)
- Mohamed Elbadawy
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan; Department of Pharmacology, Faculty of Veterinary Medicine, Benha University, 13736, Moshtohor, Toukh, Elqaliobiya, Egypt
| | - Megumi Yamanaka
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Yuta Goto
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Kimika Hayashi
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Ryouichi Tsunedomi
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Shoichi Hazama
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan; Department of Translational Research and Developmental Therapeutics Against Cancer, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Toshinori Yoshida
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Makoto Shibutani
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Ryo Ichikawa
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Junta Nakahara
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Tsutomu Omatsu
- Research and Education Center for Prevention of Global Infectious Disease of Animals, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Tetsuya Mizutani
- Research and Education Center for Prevention of Global Infectious Disease of Animals, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Yukie Katayama
- Research and Education Center for Prevention of Global Infectious Disease of Animals, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Yuta Shinohara
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan; Pet Health & Food Division, Iskara Industry CO., LTD, 1-14-2, Nihonbashi, Chuo-ku, Tokyo, 103-0027, Japan
| | - Amira Abugomaa
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Masahiro Kaneda
- Laboratory of Veterinary Anatomy, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Hideyuki Yamawaki
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, 35-1, Higashi 23 Ban-cho, Towada, Aomori, 034-8628, Japan
| | - Tatsuya Usui
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan.
| | - Kazuaki Sasaki
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
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12
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Lozano T, Chocarro S, Martin C, Lasarte-Cia A, Del Valle C, Gorraiz M, Sarrión P, Ruiz de Galarreta M, Lujambio A, Hervás-Stubbs S, Sarobe P, Casares N, Lasarte JJ. Genetic Modification of CD8 + T Cells to Express EGFR: Potential Application for Adoptive T Cell Therapies. Front Immunol 2019; 10:2990. [PMID: 31921216 PMCID: PMC6934060 DOI: 10.3389/fimmu.2019.02990] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 12/05/2019] [Indexed: 12/23/2022] Open
Abstract
Adoptive immunotherapy with ex vivo-expanded tumor-infiltrating lymphocytes (TILs) has achieved objective clinical responses in a significant number of patients with cancer. The failure of many patients to develop long-term tumor control may be, in part, due to exhaustion of transferred T cells in the presence of a hostile tumor microenvironment. In several tumor types, growth and survival of carcinoma cells appear to be sustained by a network of receptors/ligands of the ErbB family. We speculated that if transferred T cells could benefit from EGFR ligands produced by the tumor, they might proliferate better and exert their anti-tumor activities more efficiently. We found that CD8+ T cells transduced with a retrovirus to express EGFR responded to EGFR ligands activating the EGFR signaling pathway. These EGFR-expressing effector T cells proliferated better and produced more IFN-γ and TNF-α in the presence of EGFR ligands produced by tumor cells in vitro. EGFR-expressing CD8 T cells from OT-1 mice were more efficient killing B16-OVA cells than control OT-1 CD8 T cells. Importantly, EGFR-expressing OT-1 T cells injected into B16-OVA tumor bearing mice were recruited into the tumor, expressed lower levels of the exhaustion markers PD1, TIGIT, and LAG3, and were more efficient in delaying tumor growth. Our results suggest that genetic modification of CD8+ T cells to express EGFR might be considered in immunotherapeutic strategies based on adoptive transfer of anti-tumor T cells against cancers expressing EGFR ligands.
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Affiliation(s)
- Teresa Lozano
- Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Silvia Chocarro
- Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Celia Martin
- Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Aritz Lasarte-Cia
- Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Cynthia Del Valle
- Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Marta Gorraiz
- Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Patricia Sarrión
- Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Marina Ruiz de Galarreta
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Amaia Lujambio
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Sandra Hervás-Stubbs
- Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Pablo Sarobe
- Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Noelia Casares
- Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Juan J Lasarte
- Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
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13
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Keane FK, Hong TS, Zhu AX. Evolving Systemic Therapy in Hepatocellular Carcinoma: Current Management and Opportunities for Integration With Radiotherapy. Semin Radiat Oncol 2018; 28:332-341. [PMID: 30309643 DOI: 10.1016/j.semradonc.2018.06.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The majority of patients with hepatocellular carcinoma (HCC) present with advanced disease. While first-line therapy with sorafenib is considered standard of care for patients with advancedHCC, outcomes remain poor. Despite early evidence of antitumor activity from Phase II trials of multiple other tyrosine kinase inhibitors, Phase III trials have largely failed to show an improvement insurvival outcomes over sorafenib. Given the encouraging early results with liver-directed radiotherapy for patients with advanced HCC, there is an increased interest in combination of these therapies tooptimize patient outcomes and improve survival by maximizing both local and distant disease control. Phase II trials of checkpoint inhibitors in HCC have also reported encouraging results, and Phase IIItrials are ongoing. Trials of combining radiotherapy with immunotherapy in solid tumors have shown intriguing results, potentially reflecting the opportunity for synergistic effects with the use of both modalities.
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Affiliation(s)
- Florence K Keane
- Massachusetts General Hospital, Department of Radiation Oncology, Harvard Medical School, Boston, MA.
| | - Theodore S Hong
- Massachusetts General Hospital, Department of Radiation Oncology, Harvard Medical School, Boston, MA.
| | - Andrew X Zhu
- Massachusetts General Hospital, Division of Hematology-Oncology, Department of Medicine, Harvard Medical School, Boston, MA.
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14
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Kefaloyianni E, Muthu ML, Kaeppler J, Sun X, Sabbisetti V, Chalaris A, Rose-John S, Wong E, Sagi I, Waikar SS, Rennke H, Humphreys BD, Bonventre JV, Herrlich A. ADAM17 substrate release in proximal tubule drives kidney fibrosis. JCI Insight 2018; 1:87023. [PMID: 27642633 DOI: 10.1172/jci.insight.87023] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Kidney fibrosis following kidney injury is an unresolved health problem and causes significant morbidity and mortality worldwide. In a study into its molecular mechanism, we identified essential causative features. Acute or chronic kidney injury causes sustained elevation of a disintegrin and metalloprotease 17 (ADAM17); of its cleavage-activated proligand substrates, in particular of pro-TNFα and the EGFR ligand amphiregulin (pro-AREG); and of the substrates' receptors. As a consequence, EGFR is persistently activated and triggers the synthesis and release of proinflammatory and profibrotic factors, resulting in macrophage/neutrophil ingress and fibrosis. ADAM17 hypomorphic mice, specific ADAM17 inhibitor-treated WT mice, or mice with inducible KO of ADAM17 in proximal tubule (Slc34a1-Cre) were significantly protected against these effects. In vitro, in proximal tubule cells, we show that AREG has unique profibrotic actions that are potentiated by TNFα-induced AREG cleavage. In vivo, in acute kidney injury (AKI) and chronic kidney disease (CKD, fibrosis) patients, soluble AREG is indeed highly upregulated in human urine, and both ADAM17 and AREG expression show strong positive correlation with fibrosis markers in related kidney biopsies. Our results indicate that targeting of the ADAM17 pathway represents a therapeutic target for human kidney fibrosis.
