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Greenman R, Weston CJ. CCL24 and Fibrosis: A Narrative Review of Existing Evidence and Mechanisms. Cells 2025; 14:105. [PMID: 39851534 PMCID: PMC11763828 DOI: 10.3390/cells14020105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 01/06/2025] [Accepted: 01/10/2025] [Indexed: 01/26/2025] Open
Abstract
Tissue fibrosis results from a dysregulated and chronic wound healing response accompanied by chronic inflammation and angiogenesis. Regardless of the affected organ, fibrosis shares the following common hallmarks: the recruitment of immune cells, fibroblast activation/proliferation, and excessive extracellular matrix deposition. Chemokines play a pivotal role in initiating and advancing these fibrotic processes. CCL24 (eotaxin-2) is a chemokine secreted by immune cells and epithelial cells, which promotes the trafficking of immune cells and the activation of profibrotic cells through CCR3 receptor binding. Higher levels of CCL24 and CCR3 were found in the tissue and sera of patients with fibro-inflammatory diseases, including primary sclerosing cholangitis (PSC), systemic sclerosis (SSc), and metabolic dysfunction-associated steatohepatitis (MASH). This review delves into the intricate role of CCL24 in fibrotic diseases, highlighting its impact on fibrotic, immune, and vascular pathways. We focus on the preclinical and clinical evidence supporting the therapeutic potential of blocking CCL24 in diseases that involve excessive inflammation and fibrosis.
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Affiliation(s)
| | - Chris J. Weston
- Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, UK
- National Institute for Health and Care Research (NIHR), Birmingham Biomedical Research Centre, Birmingham B15 2TT, UK
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Hu Q, Zuo H, Hsu JC, Zeng C, Zhou T, Sun Z, Cai W, Tang Z, Chen W. The Emerging Landscape for Combating Resistance Associated with Energy-Based Therapies via Nanomedicine. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2308286. [PMID: 37971203 PMCID: PMC10872442 DOI: 10.1002/adma.202308286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 11/07/2023] [Indexed: 11/19/2023]
Abstract
Cancer represents a serious disease with significant implications for public health, imposing substantial economic burden and negative societal consequences. Compared to conventional cancer treatments, such as surgery and chemotherapy, energy-based therapies (ET) based on athermal and thermal ablation provide distinct advantages, including minimally invasive procedures and rapid postoperative recovery. Nevertheless, due to the complex pathophysiology of many solid tumors, the therapeutic effectiveness of ET is often limited. Nanotechnology offers unique opportunities by enabling facile material designs, tunable physicochemical properties, and excellent biocompatibility, thereby further augmenting the outcomes of ET. Numerous nanomaterials have demonstrated the ability to overcome intrinsic therapeutic resistance associated with ET, leading to improved antitumor responses. This comprehensive review systematically summarizes the underlying mechanisms of ET-associated resistance (ETR) and highlights representative applications of nanoplatforms used to mitigate ETR. Overall, this review emphasizes the recent advances in the field and presents a detailed account of novel nanomaterial designs in combating ETR, along with efforts aimed at facilitating their clinical translation.
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Affiliation(s)
- Qitao Hu
- Department of Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, China
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
| | - Huali Zuo
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
| | - Jessica C. Hsu
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison, Wisconsin 53705, United States
| | - Cheng Zeng
- Department of Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, China
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
| | - Tian Zhou
- Department of Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, China
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
| | - Zhouyi Sun
- Department of Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, China
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
| | - Weibo Cai
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison, Wisconsin 53705, United States
| | - Zhe Tang
- Department of Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, China
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weiyu Chen
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
- International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China
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Greenman R, Snir T, Katav A, Aricha R, Mishalian I, Hay O, Frankel M, Lawler J, Saffioti F, Pinzani M, Thorburn D, Peled A, Mor A, Vaknin I. The Role of CCL24 in Primary Sclerosing Cholangitis: Bridging Patient Serum Proteomics to Preclinical Data. Cells 2024; 13:209. [PMID: 38334601 PMCID: PMC10854794 DOI: 10.3390/cells13030209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 02/10/2024] Open
Abstract
Primary sclerosing cholangitis (PSC) is an inflammatory and fibrotic biliary disease lacking approved treatment. We studied CCL24, a chemokine shown to be overexpressed in damaged bile ducts, and its involvement in key disease-related mechanisms. Serum proteomics of PSC patients and healthy controls (HC) were analyzed using the Olink® proximity extension assay and compared based on disease presence, fibrosis severity, and CCL24 levels. Disease-related canonical pathways, upstream regulators, and toxicity functions were elevated in PSC patients compared to HC and further elevated in patients with high CCL24 levels. In vitro, a protein signature in CCL24-treated hepatic stellate cells (HSCs) differentiated patients by disease severity. In mice, CCL24 intraperitoneal injection selectively recruited neutrophils and monocytes. Treatment with CM-101, a CCL24-neutralizing antibody, in an α-naphthylisothiocyanate (ANIT)-induced cholestasis mouse model effectively inhibited accumulation of peribiliary neutrophils and macrophages while reducing biliary hyperplasia and fibrosis. Furthermore, in PSC patients, CCL24 levels were correlated with upregulation of monocyte and neutrophil chemotaxis pathways. Collectively, these findings highlight the distinct role of CCL24 in PSC, influencing disease-related mechanisms, affecting immune cells trafficking and HSC activation. Its blockade with CM-101 reduces inflammation and fibrosis and positions CCL24 as a promising therapeutic target in PSC.