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Affiliation(s)
| | | | - Jakob Kaeppler
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Xiaoming Sun
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Venkata Sabbisetti
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Athena Chalaris
- Institute for Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Stefan Rose-John
- Institute for Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Eitan Wong
- Weizmann Institute of Science, Rehovot, Israel
| | - Irit Sagi
- Weizmann Institute of Science, Rehovot, Israel
| | - Sushrut S Waikar
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Helmut Rennke
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Benjamin D Humphreys
- Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Joseph V Bonventre
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Andreas Herrlich
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
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15
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Thomas MB, Garrett-Mayer E, Anis M, Anderton K, Bentz T, Edwards A, Brisendine A, Weiss G, Siegel AB, Bendell J, Baron A, Duddalwar V, El-Khoueiry A. A Randomized Phase II Open-Label Multi-Institution Study of the Combination of Bevacizumab and Erlotinib Compared to Sorafenib in the First-Line Treatment of Patients with Advanced Hepatocellular Carcinoma. Oncology 2018; 94:329-339. [PMID: 29719302 PMCID: PMC7725004 DOI: 10.1159/000485384] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 11/06/2017] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To investigate the clinical efficacy and tolerability of the combination of bevacizumab (B) and erlotinib (E) compared to sorafenib (S) as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). METHODS A total of 90 patients with advanced HCC, Child-Pugh class A-B7 cirrhosis, and no prior systemic therapy were randomly assigned (1: 1) to receive either 10 mg/kg B intravenously every 14 days and 150 mg E orally daily (n = 47) (B+E) or 400 mg S orally twice daily (n = 43). The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), objective response rate based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1), time to progression, and safety and tolerability. RESULTS The median OS was 8.55 months (95% CI: 7.00-13.9) for patients treated with B+E and 8.55 months (95% CI: 5.69-12.2) for patients receiving S. The hazard ratio (HR) for OS was 0.92 (95% CI: 0.57-1.47). The median EFS was 4.37 months (95% CI: 2.99-7.36) for patients receiving B+E and 2.76 months (95% CI: 1.84-4.80) for patients receiving S. The HR for EFS was 0.67 (95% CI: 0.42-1.07; p = 0.09), favoring B+E over S. When OS was assessed among patients who were Child-Pugh class A, the median OS was 11.4 months (95% CI: 7.5-15.7) for patients treated with B+E (n = 39) and 10.26 months (95% CI: 5.9-13.0) for patients treated with S (n = 38) (HR = 0.88; 95% CI: 0.53-1.46). CONCLUSIONS There was no difference in efficacy between the B+E and S arms, although the safety and tolerability profile tended to favor B+E over S based on competing risk analysis.
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Affiliation(s)
- Melanie B Thomas
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA,
- Gibbs Cancer Center and Research Institute, Spartanburg Regional Healthcare System, Spartanburg, South Carolina, USA,
| | - Elizabeth Garrett-Mayer
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Munazza Anis
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Kate Anderton
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Tricia Bentz
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Andie Edwards
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Alan Brisendine
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Geoffrey Weiss
- Department of Oncology, University of Virginia, Charlottesville, Virginia, USA
| | - Abby B Siegel
- New York-Presbyterian Hospital, Columbia University, New York, New York, USA
| | - Johanna Bendell
- GI Oncology Research, Sarah Canon Research Institute, Nashville, Tennessee, USA
| | - Ari Baron
- California Pacific Medical Center, San Francisco, California, USA
| | - Vinay Duddalwar
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA
| | - Anthony El-Khoueiry
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA
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16
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Buckner SL, Pruitt AN, Thomas CN, Amin MY, Miller LL, Wiley FE, Sabbatini ME. Di-N-octylphthalate acts as a proliferative agent in murine cell hepatocytes by regulating the levels of TGF-β and pro-apoptotic proteins. Food Chem Toxicol 2017; 111:166-175. [PMID: 29128616 DOI: 10.1016/j.fct.2017.11.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Revised: 10/09/2017] [Accepted: 11/05/2017] [Indexed: 11/17/2022]
Abstract
Di-n-octylphthalate (DNOP) is a phthalate used in the manufacturing of a wide variety of polyvinyl chloride-containing medical and consumer products. A study on chronic exposure to DNOP in rodents showed the development of pre-neoplastic hepatic lesions following exposure to a tumor initiator. The objective of this study was to identify the mechanisms by which DNOP leads to pre-neoplastic hepatic lesions. Mouse hepatocyte AML-12 and FL83B cells were treated with DNOP. The rate of cell proliferation was increased in treated cells in a concentration-dependent manner. DNOP increased the expression of transforming growth factor-β (tgf-β) in both cell lines, and primary culture mouse hepatocytes. The TGF-β receptor inhibitor LY2109761 impaired the effect of DNOP. The presence of pro-apoptotic proteins decreased in the presence of DNOP. Our observation indicates that DNOP, through an increase in the expression of tgf-β and a decrease in the levels of pro-apoptotic proteins, acts as a proliferative agent in normal mouse hepatocytes. We also studied the morphological and functional changes of the mouse liver upon a short-term treatment of DNOP. Mice exposed to DNOP displayed an epithelial-to-mesenchymal transition and cholestasis, which was reflected in an increase in hepatic bile acids and glutathione levels.
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Affiliation(s)
- Shelby L Buckner
- Department of Biological Sciences, Summerville Campus, Augusta University, 2500 Walton Way, Augusta, GA 30904, United States
| | - Allison N Pruitt
- Department of Biological Sciences, Summerville Campus, Augusta University, 2500 Walton Way, Augusta, GA 30904, United States
| | - Cecilia N Thomas
- Department of Biological Sciences, Summerville Campus, Augusta University, 2500 Walton Way, Augusta, GA 30904, United States
| | - Monisha Y Amin
- Department of Biological Sciences, Summerville Campus, Augusta University, 2500 Walton Way, Augusta, GA 30904, United States
| | - Laurence L Miller
- Department of Psychological Sciences, Summerville Campus, Augusta University, 2500 Walton Way, Augusta, GA 30904, United States
| | - Faith E Wiley
- Department of Biological Sciences, Summerville Campus, Augusta University, 2500 Walton Way, Augusta, GA 30904, United States
| | - Maria Eugenia Sabbatini
- Department of Biological Sciences, Summerville Campus, Augusta University, 2500 Walton Way, Augusta, GA 30904, United States.
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17
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Thompson SM, Jondal DE, Butters KA, Knudsen BE, Anderson JL, Stokes MP, Jia X, Grande JP, Roberts LR, Callstrom MR, Woodrum DA. Heat stress induced, ligand-independent MET and EGFR signalling in hepatocellular carcinoma. Int J Hyperthermia 2017; 34:812-823. [PMID: 28954551 DOI: 10.1080/02656736.2017.1385859] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
PURPOSE The aims of the present study were 2-fold: first, to test the hypothesis that heat stress induces MET and EGFR signalling in hepatocellular carcinoma (HCC) cells and inhibition of this signalling decreases HCC clonogenic survival; and second, to identify signalling pathways associated with heat stress induced MET signalling. MATERIALS AND METHODS MET+ and EGFR+ HCC cells were pre-treated with inhibitors to MET, EGFR, PI3K/mTOR or vehicle and subjected to heat stress or control ± HGF or EGF growth factors and assessed by colony formation assay, Western blotting and/or quantitative mass spectrometry. IACUC approved partial laser thermal or sham ablation was performed on orthotopic N1S1 and AS30D HCC tumours and liver/tumour assessed for phospho-MET and phospho-EGFR immunostaining. RESULTS Heat-stress induced rapid MET and EGFR phosphorylation that is distinct from HGF or EGF in HCC cells and thermal ablation induced MET but not EGFR phosphorylation at the HCC tumour ablation margin. Inhibition of the MET and EGFR blocked both heat stress and growth factor induced MET and EGFR phosphorylation and inhibition of MET decreased HCC clonogenic survival following heat stress. Pathway analysis of quantitative phosphoproteomic data identified downstream pathways associated with heat stress induced MET signalling including AKT, ERK, Stat3 and JNK. However, inhibition of heat stress induced MET signalling did not block AKT signalling. CONCLUSIONS Heat-stress induced MET and EGFR signalling is distinct from growth factor mediated signalling in HCC cells and MET inhibition enhances heat stress induced HCC cell killing via a PI3K/AKT/mTOR-independent mechanism.