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Affiliation(s)
| | - Tom Snir
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
| | - Avi Katav
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
| | | | - Inbal Mishalian
- Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital Jerusalem, Jerusalem 91120, Israel
| | - Ophir Hay
- Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital Jerusalem, Jerusalem 91120, Israel
| | | | - John Lawler
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
| | - Francesca Saffioti
- UCL Institute for Liver and Digestive Health, University College of London, London NW3 2PF, UK
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Department of Gastroenterology and Hepatology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health, University College of London, London NW3 2PF, UK
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
| | - Douglas Thorburn
- UCL Institute for Liver and Digestive Health, University College of London, London NW3 2PF, UK
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
| | - Amnon Peled
- Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital Jerusalem, Jerusalem 91120, Israel
| | - Adi Mor
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
| | - Ilan Vaknin
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
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Bradshaw D, Abramowicz I, Bremner S, Verma S, Gilleece Y, Kirk S, Nelson M, Housman R, Miras H, Orkin C, Fox A, Curnock M, Jennings L, Gompels M, Clarke E, Robinson R, Lambert P, Chadwick D, Perry N. Hepmarc: A 96 week randomised controlled feasibility trial of add-on maraviroc in people with HIV and non-alcoholic fatty liver disease. PLoS One 2023; 18:e0288598. [PMID: 37450478 PMCID: PMC10348519 DOI: 10.1371/journal.pone.0288598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 06/26/2023] [Indexed: 07/18/2023] Open
Abstract
OBJECTIVES Maraviroc may reduce hepatic inflammation in people with HIV and non-alcoholic fatty liver disease (HIV-NAFLD) through CCR5-receptor antagonism, which warrants further exploration. METHODS We performed an open-label 96-week randomised-controlled feasibility trial of maraviroc plus optimised background therapy (OBT) versus OBT alone, in a 1:1 ratio, for people with virologically-suppressed HIV-1 and NAFLD without cirrhosis. Dosing followed recommendations for HIV therapy in the Summary of Product Characteristics for maraviroc. The primary outcomes were safety, recruitment and retention rates, adherence and data completeness. Secondary outcomes included the change in Fibroscan-assessed liver stiffness measurements (LSM), controlled attenuation parameter (CAP) and Enhanced Liver Fibrosis (ELF) scores. RESULTS Fifty-three participants (53/60, 88% of target) were recruited; 23 received maraviroc plus OBT; 89% were male; 19% had type 2 diabetes mellitus. The median baseline LSM, CAP & ELF scores were 6.2 (IQR 4.6-7.8) kPa, 325 (IQR 279-351) dB/m and 9.1 (IQR 8.6-9.6) respectively. Primary outcomes: all individuals eligible after screening were randomised; there was 92% (SD 6.6%) adherence to maraviroc [target >90%]; 83% (95%CI 70%-92%) participant retention [target >65%]; 5.5% of data were missing [target <20%]. There were noo Serious Adverse Reactions; mild-moderate intensity Adverse Reactions were reported by five participants (5/23, 22% (95%CI 5%-49%)) [target <10%]. All Adverse Reactions resolved. Secondary outcomes: no important differences were seen by treatment group for the change from baseline in LSM, CAP or ELF scores. CONCLUSIONS This feasibility study provides preliminary evidence of maraviroc safety amongst people with HIV-NAFLD, and acceptable recruitment, retention, and adherence rates. These data support a definitive randomised-controlled trial assessing maraviroc impact on hepatic steatosis and fibrosis. TRIAL REGISTRATION Clinical trial registry: ISCRTN, registration number 31461655.
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Affiliation(s)
- Daniel Bradshaw
- The Lawson Unit, University Hospitals Sussex NHS Foundation Trust, Brighton, United Kingdom
| | - Iga Abramowicz
- Brighton and Sussex Clinical Trials Unit, University of Sussex, Brighton, United Kingdom
| | - Stephen Bremner
- Brighton and Sussex Clinical Trials Unit, University of Sussex, Brighton, United Kingdom
- Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom
| | - Sumita Verma
- Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom
| | - Yvonne Gilleece
- The Lawson Unit, University Hospitals Sussex NHS Foundation Trust, Brighton, United Kingdom
| | - Sarah Kirk
- The Lawson Unit, University Hospitals Sussex NHS Foundation Trust, Brighton, United Kingdom
| | - Mark Nelson
- Department of HIV and Sexual Health, Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom
| | - Rosalie Housman
- Department of HIV and Sexual Health, Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom
| | - Helena Miras
- Grahame Hayton Unit, Barts Health NHS Trust, London, United Kingdom
| | - Chloe Orkin
- Grahame Hayton Unit, Barts Health NHS Trust, London, United Kingdom
| | - Ashini Fox
- Department of Genitourinary Medicine and HIV, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
| | - Michael Curnock
- Department of Genitourinary Medicine and HIV, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
| | - Louise Jennings
- Department of HIV, North Bristol NHS Trust, Bristol, United Kingdom
| | - Mark Gompels
- Department of HIV, North Bristol NHS Trust, Bristol, United Kingdom
| | - Emily Clarke
- Department of Genitourinary Medicine and HIV, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Rachel Robinson
- Department of Genitourinary Medicine and HIV, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Pauline Lambert
- Department of Infectious Diseases, South Tees Hospitals NHS Foundation Trust, Middlesbrough, United Kingdom
| | - David Chadwick
- Department of Infectious Diseases, South Tees Hospitals NHS Foundation Trust, Middlesbrough, United Kingdom
| | - Nicky Perry
- Brighton and Sussex Clinical Trials Unit, University of Sussex, Brighton, United Kingdom
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Greenman R, Segal-Salto M, Barashi N, Hay O, Katav A, Levi O, Vaknin I, Aricha R, Aharoni S, Snir T, Mishalian I, Olam D, Amer J, Salhab A, Safadi R, Maor Y, Trivedi P, Weston CJ, Saffioti F, Hall A, Pinzani M, Thorburn D, Peled A, Mor A. CCL24 regulates biliary inflammation and fibrosis in primary sclerosing cholangitis. JCI Insight 2023; 8:e162270. [PMID: 37345655 PMCID: PMC10371243 DOI: 10.1172/jci.insight.162270] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 05/04/2023] [Indexed: 06/23/2023] Open
Abstract
ˆCCL24 is a pro-fibrotic, pro-inflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation, and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease. Multidrug resistance gene 2-knockout (Mdr2-/-) mice demonstrated CCL24 expression in liver macrophages and were used as a relevant experimental PSC model. CCL24-neutralizing monoclonal antibody, CM-101, significantly improved inflammation, fibrosis, and cholestasis-related markers in the biliary area. Moreover, using spatial transcriptomics, we observed reduced proliferation and senescence of cholangiocytes following CCL24 neutralization. Next, we demonstrated that CCL24 expression was elevated under pro-fibrotic conditions in primary human cholangiocytes and macrophages, and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated following CCL24 inhibition. Correspondingly, CCL24 was found to be highly expressed in liver biopsies of patients with PSC. CCL24 serum levels correlated with Enhanced Liver Fibrosis score, most notably in patients with high alkaline phosphatase levels. These results suggest that blocking CCL24 may have a therapeutic effect in patients with PSC by reducing liver inflammation, fibrosis, and cholestasis.
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Affiliation(s)
| | | | | | - Ophir Hay
- Gene Therapy Institute, Hadassah Hebrew University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Avi Katav
- Chemomab Therapeutics Ltd., Tel Aviv, Israel
| | - Omer Levi
- Chemomab Therapeutics Ltd., Tel Aviv, Israel
| | - Ilan Vaknin
- Chemomab Therapeutics Ltd., Tel Aviv, Israel
| | | | | | - Tom Snir
- Chemomab Therapeutics Ltd., Tel Aviv, Israel
| | - Inbal Mishalian
- Gene Therapy Institute, Hadassah Hebrew University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Devorah Olam
- Gene Therapy Institute, Hadassah Hebrew University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Johnny Amer
- Institute of Gastroenterology and Liver Diseases, Department of Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Ahmad Salhab
- Institute of Gastroenterology and Liver Diseases, Department of Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Rifaat Safadi
- Institute of Gastroenterology and Liver Diseases, Department of Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Yaakov Maor
- Institute of Gastroenterology and Hepatology, Kaplan Medical Center, Rehovot, Israel
| | - Palak Trivedi
- National Institute for Health and Care Research Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Christopher J Weston
- National Institute for Health and Care Research Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Francesca Saffioti
- University College London Institute for Liver and Digestive Health, London, United Kingdom
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, United Kingdom
- Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Andrew Hall
- University College London Institute for Liver and Digestive Health, London, United Kingdom
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, United Kingdom
| | - Massimo Pinzani
- University College London Institute for Liver and Digestive Health, London, United Kingdom
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, United Kingdom
| | - Douglas Thorburn
- University College London Institute for Liver and Digestive Health, London, United Kingdom
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, United Kingdom
| | - Amnon Peled
- Gene Therapy Institute, Hadassah Hebrew University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Adi Mor
- Chemomab Therapeutics Ltd., Tel Aviv, Israel
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Liu JJ, Xin B, Du L, Chen L, Long Y, Feng GS. Pharmaceutical SH2 domain-containing protein tyrosine phosphatase 2 inhibition suppresses primary and metastasized liver tumors by provoking hepatic innate immunity. Hepatology 2023; 77:1512-1526. [PMID: 35503714 PMCID: PMC9948275 DOI: 10.1002/hep.32555] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/27/2022] [Accepted: 05/02/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS SH2 domain-containing protein tyrosine phosphatase 2 (Shp2) is the first identified pro-oncogenic tyrosine phosphatase that acts downstream of receptor tyrosine kinases (RTKs) to promote Ras-extracellular signal-regulated kinase signaling. However, this phosphatase was also shown to be antitumorigenic in HCC. This study is aimed at deciphering paradoxical Shp2 functions and mechanisms in hepatocarcinogenesis and at exploring its value as a pharmaceutical target in HCC therapy. APPROACHES AND RESULTS We took both genetic and pharmaceutical approaches to examine the effects of Shp2 inhibition on primary liver cancers driven by various oncogenes and on metastasized liver tumors. We show here that the catalytic activity of Shp2 was essential for relay of oncogenic signals from RTKs in HCC and that chemical inhibition of Shp2 robustly suppressed HCC driven by RTKs. However, in contrast to a tumor-promoting hepatic niche generated by genetically deleting Shp2 in hepatocytes, treatment with a specific Shp2 inhibitor had a tumor-suppressing effect on metastasized liver tumor progression. Mechanistically, the Shp2 inhibitor enhanced antitumor innate immunity by down-regulating inflammatory cytokines, suppressing the chemokine (C-C motif) receptor 5 signaling axis, but up-regulating interferon-β secretion. CONCLUSIONS These results unveil complex mechanisms for the tumor-suppressing effect of pharmaceutical Shp2 inhibition in the liver immune environment. We provide a proof of principle for clinical trials with specific Shp2 inhibitors in patients with primary and metastasized liver cancer.
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Affiliation(s)
- Jacey J. Liu
- Department of Molecular Biology, School of Biological Sciences, University of California at San Diego, La Jolla, California, USA
| | - Bing Xin
- Department of Pathology and Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, California, USA
| | - Li Du
- Department of Pathology and Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, California, USA
| | - Lydia Chen
- Department of Molecular Biology, School of Biological Sciences, University of California at San Diego, La Jolla, California, USA
| | - Yanyan Long
- Department of Pathology and Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, California, USA
| | - Gen-Sheng Feng
- Department of Molecular Biology, School of Biological Sciences, University of California at San Diego, La Jolla, California, USA
- Department of Pathology and Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, California, USA
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Rosenberg N, Van Haele M, Lanton T, Brashi N, Bromberg Z, Adler H, Giladi H, Peled A, Goldenberg DS, Axelrod JH, Simerzin A, Chai C, Paldor M, Markezana A, Yaish D, Shemulian Z, Gross D, Barnoy S, Gefen M, Amran O, Claerhout S, Fernández-Vaquero M, García-Beccaria M, Heide D, Shoshkes-Carmel M, Schmidt Arras D, Elgavish S, Nevo Y, Benyamini H, Tirnitz-Parker JEE, Sanchez A, Herrera B, Safadi R, Kaestner KH, Rose-John S, Roskams T, Heikenwalder M, Galun E. Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL-6 trans-signaling. J Hepatol 2022; 77:1631-1641. [PMID: 35988690 DOI: 10.1016/j.jhep.2022.07.029] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/07/2022] [Accepted: 07/19/2022] [Indexed: 12/27/2022]
Abstract
BACKGROUND & AIMS Primary liver cancers include hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA) and combined HCC-CCA tumors (cHCC-CCA). It has been suggested, but not unequivocally proven, that hepatic progenitor cells (HPCs) can contribute to hepatocarcinogenesis. We aimed to determine whether HPCs contribute to HCC, cHCC-CCA or both types of tumors. METHODS To trace progenitor cells during hepatocarcinogenesis, we generated Mdr2-KO mice that harbor a yellow fluorescent protein (YFP) reporter gene driven by the Foxl1 promoter which is expressed specifically in progenitor cells. These mice (Mdr2-KOFoxl1-CRE;RosaYFP) develop chronic inflammation and HCCs by the age of 14-16 months, followed by cHCC-CCA tumors at the age of 18 months. RESULTS In this Mdr2-KOFoxl1-CRE;RosaYFP mouse model, liver progenitor cells are the source of cHCC-CCA tumors, but not the source of HCC. Ablating the progenitors, caused reduction of cHCC-CCA tumors but did not affect HCCs. RNA-sequencing revealed enrichment of the IL-6 signaling pathway in cHCC-CCA tumors compared to HCC tumors. Single-cell RNA-sequencing (scRNA-seq) analysis revealed that IL-6 is expressed by immune and parenchymal cells during senescence, and that IL-6 is part of the senescence-associated secretory phenotype. Administration of an anti-IL-6 antibody to Mdr2-KOFoxl1-CRE;RosaYFP mice inhibited the development of cHCC-CCA tumors. Blocking IL-6 trans-signaling led to a decrease in the number and size of cHCC-CCA tumors, indicating their dependence on this pathway. Furthermore, the administration of a senolytic agent inhibited IL-6 and the development of cHCC-CCA tumors. CONCLUSION Our results demonstrate that cHCC-CCA, but not HCC tumors, originate from HPCs, and that IL-6, which derives in part from cells in senescence, plays an important role in this process via IL-6 trans-signaling. These findings could be applied to develop new therapeutic approaches for cHCC-CCA tumors. LAY SUMMARY Combined hepatocellular carcinoma-cholangiocarcinoma is the third most prevalent type of primary liver cancer (i.e. a cancer that originates in the liver). Herein, we show that this type of cancer originates in stem cells in the liver and that it depends on inflammatory signaling. Specifically, we identify a cytokine called IL-6 that appears to be important in the development of these tumors. Our results could be used for the development of novel treatments for these aggressive tumors.