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Affiliation(s)
- Scott M Thompson
- a Department of Radiology , Mayo Clinic School of Medicine , Rochester , MN , USA
| | - Danielle E Jondal
- a Department of Radiology , Mayo Clinic School of Medicine , Rochester , MN , USA
| | - Kim A Butters
- a Department of Radiology , Mayo Clinic School of Medicine , Rochester , MN , USA
| | - Bruce E Knudsen
- a Department of Radiology , Mayo Clinic School of Medicine , Rochester , MN , USA
| | - Jill L Anderson
- a Department of Radiology , Mayo Clinic School of Medicine , Rochester , MN , USA
| | - Matthew P Stokes
- b Cell Signaling Technology, Inc. 3 Trask Ln. Danvers , MA , USA
| | - Xiaoying Jia
- b Cell Signaling Technology, Inc. 3 Trask Ln. Danvers , MA , USA
| | - Joseph P Grande
- c Department of Laboratory Medicine and Pathology , Mayo Clinic School of Medicine , Rochester , MN , USA
| | - Lewis R Roberts
- d Division of Gastroenterology and Hepatology , Mayo Clinic School of Medicine , Rochester , MN , USA
| | - Matthew R Callstrom
- a Department of Radiology , Mayo Clinic School of Medicine , Rochester , MN , USA
| | - David A Woodrum
- a Department of Radiology , Mayo Clinic School of Medicine , Rochester , MN , USA
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18
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Rinninella E, Cerrito L, Spinelli I, Cintoni M, Mele MC, Pompili M, Gasbarrini A. Chemotherapy for Hepatocellular Carcinoma: Current Evidence and Future Perspectives. J Clin Transl Hepatol 2017; 5:235-248. [PMID: 28936405 PMCID: PMC5606970 DOI: 10.14218/jcth.2017.00002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 04/29/2017] [Accepted: 04/29/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatocarcinogenesis is a multistep process, heralded by abnormalities in cell differentiation and proliferation and sustained by an aberrant neoangiogenesis. Understanding the underlying molecular pathogenesis leading to hepatocellular carcinoma is a prerequisite to develop new drugs that will hamper or block the steps of these pathways. As hepatocellular carcinoma has higher arterial vascularization than normal liver, this could be a good target for novel molecular therapies. Introduction of the antiangiogenic drug sorafenib into clinical practice since 2008 has led to new perspectives in the management of this tumor. The importance of this drug lies not only in the modest gain of patients' survival, but in having opened a roadmap towards the development of new molecules and targets. Unfortunately, after the introduction of sorafenib, during the last years, a wide number of clinical trials on antiangiogenic therapies failed in achieving significant results. However, many of these trials are still ongoing and promise to improve overall survival and progression-free survival. A recent clinical trial has proven regorafenib effective in patients showing tumor progression under sorafenib, thus opening new interesting therapeutic perspectives. Many other expectations have been borne from the discovery of the immune checkpoint blockade, already known in other solid malignancies. Furthermore, a potential role in hepatocellular carcinoma therapy may derive from the use of branched-chain amino acids and of nutritional support. This review analyses the biomolecular pathways of hepatocellular carcinoma and the ongoing studies, the actual evidence and the future perspectives concerning drug therapy in this open field.
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Affiliation(s)
- Emanuele Rinninella
- Internal Medicine and Gastroenterology Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
- Clinical Nutrition Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Lucia Cerrito
- Internal Medicine and Gastroenterology Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Irene Spinelli
- Internal Medicine and Gastroenterology Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Marco Cintoni
- Clinical Nutrition Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Maria Cristina Mele
- Clinical Nutrition Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
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19
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Lee SJ, Lim HY. Hepatocellular carcinoma treatment: a comparative review of emerging growth factor receptor antagonists. Expert Opin Emerg Drugs 2017; 22:191-200. [PMID: 28506080 DOI: 10.1080/14728214.2017.1330886] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Su Jin Lee
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ho Yeong Lim
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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20
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Taniguchi H, Takeuchi S, Fukuda K, Nakagawa T, Arai S, Nanjo S, Yamada T, Yamaguchi H, Mukae H, Yano S. Amphiregulin triggered epidermal growth factor receptor activation confers in vivo crizotinib-resistance of EML4-ALK lung cancer and circumvention by epidermal growth factor receptor inhibitors. Cancer Sci 2017; 108:53-60. [PMID: 27783866 PMCID: PMC5276841 DOI: 10.1111/cas.13111] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 10/17/2016] [Accepted: 10/22/2016] [Indexed: 12/30/2022] Open
Abstract
Crizotinib, a first-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, is known to be effective against echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive non-small cell lung cancers. Nonetheless, the tumors subsequently become resistant to crizotinib and recur in almost every case. The mechanism of the acquired resistance needs to be deciphered. In this study, we established crizotinib-resistant cells (A925LPE3-CR) via long-term administration of crizotinib to a mouse model of pleural carcinomatous effusions; this model involved implantation of the A925LPE3 cell line, which harbors the EML4-ALK gene rearrangement. The resistant cells did not have the secondary ALK mutations frequently occurring in crizotinib-resistant cells, and these cells were cross-resistant to alectinib and ceritinib as well. In cell clone #2, which is one of the clones of A925LPE3-CR, crizotinib sensitivity was restored via the inhibition of epidermal growth factor receptor (EGFR) by means of an EGFR tyrosine-kinase inhibitor (erlotinib) or an anti-EGFR antibody (cetuximab) in vitro and in the murine xenograft model. Cell clone #2 did not have an EGFR mutation, but the expression of amphiregulin (AREG), one of EGFR ligands, was significantly increased. A knockdown of AREG with small interfering RNAs restored the sensitivity to crizotinib. These data suggest that overexpression of EGFR ligands such as AREG can cause resistance to crizotinib, and that inhibition of EGFR signaling may be a promising strategy to overcome crizotinib resistance in EML4-ALK lung cancer.
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Affiliation(s)
- Hirokazu Taniguchi
- Division of Medical OncologyCancer Research InstituteKanazawa UniversityKanazawaJapan
- Department of Respiratory MedicineNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
| | - Shinji Takeuchi
- Division of Medical OncologyCancer Research InstituteKanazawa UniversityKanazawaJapan
| | - Koji Fukuda
- Division of Medical OncologyCancer Research InstituteKanazawa UniversityKanazawaJapan
| | - Takayuki Nakagawa
- Division of Medical OncologyCancer Research InstituteKanazawa UniversityKanazawaJapan
- Tsukuba LaboratoryEisai Co., LtdTsukubaJapan
| | - Sachiko Arai
- Division of Medical OncologyCancer Research InstituteKanazawa UniversityKanazawaJapan
| | - Shigeki Nanjo
- Division of Medical OncologyCancer Research InstituteKanazawa UniversityKanazawaJapan
| | - Tadaaki Yamada
- Division of Medical OncologyCancer Research InstituteKanazawa UniversityKanazawaJapan
| | - Hiroyuki Yamaguchi
- Department of Respiratory MedicineNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
| | - Hiroshi Mukae
- Department of Respiratory MedicineNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
| | - Seiji Yano
- Division of Medical OncologyCancer Research InstituteKanazawa UniversityKanazawaJapan
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Jiang S, Wang Q, Feng M, Li J, Guan Z, An D, Dong M, Peng Y, Kuerban K, Ye L. C2-ceramide enhances sorafenib-induced caspase-dependent apoptosis via PI3K/AKT/mTOR and Erk signaling pathways in HCC cells. Appl Microbiol Biotechnol 2016; 101:1535-1546. [PMID: 27807662 DOI: 10.1007/s00253-016-7930-9] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Revised: 10/04/2016] [Accepted: 10/10/2016] [Indexed: 02/06/2023]
Abstract
Sorafenib as an effective multikinase inhibitor has been approved for the clinical treatment against advanced hepatocellular carcinoma (HCC). HCC treatment requires usually combined therapy because of its complex pathogenesis. Ceramide has been confirmed to induce remarkable apoptosis in human tumor cells and has attracted increasing attention in investigations on combination therapy. In this paper, the anti-HCC effect of sorafenib combined with C2-ceramide was investigated on cell vitality, apoptosis, and migration, and the underlying mechanism was examined using flow cytometry and western blot. Bel7402 cells coincubated with sorafenib and C2-ceramide exhibited lower cell vitality and more irregular cellular morphology and cell cycle arrest. Sorafenib plus C2-ceramide stimulated significantly the production of reactive oxygen species (ROS) and mitochondrial depolarization, which promoted caspases-dependent cell apoptosis as illustrated by related protein expression including caspase 3, caspase 9, Bax, Bcl-2, and cytochrome c. Combination treatment of sorafenib and C2-ceramide inhibited obviously cell growth and proliferation via PI3K/AKT/mTOR and Erk signaling pathways. Furthermore, the combination treatment was proved to inhibit cell migration and epithelial-mesenchymal transition (EMT). These findings indicated that the combination of C2-ceramide and sorafenib provided synergistic inhibitory effects on HCC cells.