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Affiliation(s)
- Nofar Rosenberg
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Matthias Van Haele
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium; Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Tali Lanton
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Neta Brashi
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Zohar Bromberg
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Hanan Adler
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Hilla Giladi
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Amnon Peled
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Daniel S Goldenberg
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Jonathan H Axelrod
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Alina Simerzin
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Chofit Chai
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Mor Paldor
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Auerlia Markezana
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Dayana Yaish
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Zohar Shemulian
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Dvora Gross
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Shanny Barnoy
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Maytal Gefen
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Osher Amran
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Sofie Claerhout
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
| | - Mirian Fernández-Vaquero
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - María García-Beccaria
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Danijela Heide
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michal Shoshkes-Carmel
- Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Center for Translational Research, Philadelphia, USA
| | - Dirk Schmidt Arras
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany; Department of Biosciences, University of Salzburg, Salzburg, Austria
| | - Sharona Elgavish
- Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Yuval Nevo
- Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Hadar Benyamini
- Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Janina E E Tirnitz-Parker
- Centre for Medical Research, University of Western Australia & Harry Perkins Institute of Medical Research, Crawley, Australia
| | - Aranzazu Sanchez
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Spain
| | - Blanca Herrera
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Spain
| | - Rifaat Safadi
- The Liver Institute, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Klaus H Kaestner
- Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Center for Translational Research, Philadelphia, USA
| | - Stefan Rose-John
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Tania Roskams
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; The M3 Research Institute, Rosenauer Weg 30, Medical Faculty Tuebingen (MFT), 72076 Tuebingen, Germany.
| | - Eithan Galun
- Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
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8
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Single-cell transcriptomics reveals the role of Macrophage-Naïve CD4 + T cell interaction in the immunosuppressive microenvironment of primary liver carcinoma. J Transl Med 2022; 20:466. [PMID: 36221095 PMCID: PMC9552358 DOI: 10.1186/s12967-022-03675-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 09/28/2022] [Indexed: 11/30/2022] Open
Abstract
Background Liver carcinoma generally presents as an immunosuppressive microenvironment that promotes tumor evasion. The intercellular crosstalk of immune cells significantly influences the construction of an immunosuppressive microenvironment. This study aimed to investigate the important interactions between immune cells and their targeting drugs in liver carcinoma, by using single-cell and bulk transcriptomic data. Methods Single-cell and bulk transcriptomic data were retrieved from Gene Expression Omnibus (GSE159977, GSE136103, and GSE125449) and The Cancer Genome Atlas (TGCA-LIHC), respectively. Quality control, dimension reduction, clustering, and annotation were performed according to the Scanpy workflow based on Python. Cell–cell interactions were explored using the CellPhone database and CellChat. Trajectory analysis was executed using a partition-based graph abstraction method. The transcriptomic factors (TFs) were predicted using single-cell regulatory network inference and clustering (SCENIC). The target genes from TFs were used to establish a related score based on the TCGA cohort; this score was subsequently validated by survival, gene set enrichment, and immune cell infiltration analyses. Drug prediction was performed based on the Cancer Therapeutics Response Portal and PRISM Repurposing datasets. Results Thirty-one patients at four different states, including health, hepatitis, cirrhosis, and cancer, were enrolled in this study. After dimension reduction and clustering, twenty-two clusters were identified. Cell–cell interaction analyses indicated that macrophage-naive CD4 + T cell interaction significantly affect cancerous state. In brief, macrophages interact with naive CD4 + T cells via different pathways in different states. The results of SCENIC indicated that macrophages present in cancer cells were similar to those present during cirrhosis. A macrophage-naive CD4 + T cell (MNT) score was generated by the SCENIC-derived target genes. Based on the MNT score, five relevant drugs (inhibitor of polo-like kinase 1, inhibitor of kinesin family member 11, dabrafenib, ispinesib, and epothilone-b) were predicted. Conclusions This study reveals the crucial role of macrophage-naive CD4 + T cell interaction in the immunosuppressive microenvironment of liver carcinoma. Tumor-associated macrophages may be derived from cirrhosis and can initiate liver carcinoma. Predictive drugs that target the macrophage-naive CD4 + T cell interaction may help to improve the immunosuppressive microenvironment and prevent immune evasion. The relevant mechanisms need to be further validated in experiments and cohort studies. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03675-2.
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9
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Silveira CRF, Corveloni AC, Caruso SR, Macêdo NA, Brussolo NM, Haddad F, Fernandes TR, de Andrade PV, Orellana MD, Guerino-Cunha RL. Cytokines as an important player in the context of CAR-T cell therapy for cancer: Their role in tumor immunomodulation, manufacture, and clinical implications. Front Immunol 2022; 13:947648. [PMID: 36172343 PMCID: PMC9512053 DOI: 10.3389/fimmu.2022.947648] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 08/23/2022] [Indexed: 12/02/2022] Open
Abstract
CAR-T cell therapies have been recognized as one of the most advanced and efficient strategies to treat patients with hematologic malignancies. However, similar results have not been observed for the treatment of solid tumors. One of the explanations is the fact that tumors have extremely hostile microenvironments for the infiltration and effector activity of T-cells, mainly due to the presence of highly suppressive cytokines, hypoxia, and reactive oxygen species. Taking advantage of cytokines functionally, new fourth-generation CAR constructs have been developed to target tumor cells and additionally release cytokines that can contribute to the cytotoxicity of T-cells. The manufacturing process, including the use of cytokines in the expansion and differentiation of T cells, is also discussed. Finally, the clinical aspects and the influence of cytokines on the clinical condition of patients, such as cytokine release syndrome, who receive treatment with CAR-T cells are addressed. Therefore, this review aims to highlight how important cytokines are as one of the major players of cell therapy.
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Affiliation(s)
| | | | - Sâmia Rigotto Caruso
- Cell Therapy Laboratory, Fundação Hemocentro de Ribeirão Preto, São Paulo, Brazil
| | - Nathália Araújo Macêdo
- Advanced Cellular Therapy Laboratory, Fundação Hemocentro de Ribeirão Preto, São Paulo, Brazil
| | | | - Felipe Haddad
- Advanced Cellular Therapy Laboratory, Fundação Hemocentro de Ribeirão Preto, São Paulo, Brazil
| | | | - Pamela Viani de Andrade
- Advanced Cellular Therapy Laboratory, Fundação Hemocentro de Ribeirão Preto, São Paulo, Brazil
| | | | - Renato Luiz Guerino-Cunha
- Advanced Cellular Therapy Laboratory, Fundação Hemocentro de Ribeirão Preto, São Paulo, Brazil
- Department of Medical Images, Hematology and Clinical Oncology, Ribeirão Preto Medical School of University of São Paulo, Ribeirão Preto, Brazil
- *Correspondence: Renato Luiz Guerino-Cunha,
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10
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EMT and Inflammation: Crossroads in HCC. J Gastrointest Cancer 2022; 54:204-212. [PMID: 35020133 DOI: 10.1007/s12029-021-00801-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/29/2021] [Indexed: 10/19/2022]
Abstract
Hepatocellular carcinoma is one of the major causes of cancer-related deaths worldwide and is associated with several inflammatory mediators, since 90% of HCCs occur based on chronic hepatitis B or C, alcoholism or increasingly metabolic syndrome-associated inflammation. EMT is a physiological process, with coordinated changes in epithelial gene signatures and is regulated by multiple factors, including cytokines and growth factors such as TGFβ, EGF, and FGF. Recent reports propose a strong association between EMT and inflammation, which is also correlated with tumor aggressiveness and poor outcomes. Cellular heterogeneity results collectively as an outcome of EMT, inflammation, and the tumor microenvironment, and it plays a fundamental role in the progression, complexity of cancer, and chemoresistance. In this review, we highlight recent developments concerning the association of EMT and inflammation in the context of HCC progression. Identifying potential EMT-related biomarkers and understanding EMT regulatory molecules will likely contribute to promising developments in clinical practice and will be a valuable tool for predicting metastasis in general and specifically in HCC.
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11
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Zhang C, Yang M. Targeting T Cell Subtypes for NAFLD and NAFLD-Related HCC Treatment: An Opinion. Front Med (Lausanne) 2021; 8:789859. [PMID: 34869507 PMCID: PMC8637206 DOI: 10.3389/fmed.2021.789859] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 10/28/2021] [Indexed: 12/12/2022] Open
Affiliation(s)
- Chunye Zhang
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, United States
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO, United States
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12
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Levite M, Safadi R, Milgrom Y, Massarwa M, Galun E. Neurotransmitters and Neuropeptides decrease PD-1 in T cells of healthy subjects and patients with hepatocellular carcinoma (HCC), and increase their proliferation and eradication of HCC cells. Neuropeptides 2021; 89:102159. [PMID: 34293596 DOI: 10.1016/j.npep.2021.102159] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/04/2021] [Accepted: 05/09/2021] [Indexed: 01/29/2023]
Abstract
T cells of aged people, and of patients with either cancer or severe infections (including COVID-19), are often exhausted, senescent and dysfunctional, leading to increased susceptibilities, complications and mortality. Neurotransmitters and Neuropeptides bind their receptors in T cells, and induce multiple beneficial T cell functions. Yet, T cells of different people vary in the expression levels of Neurotransmitter and Neuropeptide receptors, and in the magnitude of the corresponding effects. Therefore, we performed an individual-based study on T cells of 3 healthy subjects, and 3 Hepatocellular Carcinoma (HCC) patients. HCC usually develops due to chronic inflammation. The inflamed liver induces reduction and inhibition of CD4+ T cells and Natural Killer (NK) cells. Immune-based therapies for HCC are urgently needed. We tested if selected Neurotransmitters and Neuropeptides decrease the key checkpoint protein PD-1 in human T cells, and increase proliferation and killing of HCC cells. First, we confirmed human T cells express all dopamine receptors (DRs), and glutamate receptors (GluRs): AMPA-GluR3, NMDA-R and mGluR. Second, we discovered that either Dopamine, Glutamate, GnRH-II, Neuropeptide Y and/or CGRP (10nM), as well as DR and GluR agonists, induced the following effects: 1. Decreased significantly both %PD-1+ T cells and PD-1 expression level per cell (up to 60% decrease, within 1 h only); 2. Increased significantly the number of T cells that proliferated in the presence of HCC cells (up to 7 fold increase), 3. Increased significantly T cell killing of HCC cells (up to 2 fold increase). 4. Few non-conventional combinations of Neurotransmitters and Neuropeptides had surprising synergistic beneficial effects. We conclude that Dopamine, Glutamate, GnRH-II, Neuropeptide Y and CGRP, alone or in combinations, can decrease % PD-1+ T cells and PD-1 expression per cell, in T cells of both healthy subjects and HCC patients, and increase their proliferation in response to HCC cells and killing of HCC cells. Yet, testing T cells of many more cancer patients is absolutely needed. Based on these findings and previous ones, we designed a novel "Personalized Adoptive Neuro-Immunotherapy", calling for validation of safety and efficacy in clinical trials.