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Affiliation(s)
- Shanshan Jiang
- Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Qian Wang
- Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Meiqing Feng
- Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Jiyang Li
- Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Zhongbin Guan
- Shanghai Institute For Food And Drug Control, Shanghai, China
| | - Duopeng An
- Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Mengxue Dong
- Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Yuzhe Peng
- Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Kudelaidi Kuerban
- Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Li Ye
- Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
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22
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Komposch K, Sibilia M. EGFR Signaling in Liver Diseases. Int J Mol Sci 2015; 17:E30. [PMID: 26729094 PMCID: PMC4730276 DOI: 10.3390/ijms17010030] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Revised: 12/17/2015] [Accepted: 12/21/2015] [Indexed: 02/07/2023] Open
Abstract
The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that is activated by several ligands leading to the activation of diverse signaling pathways controlling mainly proliferation, differentiation, and survival. The EGFR signaling axis has been shown to play a key role during liver regeneration following acute and chronic liver damage, as well as in cirrhosis and hepatocellular carcinoma (HCC) highlighting the importance of the EGFR in the development of liver diseases. Despite the frequent overexpression of EGFR in human HCC, clinical studies with EGFR inhibitors have so far shown only modest results. Interestingly, a recent study has shown that in human HCC and in mouse HCC models the EGFR is upregulated in liver macrophages where it plays a tumor-promoting function. Thus, the role of EGFR in liver diseases appears to be more complex than what anticipated. Further studies are needed to improve the molecular understanding of the cell-specific signaling pathways that control disease development and progression to be able to develop better therapies targeting major components of the EGFR signaling network in selected cell types. In this review, we compiled the current knowledge of EGFR signaling in different models of liver damage and diseases, mainly derived from the analysis of HCC cell lines and genetically engineered mouse models (GEMMs).
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Affiliation(s)
- Karin Komposch
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
| | - Maria Sibilia
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
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23
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Scheving LA, Zhang X, Stevenson MC, Weintraub MA, Abbasi A, Clarke AM, Threadgill DW, Russell WE. Loss of hepatocyte ERBB3 but not EGFR impairs hepatocarcinogenesis. Am J Physiol Gastrointest Liver Physiol 2015; 309:G942-54. [PMID: 26492920 PMCID: PMC4683301 DOI: 10.1152/ajpgi.00089.2015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 10/18/2015] [Indexed: 01/31/2023]
Abstract
Epidermal growth factor receptor (EGFR) and ERBB3 have been implicated in hepatocellular carcinogenesis (HCC). However, it is not known whether altering the activity of either EGFR or ERBB3 affects HCC development. We now show that Egfr(Dsk5) mutant mice, which have a gain-of-function allele that increases basal EGFR kinase activity, develop spontaneous HCC by 10 mo of age. Their tumors show increased activation of EGFR, ERBB2, and ERBB3 as well as AKT and ERK1,2. Hepatocyte-specific models of EGFR and ERBB3 gene ablation were generated to evaluate how the loss of these genes affected tumor progression. Loss of either receptor tyrosine kinase did not alter liver development or regenerative liver growth following carbon tetrachloride injection. However, using a well-characterized model of HCC in which N-nitrosodiethylamine is injected into 14-day-old mice, we discovered that loss of hepatocellular ERBB3 but not EGFR, which occurred after tumor initiation, retarded liver tumor formation and cell proliferation. We found no evidence that this was due to increased apoptosis or diminished phosphatidylinositol-3-kinase activity in the ERBB3-null cells. However, the relative amount of phospho-STAT3 was diminished in tumors derived from these mice, suggesting that ERBB3 may promote HCC through STAT3 activation.
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Affiliation(s)
- Lawrence A. Scheving
- 1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee;
| | - Xiuqi Zhang
- 1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee;
| | - Mary C. Stevenson
- 1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee;
| | - Michael A. Weintraub
- 1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee;
| | - Annam Abbasi
- 1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee;
| | - Andrea M. Clarke
- 1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee;
| | - David W. Threadgill
- 6Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas; and ,7Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas
| | - William E. Russell
- 1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; ,5Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee;
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Gao JJ, Shi ZY, Xia JF, Inagaki Y, Tang W. Sorafenib-based combined molecule targeting in treatment of hepatocellular carcinoma. World J Gastroenterol 2015; 21:12059-12070. [PMID: 26576091 PMCID: PMC4641124 DOI: 10.3748/wjg.v21.i42.12059] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 07/28/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Sorafenib is the only and standard systematic chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC) at the current stage. Although sorafenib showed survival benefits in large randomized phase III studies, its clinical benefits remain modest and most often consist of temporary tumor stabilization, indicating that more effective first-line treatment regimens or second-line salvage therapies are required. The molecular pathogenesis of HCC is very complex, involving hyperactivated signal transduction pathways such as RAS/RAF/MEK/ERK and PI3K/AKT/mTOR and aberrant expression of molecules such as receptor tyrosine kinases and histone deacetylases. Simultaneous or sequential abrogation of these critical pathways or the functions of these key molecules involved in angiogenesis, proliferation, and apoptosis may yield major improvements in the management of HCC. In this review, we summarize the emerging sorafenib-based combined molecule targeting for HCC treatment and analyze the rationales of these combinations.
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25
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Poojari R, Kini S, Srivastava R, Panda D. A Chimeric Cetuximab-Functionalized Corona as a Potent Delivery System for Microtubule-Destabilizing Nanocomplexes to Hepatocellular Carcinoma Cells: A Focus on EGFR and Tubulin Intracellular Dynamics. Mol Pharm 2015; 12:3908-3923. [PMID: 26426829 DOI: 10.1021/acs.molpharmaceut.5b00337] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
In this study, we have developed microtubule destabilizing agents combretastatin A4 (CA4) or 2-methoxyestradiol (2ME) encapsulated poly(d,l-lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-b-PEG) nanocomplexes for targeted delivery to human hepatocellular carcinoma (HCC) cells. An epidermal growth factor receptor (EGFR) is known to be overexpressed in HCC cells. Therefore, the targeting moiety cetuximab (Cet), an anti-EGFR chimeric monoclonal antibody, is functionalized on the surface of these diblock copolymeric coronas. Cetuximab is associated with the extracellular domain of the EGFR; therefore, the uptake of the cetuximab conjugated nanocomplexes occurred efficiently in EGFR overexpressing HCC cells indicating potent internalization of the complex. The cetuximab targeted-PLGA-b-PEG nanocomplexes encapsulating CA4 or 2ME strongly inhibited phospho-EGFR expression, depolymerized microtubules, produced spindle abnormalities, stalled mitosis, and induced apoptosis in Huh7 cells compared to the free drugs, CA4 or 2ME. Further, the combinatorial strategy of targeted nanocomplexes, Cet-PLGA-b-PEG-CA4 NP and Cet-PLGA-b-PEG-2ME NP, significantly reduced the migration of Huh7 cells, and markedly enhanced the anticancer effects of the microtubule-targeted drugs in Huh7 cells compared to the free drugs, CA4 or 2ME. The results indicated that EGFR receptor-mediated internalization via cetuximab facilitated enhanced uptake of the nanocomplexes leading to potent anticancer efficacy in Huh7 cells. Cetuximab-functionalized PLGA-b-PEG nanocomplexes possess a strong potential for the targeted delivery of CA4 or 2ME in EGFR overexpressed HCC cells, and the strategy may be useful for selectively targeting microtubules in these cells.
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Affiliation(s)
- Radhika Poojari
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay , Mumbai 400076, India
| | - Sudarshan Kini
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay , Mumbai 400076, India
| | - Rohit Srivastava
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay , Mumbai 400076, India
| | - Dulal Panda
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay , Mumbai 400076, India
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26
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Shu G, Zhao W, Yue L, Su H, Xiang M. Antitumor immunostimulatory activity of polysaccharides from Salvia chinensis Benth. JOURNAL OF ETHNOPHARMACOLOGY 2015; 168:237-247. [PMID: 25858511 DOI: 10.1016/j.jep.2015.03.065] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 02/16/2015] [Accepted: 03/30/2015] [Indexed: 06/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Salvia chinensis Benth (S. chinensis) is a traditional herb applied in the treatment of hepatocellular carcinoma (HCC). Polysaccharides abundantly exist in this plant. However, it remains poorly understood if polysaccharides from S. chinensis (PSSC) contribute to its anti-HCC activity. MATERIALS AND METHODS The in vivo anti-HCC activity of PSSC was evaluated in Kunming mice bearing H22 ascitic hepatoma cells. An array of physiological indexes was measured to evaluate toxicological effects on host animals. Subgroups of immune cells were purified by a magnetic-activated cell sorting system and analyzed by flow cytometry. Reverse transcription real-time PCR and immunoblotting were recruited to determine the effects of PSSC on the cellular signaling of different subgroup of immune cells. RESULTS PSSC suppressed in vivo proliferation of H22 cells with undetectable toxic effects on tumor-bearing mice. PSSC alleviated tumor transplantation-induced CD4+ T cell apoptosis and dysregulation of serum cytokine profiles, which elevated cytotoxic activities of natural killer and CD8+ T cells. PSSC reduced serum levels of prostaglandin E2 (PGE2). Injection of exogenous PGE2 completely abrogated the antitumor immunostimulatory activity of PSSC. Cyclic adenosine monophosphate (cAMP) is the second messager of PGE2. In CD4+ T cells, PSSC substantially declined intracellular cAMP. This event elevated protein levels of JAK3, enhancing STAT5 phosphorylation and STAT5-dependent expression of anti-apoptotic genes. Cyclooxygenase-2 is the key enzyme mediating biosynthesis of PGE2. PSSC suppressed the transcription and translation of cyclooxygenase-2 in tumor associated macrophages. CONCLUSION Our data clearly showed antitumor immunostimulatory activity of PSSC against transplanted H22 HCC cells. Suppressing tumor transplantation-induced PGE2 production was implicated in the anti-tumor immunostimulatory activity of PSSC. These works provides novel insights into the traditional application of S. chinensis against HCC and supported considering PSSC as an adjuvant reagent in clinical HCC treatment.
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Affiliation(s)
- Guangwen Shu
- College of Pharmacy, South-Central University for Nationalities, Wuhan, PR China
| | - Wenhao Zhao
- College of Pharmacy, South-Central University for Nationalities, Wuhan, PR China
| | - Ling Yue
- Endocrinology department, Wuhan General Hospital of Guangzhou Military Command, Wuhan, PR China
| | - Hanwen Su
- Renmin Hospital of Wuhan University, Wuhan, PR China
| | - Meixian Xiang
- College of Pharmacy, South-Central University for Nationalities, Wuhan, PR China.
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27
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Wu L, Claas AM, Sarkar A, Lauffenburger DA, Han J. High-throughput protease activity cytometry reveals dose-dependent heterogeneity in PMA-mediated ADAM17 activation. Integr Biol (Camb) 2015; 7:513-24. [PMID: 25832727 PMCID: PMC4428935 DOI: 10.1039/c5ib00019j] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
As key components of autocrine signaling, pericellular proteases, a disintegrin and metalloproteinases (ADAMs) in particular, are known to impact the microenvironment of individual cells and have significant implications in various pathological situations including cancer, inflammatory and vascular diseases. There is great incentive to develop a high-throughput platform for single-cell measurement of pericellular protease activity, as it is essential for studying the heterogeneity of protease response and the corresponding cell behavioral consequences. In this work, we developed a microfluidic platform to simultaneously monitor protease activity of many single cells in a time-dependent manner. This platform isolates individual microwells rapidly on demand and thus allows single-cell activity measurement of both cell-surface and secreted proteases by confining individual cells with diffusive FRET-based substrates. With this platform, we observed dose-dependent heterogeneous protease activation of HepG2 cells treated with phorbol 12-myristate 13-acetate (PMA). To study the temporal behavior of PMA-induced protease response, we monitored the pericellular protease activity of the same single cells during three different time periods and revealed the diversity in the dynamic patterns of single-cell protease activity profile upon PMA stimulation. The unique temporal information of single-cell protease response can help unveil the complicated functional role of pericellular proteases.
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Affiliation(s)
- Lidan Wu
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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28
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Amphiregulin activates human hepatic stellate cells and is upregulated in non alcoholic steatohepatitis. Sci Rep 2015; 5:8812. [PMID: 25744849 PMCID: PMC4351520 DOI: 10.1038/srep08812] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 02/04/2015] [Indexed: 01/11/2023] Open
Abstract
Amphiregulin (AR) involvement in liver fibrogenesis and hepatic stellate cells (HSC) regulation is under study. Non-alcoholic fatty liver disease (NAFLD) and its more severe form non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular cancer (HCC). Our aim was to investigate ex vivo the effect of AR on human primary HSC (hHSC) and verify in vivo the relevance of AR in NAFLD fibrogenesis. hHSC isolated from healthy liver segments were analyzed for expression of AR and its activator, TNF-α converting enzyme (TACE). AR induction of hHSC proliferation and matrix production was estimated in the presence of antagonists. AR involvement in fibrogenesis was also assessed in a mouse model of NASH and in humans with NASH. hHSC time dependently expressed AR and TACE. AR increased hHSC proliferation through several mitogenic signaling pathways such as EGFR, PI3K and p38. AR also induced marked upregulation of hHSC fibrogenic markers and reduced hHSC death. AR expression was enhanced in the HSC of a murine model of NASH and of severe human NASH. In conclusion, AR induces hHSC fibrogenic activity via multiple mitogenic signaling pathways, and is upregulated in murine and human NASH, suggesting that AR antagonists may be clinically useful anti-fibrotics in NAFLD.