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Affiliation(s)
- Mia Levite
- Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel; Institute of Gene Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem 91120, Israel.
| | - Rifaat Safadi
- The Liver Unit, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem 91120, Israel
| | - Yael Milgrom
- The Liver Unit, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem 91120, Israel
| | - Muhammad Massarwa
- The Liver Unit, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem 91120, Israel
| | - Eithan Galun
- Institute of Gene Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem 91120, Israel
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13
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Wei B, Yu M, Yao J, Jiang M, An J, Yang J, Lin J, Zhao Y, Zhu Y. Multidimensional Analyses of Tumor Immune Microenvironment Reveal the Possible Rationality of Immunotherapy and Identify High Immunotherapy Response Subtypes for Renal Papillary Cell Carcinoma. Front Immunol 2021; 12:657951. [PMID: 34531849 PMCID: PMC8438207 DOI: 10.3389/fimmu.2021.657951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 08/10/2021] [Indexed: 11/13/2022] Open
Abstract
Kidney renal papillary cell carcinoma (KIRP), the second most common subtype of renal cell carcinoma, still lacks effective treatment regimens for individualized immunotherapy because of the heterogeneity of its elusive immune microenvironment. Therefore, we aimed to comprehensively evaluate the immune microenvironment of KIRP by using the computational biology strategy to analyze the expression profile data of 289 KIRP patients obtained from The Cancer Genome Atlas database. Based on multidimensional, multi-omics bioinformatics analysis, we found that the tumor of patients with KIRP exhibited “hot” tumor characteristics but the CD8+ T cells in the tumor tissues did not limit tumor progression. Thus, patients with KIRP may realize higher clinical benefits by receiving treatment that can reverse CD8+ T-cell exhaustion. Among them, C1 and C3 immune subtypes could realize the best efficacy of reversing CD8+ T-cell exhaustion. Moreover, CCL5 and FASLG expression may be related to the formation of the immunosuppressive microenvironment in the tumors of patients with KIRP. In conclusion, the immune microenvironment landscape presented in this study provides a novel insight for further experimental and clinical exploration of tailored immunotherapy for patients with KIRP.
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Affiliation(s)
- Baojun Wei
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
| | - Meng Yu
- Department of Laboratory Animal Science, China Medical University, Shenyang, China.,Key Laboratory of Transgenic Animal Research, China Medical University, Shenyang, China
| | - Jihang Yao
- Department of Gynecology, The First Hospital of China Medical University, Shenyang, China
| | - Mingzhe Jiang
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
| | - Jun An
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
| | - Jieping Yang
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
| | - Jiaxing Lin
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
| | - Yongkang Zhao
- National Institute of Health and Medical Big Data, China Medical University, Shenyang, China.,Joint Laboratory of Artificial Intelligence and Precision Medicine of China Medical University and Northeastern University, Northeastern University, Shenyang, China
| | - Yuyan Zhu
- Department of Urology, The First Hospital of China Medical University, Shenyang, China.,Joint Laboratory of Artificial Intelligence and Precision Medicine of China Medical University and Northeastern University, Northeastern University, Shenyang, China
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14
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Shriki A, Lanton T, Sonnenblick A, Levkovitch-Siany O, Eidelshtein D, Abramovitch R, Rosenberg N, Pappo O, Elgavish S, Nevo Y, Safadi R, Peled A, Rose-John S, Galun E, Axelrod JH. Multiple Roles of IL6 in Hepatic Injury, Steatosis, and Senescence Aggregate to Suppress Tumorigenesis. Cancer Res 2021; 81:4766-4777. [PMID: 34117031 DOI: 10.1158/0008-5472.can-21-0321] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/05/2021] [Accepted: 06/10/2021] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma (HCC) typically develops on a background of chronic hepatitis for which the proinflammatory cytokine IL6 is conventionally considered a crucial driving factor. Paradoxically, IL6 also acts as a hepatoprotective factor in chronic liver injury. Here we used the multidrug-resistant gene 2 knockout (Mdr2-/-) mouse model to elucidate potential roles of IL6 in chronic hepatitis-associated liver cancer. Long-term analysis of three separate IL6/Stat3 signaling-deficient Mdr2-/- strains revealed aggravated liver injury with increased dysplastic nodule formation and significantly accelerated tumorigenesis in all strains. Tumorigenesis in the IL6/Stat3-perturbed models was strongly associated with enhanced macrophage accumulation and hepatosteatosis, phenotypes of nonalcoholic steatohepatitis (NASH), as well as with significant reductions in senescence and the senescence-associated secretory phenotype (SASP) accompanied by increased hepatocyte proliferation. These findings reveal a crucial suppressive role for IL6/Stat3 signaling in chronic hepatitis-associated hepatocarcinogenesis by impeding protumorigenic NASH-associated phenotypes and by reinforcing the antitumorigenic effects of the SASP. SIGNIFICANCE: These findings describe a context-dependent role of IL6 signaling in hepatocarcinogenesis and predict that increased IL6-neutralizing sgp130 levels in some patients with NASH may herald early HCC development.See related commentary by Huynh and Ernst, p. 4671.
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Affiliation(s)
- Anat Shriki
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Tali Lanton
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Amir Sonnenblick
- Oncology Division, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Orr Levkovitch-Siany
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Dana Eidelshtein
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Rinat Abramovitch
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
- The Wohl Institute for Translational Medicine, Human Biology Research Center, Hadassah University Medical Center, Jerusalem, Israel
| | - Nofar Rosenberg
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Orit Pappo
- Department of Pathology, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Sharona Elgavish
- Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical School, Ein Karem, Jerusalem, Israel
| | - Yuval Nevo
- Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical School, Ein Karem, Jerusalem, Israel
| | - Rifaat Safadi
- Liver Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Amnon Peled
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Stefan Rose-John
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Eithan Galun
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
| | - Jonathan H Axelrod
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
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15
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Czauderna C, Poplawski A, O Rourke CJ, Castven D, Pérez-Aguilar B, Becker D, Heilmann-Heimbach S, Odenthal M, Amer W, Schmiel M, Drebber U, Binder H, Ridder DA, Schindeldecker M, Straub BK, Galle PR, Andersen JB, Thorgeirsson SS, Park YN, Marquardt JU. Epigenetic modifications precede molecular alterations and drive human hepatocarcinogenesis. JCI Insight 2021; 6:e146196. [PMID: 34375307 PMCID: PMC8492348 DOI: 10.1172/jci.insight.146196] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 07/22/2021] [Indexed: 12/24/2022] Open
Abstract
Development of primary liver cancer is a multi-stage process. Detailed understanding of sequential epigenetic alterations is largely missing. Here, we performed Infinium Human Methylation 450k BeadChips and RNA sequencing analyses for genome-wide methylome and transcriptome profiling of cirrhotic liver (n=7), low- (n=4) and high-grade (n=9) dysplastic lesions, early (n=5) and progressed (n=3) hepatocellular carcinomas (HCC) synchronously detected in eight HCC patients with chronic hepatitis B infection. Integrative analyses of epigenetically driven molecular changes were identified and validated in two independent cohorts comprising 887 HCC. Mitochondrial DNA sequencing was further employed for clonality analyses and indicates multi-clonal origin in the majority of investigated HCC. Alterations in DNA methylation progressively increased from CL to dysplastic lesions and reached a maximum in early HCC. Associated early alterations identified by IPA pathway analyses involved apoptosis, immune regulation and stemness pathways, while late changes centered on cell survival, proliferation and invasion. We further validated putative 23 epi-drivers with concomitant expression changes and associated with overall survival. Functionally, Striatin 4 (STRN4) was demonstrated to be epigenetically regulated and inhibition of STRN4 significantly suppressed tumorigenicity of HCC cell lines.Overall, application of integrative genomic analyses defines epigenetic driver alterations and provides promising targets for novel therapeutic approaches.