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Zhu AX, Rosmorduc O, Evans TRJ, Ross PJ, Santoro A, Carrilho FJ, Bruix J, Qin S, Thuluvath PJ, Llovet JM, Leberre MA, Jensen M, Meinhardt G, Kang YK. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2015; 33:559-66. [PMID: 25547503 DOI: 10.1200/jco.2013.53.7746] [Citation(s) in RCA: 427] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE To compare the clinical outcomes of sorafenib plus either erlotinib or placebo in patients with advanced hepatocellular carcinoma (HCC) in a multicenter, multinational, randomized, phase III trial. PATIENTS AND METHODS Patients with advanced HCC and underlying Child-Pugh class A cirrhosis, who were naive to systemic treatment (N = 720), were randomly assigned to sorafenib plus either erlotinib (n = 362) or placebo (n = 358). The primary end point was overall survival (OS). RESULTS Median OS was similar in the sorafenib plus erlotinib and sorafenib plus placebo groups (9.5 v 8.5 months, respectively; hazard ratio [HR], 0.929; P = .408), as was median time to progression (3.2 v 4.0 months, respectively; HR, 1.135; P = .18). In the sorafenib/erlotinib arm versus the sorafenib/placebo arm, the overall response rate trended higher (6.6% v 3.9%, respectively; P = .102), whereas the disease control rate was significantly lower (43.9% v 52.5%, respectively; P = .021). The median durations of treatment with sorafenib were 86 days in the sorafenib/erlotinib arm and 123 days in the sorafenib/placebo arm. In the sorafenib/erlotinib and sorafenib/placebo arms, the rates of treatment-emergent serious AEs (58.0% v 54.6%, respectively) and drug-related serious AEs (21.0% v 22.8%, respectively) were similar. AEs matched the known safety profiles of both agents, but rates of rash/desquamation, anorexia, and diarrhea were higher in the sorafenib/erlotinib arm, whereas rates of alopecia and hand-foot skin reaction were higher in the sorafenib/placebo arm. Withdrawal rates for AEs during cycles 1 to 3 were higher in the sorafenib/erlotinib arm. CONCLUSION Adding erlotinib to sorafenib did not improve survival in patients with advanced HCC.
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Affiliation(s)
- Andrew X Zhu
- Andrew X. Zhu, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Olivier Rosmorduc, Service d'Hépatologie, Hôpital Saint-Antoine, Paris; Marie-Aude Leberre, Bayer HealthCare Pharmaceuticals, Loos, France; T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow; Paul J. Ross, King's College Hospital, London, United Kingdom; Armando Santoro, Humanitas Cancer Center, Milan, Italy; Flair Jose Carrilho, University of São Paulo School of Medicine, São Paulo, Brazil; Jordi Bruix and Josep M. Llovet, Barcelona Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona; Josep M. Llovet, Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain; Shukui Qin, People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Jiangsu, China; Paul J. Thuluvath, Institute for Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, MD; Josep M. Llovet, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY; Markus Jensen, Bayer Vital GmbH, Leverkusen, Germany; Gerold Meinhardt, Bayer HealthCare Pharmaceuticals, Montville, NJ; and Yoon-Koo Kang, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
| | - Olivier Rosmorduc
- Andrew X. Zhu, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Olivier Rosmorduc, Service d'Hépatologie, Hôpital Saint-Antoine, Paris; Marie-Aude Leberre, Bayer HealthCare Pharmaceuticals, Loos, France; T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow; Paul J. Ross, King's College Hospital, London, United Kingdom; Armando Santoro, Humanitas Cancer Center, Milan, Italy; Flair Jose Carrilho, University of São Paulo School of Medicine, São Paulo, Brazil; Jordi Bruix and Josep M. Llovet, Barcelona Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona; Josep M. Llovet, Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain; Shukui Qin, People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Jiangsu, China; Paul J. Thuluvath, Institute for Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, MD; Josep M. Llovet, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY; Markus Jensen, Bayer Vital GmbH, Leverkusen, Germany; Gerold Meinhardt, Bayer HealthCare Pharmaceuticals, Montville, NJ; and Yoon-Koo Kang, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - T R Jeffry Evans
- Andrew X. Zhu, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Olivier Rosmorduc, Service d'Hépatologie, Hôpital Saint-Antoine, Paris; Marie-Aude Leberre, Bayer HealthCare Pharmaceuticals, Loos, France; T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow; Paul J. Ross, King's College Hospital, London, United Kingdom; Armando Santoro, Humanitas Cancer Center, Milan, Italy; Flair Jose Carrilho, University of São Paulo School of Medicine, São Paulo, Brazil; Jordi Bruix and Josep M. Llovet, Barcelona Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona; Josep M. Llovet, Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain; Shukui Qin, People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Jiangsu, China; Paul J. Thuluvath, Institute for Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, MD; Josep M. Llovet, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY; Markus Jensen, Bayer Vital GmbH, Leverkusen, Germany; Gerold Meinhardt, Bayer HealthCare Pharmaceuticals, Montville, NJ; and Yoon-Koo Kang, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Paul J Ross
- Andrew X. Zhu, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Olivier Rosmorduc, Service d'Hépatologie, Hôpital Saint-Antoine, Paris; Marie-Aude Leberre, Bayer HealthCare Pharmaceuticals, Loos, France; T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow; Paul J. Ross, King's College Hospital, London, United Kingdom; Armando Santoro, Humanitas Cancer Center, Milan, Italy; Flair Jose Carrilho, University of São Paulo School of Medicine, São Paulo, Brazil; Jordi Bruix and Josep M. Llovet, Barcelona Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona; Josep M. Llovet, Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain; Shukui Qin, People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Jiangsu, China; Paul J. Thuluvath, Institute for Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, MD; Josep M. Llovet, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY; Markus Jensen, Bayer Vital GmbH, Leverkusen, Germany; Gerold Meinhardt, Bayer HealthCare Pharmaceuticals, Montville, NJ; and Yoon-Koo Kang, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Armando Santoro
- Andrew X. Zhu, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Olivier Rosmorduc, Service d'Hépatologie, Hôpital Saint-Antoine, Paris; Marie-Aude Leberre, Bayer HealthCare Pharmaceuticals, Loos, France; T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow; Paul J. Ross, King's College Hospital, London, United Kingdom; Armando Santoro, Humanitas Cancer Center, Milan, Italy; Flair Jose Carrilho, University of São Paulo School of Medicine, São Paulo, Brazil; Jordi Bruix and Josep M. Llovet, Barcelona Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona; Josep M. Llovet, Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain; Shukui Qin, People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Jiangsu, China; Paul J. Thuluvath, Institute for Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, MD; Josep M. Llovet, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY; Markus Jensen, Bayer Vital GmbH, Leverkusen, Germany; Gerold Meinhardt, Bayer HealthCare Pharmaceuticals, Montville, NJ; and Yoon-Koo Kang, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Flair Jose Carrilho
- Andrew X. Zhu, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Olivier Rosmorduc, Service d'Hépatologie, Hôpital Saint-Antoine, Paris; Marie-Aude Leberre, Bayer HealthCare Pharmaceuticals, Loos, France; T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow; Paul J. Ross, King's College Hospital, London, United Kingdom; Armando Santoro, Humanitas Cancer Center, Milan, Italy; Flair Jose Carrilho, University of São Paulo School of Medicine, São Paulo, Brazil; Jordi Bruix and Josep M. Llovet, Barcelona Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona; Josep M. Llovet, Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain; Shukui Qin, People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Jiangsu, China; Paul J. Thuluvath, Institute for Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, MD; Josep M. Llovet, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY; Markus Jensen, Bayer Vital GmbH, Leverkusen, Germany; Gerold Meinhardt, Bayer HealthCare Pharmaceuticals, Montville, NJ; and Yoon-Koo Kang, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Jordi Bruix
- Andrew X. Zhu, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Olivier Rosmorduc, Service d'Hépatologie, Hôpital Saint-Antoine, Paris; Marie-Aude Leberre, Bayer HealthCare Pharmaceuticals, Loos, France; T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow; Paul J. Ross, King's College Hospital, London, United Kingdom; Armando Santoro, Humanitas Cancer Center, Milan, Italy; Flair Jose Carrilho, University of São Paulo School of Medicine, São Paulo, Brazil; Jordi Bruix and Josep M. Llovet, Barcelona Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona; Josep M. Llovet, Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain; Shukui Qin, People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Jiangsu, China; Paul J. Thuluvath, Institute for Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, MD; Josep M. Llovet, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY; Markus Jensen, Bayer Vital GmbH, Leverkusen, Germany; Gerold Meinhardt, Bayer HealthCare Pharmaceuticals, Montville, NJ; and Yoon-Koo Kang, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Shukui Qin