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Affiliation(s)
- Carolin Czauderna
- Department of Medicine I, University Medical Center Mainz, Mainz, Germany
| | - Alicia Poplawski
- Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), Johannes Gutenberg University, Mainz, Germany
| | - Colm J O Rourke
- Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Darko Castven
- Department of Medicine I, University Medical Center Mainz, Mainz, Germany
| | | | - Diana Becker
- Department of Medicine I, University Medical Center Mainz, Mainz, Germany
| | | | | | - Wafa Amer
- Institute of Pathology, University of Cologne, Cologne, Germany
| | - Marcel Schmiel
- Institute of Pathology, University of Cologne, Cologne, Germany
| | - Uta Drebber
- Institute of Pathology, University of Cologne, Cologne, Germany
| | - Harald Binder
- Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Dirk A Ridder
- Department of Pathology, University Medical Center Mainz, Mainz, Germany
| | | | - Beate K Straub
- Department of Pathology, University Medical Center Mainz, Mainz, Germany
| | - Peter R Galle
- Department of Medicine I, University Medical Center Mainz, Mainz, Germany
| | - Jesper B Andersen
- Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Snorri S Thorgeirsson
- Laboratory of Experimental Carcinogenesis (LEC), National Cancer Institute, NIH, Bethesda, United States of America
| | - Young Nyun Park
- Department of Pathology, Yonsei University, Seoul, Korea, Republic of
| | - Jens U Marquardt
- Department of Medicine I, University Medical Center Mainz, Mainz, Germany
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16
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Zhuang Y, Zhao X, Yuan B, Zeng Z, Chen Y. Blocking the CCL5-CCR5 Axis Using Maraviroc Promotes M1 Polarization of Macrophages Cocultured with Irradiated Hepatoma Cells. J Hepatocell Carcinoma 2021; 8:599-611. [PMID: 34178876 PMCID: PMC8219307 DOI: 10.2147/jhc.s300165] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 05/06/2021] [Indexed: 12/14/2022] Open
Abstract
Purpose The C-C chemokine ligand 5 (CCL5)–C-C chemokine receptor (CCR5) axis facilitates tumor progression via multiple mechanisms. Herein, we elucidated the effect of a CCR5 antagonist (maraviroc [MVC]; blocking the CCL5–CCR5 axis) on the phenotype of macrophages cocultured with irradiated hepatoma cells. In addition, we investigated whether modulation of macrophage polarization can alter tumor cell sensitivity to radiation. Materials and Methods Quantitative reverse-transcription polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assays were applied to examine the levels of macrophage-associated markers. The mechanisms of macrophage polarization were explored by Western blotting in an in vitro model of coculture of human hepatoma cells with macrophages. The radiation sensitivity was examined in a clonogenic radiosensitivity assay. Tumor cell apoptosis was detected by Western blotting and flow cytometry. A mouse model of a subcutaneous tumor was also established. Results CCL5 skewed THP-1 M0 macrophages toward an M2-like phenotype. In coculture with hepatoma cells, macrophages manifested high levels of interleukin (IL) 10, IL-12, tumor necrosis factor α (TNF-α), transforming growth factor β1 (TGF-β1), arginase 1 (ARG1), and IL-1β. Tumor cell irradiation further upregulated these markers in macrophages. After incubation of macrophages with MVC for 24 h, levels of M1 cytokines significantly increased, whereas those of M2 phenotype factors ARG1, TGF-β1, and IL-10 decreased, accompanied by the activation of signal transducer and activator of transcription 3 (STAT3) and downregulation of suppressor of cytokine signaling 3 (SOCS3). The macrophage phenotype reverted to M2 states after treatment with a STAT3 inhibitor. The shift of macrophages toward the M1 phenotype enhanced the radiosensitivity and apoptosis of hepatoma cells. Mice receiving a combination of X-ray irradiation and MVC experienced a better antitumor effect than those receiving either MVC or irradiation alone did. Conclusion M2 polarization of macrophages induced by CCL5–CCR5 signaling can be inhibited using MVC via the STAT3–SOCS3 pathway. The shift of macrophages toward the M1 phenotype promotes the sensitivity of human hepatoma cells to X-ray irradiation.