- Andrew X. Zhu, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Olivier Rosmorduc, Service d'Hépatologie, Hôpital Saint-Antoine, Paris; Marie-Aude Leberre, Bayer HealthCare Pharmaceuticals, Loos, France; T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow; Paul J. Ross, King's College Hospital, London, United Kingdom; Armando Santoro, Humanitas Cancer Center, Milan, Italy; Flair Jose Carrilho, University of São Paulo School of Medicine, São Paulo, Brazil; Jordi Bruix and Josep M. Llovet, Barcelona Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona; Josep M. Llovet, Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain; Shukui Qin, People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Jiangsu, China; Paul J. Thuluvath, Institute for Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, MD; Josep M. Llovet, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY; Markus Jensen, Bayer Vital GmbH, Leverkusen, Germany; Gerold Meinhardt, Bayer HealthCare Pharmaceuticals, Montville, NJ; and Yoon-Koo Kang, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Paul J Thuluvath
- Andrew X. Zhu, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Olivier Rosmorduc, Service d'Hépatologie, Hôpital Saint-Antoine, Paris; Marie-Aude Leberre, Bayer HealthCare Pharmaceuticals, Loos, France; T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow; Paul J. Ross, King's College Hospital, London, United Kingdom; Armando Santoro, Humanitas Cancer Center, Milan, Italy; Flair Jose Carrilho, University of São Paulo School of Medicine, São Paulo, Brazil; Jordi Bruix and Josep M. Llovet, Barcelona Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona; Josep M. Llovet, Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain; Shukui Qin, People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Jiangsu, China; Paul J. Thuluvath, Institute for Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, MD; Josep M. Llovet, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY; Markus Jensen, Bayer Vital GmbH, Leverkusen, Germany; Gerold Meinhardt, Bayer HealthCare Pharmaceuticals, Montville, NJ; and Yoon-Koo Kang, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Josep M Llovet
- Andrew X. Zhu, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Olivier Rosmorduc, Service d'Hépatologie, Hôpital Saint-Antoine, Paris; Marie-Aude Leberre, Bayer HealthCare Pharmaceuticals, Loos, France; T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow; Paul J. Ross, King's College Hospital, London, United Kingdom; Armando Santoro, Humanitas Cancer Center, Milan, Italy; Flair Jose Carrilho, University of São Paulo School of Medicine, São Paulo, Brazil; Jordi Bruix and Josep M. Llovet, Barcelona Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona; Josep M. Llovet, Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain; Shukui Qin, People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Jiangsu, China; Paul J. Thuluvath, Institute for Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, MD; Josep M. Llovet, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY; Markus Jensen, Bayer Vital GmbH, Leverkusen, Germany; Gerold Meinhardt, Bayer HealthCare Pharmaceuticals, Montville, NJ; and Yoon-Koo Kang, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Marie-Aude Leberre
- Andrew X. Zhu, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Olivier Rosmorduc, Service d'Hépatologie, Hôpital Saint-Antoine, Paris; Marie-Aude Leberre, Bayer HealthCare Pharmaceuticals, Loos, France; T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow; Paul J. Ross, King's College Hospital, London, United Kingdom; Armando Santoro, Humanitas Cancer Center, Milan, Italy; Flair Jose Carrilho, University of São Paulo School of Medicine, São Paulo, Brazil; Jordi Bruix and Josep M. Llovet, Barcelona Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona; Josep M. Llovet, Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain; Shukui Qin, People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Jiangsu, China; Paul J. Thuluvath, Institute for Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, MD; Josep M. Llovet, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY; Markus Jensen, Bayer Vital GmbH, Leverkusen, Germany; Gerold Meinhardt, Bayer HealthCare Pharmaceuticals, Montville, NJ; and Yoon-Koo Kang, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Markus Jensen
- Andrew X. Zhu, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Olivier Rosmorduc, Service d'Hépatologie, Hôpital Saint-Antoine, Paris; Marie-Aude Leberre, Bayer HealthCare Pharmaceuticals, Loos, France; T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow; Paul J. Ross, King's College Hospital, London, United Kingdom; Armando Santoro, Humanitas Cancer Center, Milan, Italy; Flair Jose Carrilho, University of São Paulo School of Medicine, São Paulo, Brazil; Jordi Bruix and Josep M. Llovet, Barcelona Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona; Josep M. Llovet, Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain; Shukui Qin, People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Jiangsu, China; Paul J. Thuluvath, Institute for Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, MD; Josep M. Llovet, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY; Markus Jensen, Bayer Vital GmbH, Leverkusen, Germany; Gerold Meinhardt, Bayer HealthCare Pharmaceuticals, Montville, NJ; and Yoon-Koo Kang, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Gerold Meinhardt
- Andrew X. Zhu, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Olivier Rosmorduc, Service d'Hépatologie, Hôpital Saint-Antoine, Paris; Marie-Aude Leberre, Bayer HealthCare Pharmaceuticals, Loos, France; T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow; Paul J. Ross, King's College Hospital, London, United Kingdom; Armando Santoro, Humanitas Cancer Center, Milan, Italy; Flair Jose Carrilho, University of São Paulo School of Medicine, São Paulo, Brazil; Jordi Bruix and Josep M. Llovet, Barcelona Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona; Josep M. Llovet, Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain; Shukui Qin, People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Jiangsu, China; Paul J. Thuluvath, Institute for Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, MD; Josep M. Llovet, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY; Markus Jensen, Bayer Vital GmbH, Leverkusen, Germany; Gerold Meinhardt, Bayer HealthCare Pharmaceuticals, Montville, NJ; and Yoon-Koo Kang, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Yoon-Koo Kang
- Andrew X. Zhu, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Olivier Rosmorduc, Service d'Hépatologie, Hôpital Saint-Antoine, Paris; Marie-Aude Leberre, Bayer HealthCare Pharmaceuticals, Loos, France; T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow; Paul J. Ross, King's College Hospital, London, United Kingdom; Armando Santoro, Humanitas Cancer Center, Milan, Italy; Flair Jose Carrilho, University of São Paulo School of Medicine, São Paulo, Brazil; Jordi Bruix and Josep M. Llovet, Barcelona Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona; Josep M. Llovet, Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain; Shukui Qin, People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Jiangsu, China; Paul J. Thuluvath, Institute for Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, MD; Josep M. Llovet, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY; Markus Jensen, Bayer Vital GmbH, Leverkusen, Germany; Gerold Meinhardt, Bayer HealthCare Pharmaceuticals, Montville, NJ; and Yoon-Koo Kang, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
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Gao JZ, DU JL, Wang YL, Li J, Wei LX, Guo MZ. Synergistic effects of curcumin and bevacizumab on cell signaling pathways in hepatocellular carcinoma. Oncol Lett 2014; 9:295-299. [PMID: 25435978 PMCID: PMC4246621 DOI: 10.3892/ol.2014.2694] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 09/26/2014] [Indexed: 12/22/2022] Open
Abstract
The aim of the present study was to explore the effects of curcumin in combination with bevacizumab on the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)/K-ras pathway in hepatocellular carcinoma. A total of 30 Sprague Dawley (SD) rats were randomly divided into five groups: Control, model, curcumin, VEGF blocker, and curcumin + VEGF blocker groups. The mRNA levels of VEGF and VEGFR in all groups were subsequently measured by quantitative reverse transcriptase-polymerase chain reaction and the protein expression of K-ras was detected by western blot analysis. Compared with the control group, the mRNA levels of VEGF and VEGFR were revealed to be significantly increased in the model, curcumin and VEGF blocker groups. The VEGF mRNA levels in the curcumin, VEGF blocker and curcumin + VEGF blocker groups were all decreased when compared with the model group. In addition, the VEGF mRNA levels in the curcumin + VEGF blocker group were significantly lower compared with the curcumin group (P<0.05). The VEGF mRNA levels in the curcumin, VEGF blocker and curcumin + VEGF blocker groups were decreased when compared with the model group (P=0.0001). No significant differences in VEGF mRNA levels were identified between the VEGF blocker and curcumin groups (P=0.863), whereas the VEGF mRNA levels in the curcumin + VEGF blocker group were significantly lower than that of the curcumin group (P=0.025). Curcumin and the VEGF blocker are each capable of inhibiting hepatocellular carcinoma progression by regulating the VEGF/VEGFR/K-ras pathway. The combination of the two compounds has a synergistic effect on the inhibition of the effects of the VEGF signaling pathways in hepatocellular carcinoma progression.
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Affiliation(s)
- Jian-Zhi Gao
- Department of Pathology, General Hospital of the People's Liberation Army, Beijing 100853, P.R. China ; Basic Medical College of Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Jing-Li DU
- Department of Gastroenterology and Hepatology, General Hospital of the People's Liberation Army, Beijing 100853, P.R. China ; Department of Gastroenterology, Armed Police Corps Hospital of Qinghai, Xining, Qinghai 810006, P.R. China
| | - Yong-Ling Wang
- Basic Medical College of Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Jia Li
- Department of Pathology, General Hospital of the People's Liberation Army, Beijing 100853, P.R. China
| | - Li-Xin Wei
- Department of Pathology, General Hospital of the People's Liberation Army, Beijing 100853, P.R. China
| | - Ming-Zhou Guo
- Department of Gastroenterology and Hepatology, General Hospital of the People's Liberation Army, Beijing 100853, P.R. China
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Li SQ, Zhu S, Wan XD, Xu ZS, Ma Z. Neutralization of ADAM8 ameliorates liver injury and accelerates liver repair in carbon tetrachloride-induced acute liver injury. J Toxicol Sci 2014; 39:339-51. [PMID: 24646716 DOI: 10.2131/jts.39.339] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Although some studies have described the function of ADAM8 (a disintegrin and metalloprotease 8) related with rheumatoid arthritis, cancer and asthma, etc., the concrete role of ADAM8 in acute liver injury is still unknown. So mice respectively received anti-ADAM8 monoclonal antibody (mAb) of 100 μg/100 μl, 200 μg/100 μl or 300 μg/100 μl in PBS or PBS pre-injection. Then acute liver injury was induced in the mice by intraperitoneal (i.p.) injection of carbon tetrachloride (CCl₄). Serum AST and ALT level, Haematoxylin-eosin (H&E) staining, the expression level of vascular endothelial growth factor (VEGF), cytochrome P450 1A2 (CYP1A2) and proliferating cell nuclear antigen (PCNA) were detected in the mice after CCl4 administration. Our results showed that anti-ADAM8 mAb pre-injection could effectively lower AST and ALT levels (P < 0.05 or P < 0.01) and reduce liver injury (P < 0.05 or P <0.01), induce the expression of VEGF, CYP1A2 and PCNA (P <0.05 or P < 0.01) in dose-dependent manner compared with the control mice which received PBS pre-injection. In summary, our study suggested that ADAM8 might promote liver injury by inhibiting the proliferation of hepatocytes, angiogenesis and affecting the metabolism function of liver during acute liver injury induced by CCl₄. Anti-ADAM8 mAb injection might be suitable as a potential method for acute liver injury therapy.
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Affiliation(s)
- San-Qiang Li
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, Medical College, Henan University of Science and Technology, China
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The metalloproteinase ADAM17 and the epidermal growth factor receptor (EGFR) signaling drive the inflammatory epithelial response in Sjögren’s syndrome. Clin Exp Med 2014; 15:215-25. [DOI: 10.1007/s10238-014-0279-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 03/10/2014] [Indexed: 12/12/2022]
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Berasain C, Avila MA. Amphiregulin. Semin Cell Dev Biol 2014; 28:31-41. [PMID: 24463227 DOI: 10.1016/j.semcdb.2014.01.005] [Citation(s) in RCA: 238] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Revised: 01/10/2014] [Accepted: 01/14/2014] [Indexed: 12/26/2022]
Abstract
Amphiregulin (AREG) is a ligand of the epidermal growth factor receptor (EGFR), a widely expressed transmembrane tyrosine kinase. AREG is synthesized as a membrane-anchored precursor protein that can engage in juxtacrine signaling on adjacent cells. Alternatively, after proteolytic processing by cell membrane proteases, mainly TACE/ADAM17, AREG is secreted and behaves as an autocrine or paracrine factor. AREG gene expression and release is induced by a plethora of stimuli including inflammatory lipids, cytokines, hormones, growth factors and xenobiotics. Through EGFR binding AREG activates major intracellular signaling cascades governing cell survival, proliferation and motility. Physiologically, AREG plays an important role in the development and maturation of mammary glands, bone tissue and oocytes. Chronic elevation of AREG expression is increasingly associated with different pathological conditions, mostly of inflammatory and/or neoplastic nature. Here we review the essential aspects of AREG structure, function and regulation, discuss the basis for its differential role within the EGFR family of ligands, and identify emerging aspects in AREG research with translational potential.
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Affiliation(s)
- Carmen Berasain
- Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain; CIBERehd, Clinica Universidad de Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain.
| | - Matías A Avila
- Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain; CIBERehd, Clinica Universidad de Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain.
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Kiguchi K, DiGiovanni J. Role of Growth Factor Signaling Pathways in Biliary Tract Cancer. BILIARY TRACT AND GALLBLADDER CANCER 2014. [DOI: 10.1007/978-3-642-40558-7_2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Scozzari G, Balmativola D, Trapani R, Toppino M, Morino M. Gastric Cancer After Restrictive Bariatric Surgery: A Clinical Pitfall. Int J Surg Pathol 2013; 22:442-6. [PMID: 23999114 DOI: 10.1177/1066896913501380] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Although vertical banded gastroplasty is rarely performed at present, most bariatric surgery departments continue to follow up patients who underwent this procedure in the past few decades. In view of this, it is advisable for bariatric and general surgeons to know how to diagnose the very rare event of the development of a gastric cancer after this restrictive procedure. In this report, 2 cases of gastric cancer occurring years after vertical banded gastroplasty are presented, and clinical presentation and diagnostic difficulties are discussed.
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Tang W, Weng S, Zhang S, Wu W, Dong L, Shen X, Zhang S, Gu J, Xue R. Direct interaction between surface β1,4-galactosyltransferase 1 and epidermal growth factor receptor (EGFR) inhibits EGFR activation in hepatocellular carcinoma. Biochem Biophys Res Commun 2013; 434:449-454. [PMID: 23583406 DOI: 10.1016/j.bbrc.2013.03.094] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 03/19/2013] [Indexed: 11/30/2022]
Abstract
Our previous studies showed that cell surface β1,4-galactosyltransferase 1 (β1,4GT1) negatively regulated cell survival through inhibition and modulation of the epidermal growth factor receptor (EGFR) signaling pathway in human hepatocellular carcinoma (HCC) SMMC-7721 cells. However, the underlying mechanism remains unclear. Here we demonstrated that β1,4-galactosyltransferase 1 (β1,4GT1) interacted with EGFR in vitro by GST pull-down analysis. Furthermore, we demonstrated that β1,4GT1 bound to EGFR in vivo by co-immunoprecipitation and determined the co-localization of β1,4GT1 and EGFR on the cell surface via confocal laser scanning microscopy analysis. Finally, using (125)I-EGF binding experiments and Western blot analysis, we found that overexpression of β1,4GT1 inhibited (125)I-EGF binding to EGFR, and consequently reduced the levels of EGFR dimerization and phosphorylation. In contrast, RNAi-mediated knockdown of β1,4GT1 increased the levels of EGFR dimerization and phosphorylation. These data suggest that cell surface β1,4GT1 interacts with EGFR and inhibits EGFR activation.
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Affiliation(s)
- Wenqing Tang
- Department of Gastroenterology and Hepatology of Zhongshan Hospital, Fudan University, Shanghai 200032, China
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