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Affiliation(s)
- Yuan Zhuang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Xiaomei Zhao
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Baoying Yuan
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Zhaochong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Yixing Chen
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
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17
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Rahman M, Almalki WH, Afzal O, Alfawaz Altamimi AS, Kazmi I, Al-Abbasi FA, Choudhry H, Alenezi SK, Barkat MA, Beg S, Kumar V, Alhalmi A. Cationic Solid Lipid Nanoparticles of Resveratrol for Hepatocellular Carcinoma Treatment: Systematic Optimization, in vitro Characterization and Preclinical Investigation. Int J Nanomedicine 2020; 15:9283-9299. [PMID: 33262588 PMCID: PMC7695602 DOI: 10.2147/ijn.s277545] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 10/29/2020] [Indexed: 11/23/2022] Open
Abstract
Aim The present study focuses on the development and evaluation of the resveratrol (RV)-loaded cationic solid lipid nanoparticles (RV-c-SLNs) for the management of hepatocellular carcinoma (HCC). Materials and Methods Optimization of formulation was performed using factorial design, and further in vitro drug release, cytotoxicity, biodistribution, in vivo preclinical, and biochemical evaluation were carried out. Results The optimized formulation exhibited uniform size, homogeneous disparity, positive zeta potential, and stability over 12-week storage at 25°C/60% RH. The in vitro drug release and cytotoxicity study showed 60% drug release within the first 6 hours and comparatively higher cytotoxicity on HepG2 cell line by resveratrol-solid lipid nanoparticle (RV-SLN) as compared to the RV solution. In addition, an anticancer action and biodistribution study on a rat model of HCC showed significant reduction of tumor volume and higher accumulation in the tumor tissue from RV-c-SLN (P<0.01) over RV solution and RV-SLN. Furthermore, RV-c-SLN showed significant down-regulation in the levels of pro-inflammatory cytokines and balancing of antioxidant enzymes. Histopathological investigation showed reduced occurrence of hepatic nodules, necrosis formation, infiltration of inflammatory cells, blood vessels inflammation, and cell swelling. Conclusion Overall, the obtained results construed that RV-c-SLN with improved antitumor activity as clearly evident from in vitro, in vivo, and biochemical investigations.
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Affiliation(s)
- Mahfoozur Rahman
- Department of Pharmaceutical Sciences, Shalom Institute of Health & Allied Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad, India
| | - Waleed H Almalki
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, AlKharj 11942, Saudi Arabia
| | | | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Fahad A Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hani Choudhry
- Department of Biochemistry, Cancer Metabolism & Epigenetic Unit, Faculty of Science, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sattam K Alenezi
- Department of Pharmacology & Toxicology, Unaizah College of Pharmacy, Qassim University, Qassim, Saudi Arabia
| | - Md Abul Barkat
- Department of Pharmaceutics, College of Pharmacy, University of Hafr Al Batin, Al Jamiah, Hafr Al Batin, Saudi Arabia
| | - Sarwar Beg
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Nanomedicine Research Lab, Jamia Hamdard, New Delhi, India
| | - Vikas Kumar
- Department of Pharmaceutical Sciences, Shalom Institute of Health & Allied Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad, India
| | - Abdulsalam Alhalmi
- Department of Pharmaceutical Science, Collage of Pharmacy, Aden University, Aden, Yemen
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Piconi S, Foschi A, Malagoli A, Carli F, Zona S, Milic J, Ricci ED, Rizzardini G, Guaraldi G. Impact of prolonged maraviroc treatment on non-AIDS-related comorbidities in HIV-positive patients: a retrospective cohort study. J Antimicrob Chemother 2020; 74:2723-2731. [PMID: 31139818 DOI: 10.1093/jac/dkz227] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/29/2019] [Accepted: 04/29/2019] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVES This retrospective study evaluates the effect of maraviroc, the first CCR5 receptor antagonist, on non-AIDS-related comorbidity incidence and its impact on inflammatory and lipid parameters. METHODS Seventy-four HIV patients on maraviroc treatment were compared with 312 patients never exposed to maraviroc (matched for sex, age and CD4 nadir). RESULTS At baseline (T0), maraviroc patients presented a longer duration of HIV infection, a higher prevalence of comorbidities and a greater frequency of polypharmacy. Non-AIDS-defining disease incidence was lower in the maraviroc group than in the non-maraviroc group (without achieving statistical significance). Except triglycerides (TGL), which dropped only in the maraviroc group, inflammatory and immunological parameters did not significantly change in either group by the end of the study period (T3). At T3, high-sensitivity C-reactive protein (hsCRP) and high-density lipoprotein were inversely correlated in both groups (Spearman's rho: maraviroc -0.30, P = 0.05; non-maraviroc -0.23, P = 0.0003). Only in the non-maraviroc group was the positive correlation between hsCRP and lipids observed both at T0 (hsCRP/low-density lipoprotein (LDL) +0.17, P = 0.004; hsCRP/total cholesterol +0.20, P = 0.0007; hsCRP/TGL +0.12, P = 0.04) and T3 (hsCRP/LDL +0.26, P < 0.0001; hsCRP/total cholesterol +0.24, P = 0.0001; hsCRP/TGL +0.15, P = 0.02). These correlations were not found in the maraviroc group. A significant positive correlation was found at T0 and at T3 between hsCRP and D-dimer in both groups (maraviroc: T0 +0.46, P = 0.0007; T3 +0.41, P = 0.006; non-maraviroc: T0 +0.17, P = 0.02; T3: +0.17, P = 0.017). CONCLUSIONS These data suggest a possible protective role of maraviroc in the incidence of non-AIDS-related comorbidities in a population with longer-lasting infection and allow us to hypothesize its role in the modulation of lipid-dependent inflammation.
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Affiliation(s)
- Stefania Piconi
- First Infectious Diseases Department, Ospedale Luigi Sacco, Milano, Italy
| | - Antonella Foschi
- First Infectious Diseases Department, Ospedale Luigi Sacco, Milano, Italy
| | - Andrea Malagoli
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Federica Carli
- HIV Metabolic Clinic, Infectious Diseases, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefano Zona
- HIV Metabolic Clinic, Infectious Diseases, University of Modena and Reggio Emilia, Modena, Italy
| | - Jovana Milic
- HIV Metabolic Clinic, Infectious Diseases, University of Modena and Reggio Emilia, Modena, Italy
| | | | | | - Giovanni Guaraldi
- HIV Metabolic Clinic, Infectious Diseases, University of Modena and Reggio Emilia, Modena, Italy
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Wang Y, Ren S, Wang Z, Wang Z, Zhu N, Cai D, Ye Z, Ruan J. Chemokines in bone-metastatic breast cancer: Therapeutic opportunities. Int Immunopharmacol 2020; 87:106815. [PMID: 32711376 DOI: 10.1016/j.intimp.2020.106815] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/13/2020] [Accepted: 07/14/2020] [Indexed: 12/12/2022]
Abstract
Due to non-response to chemotherapy, incomplete surgical resection, and resistance to checkpoint inhibitors, breast cancer with bone metastasis is notoriously difficult to cure. Therefore, the development of novel, efficient strategies to tackle bone metastasis of breast cancer is urgently needed. Chemokines, which induce directed migration of immune cells and act as guide molecules between diverse cells and tissues, are small proteins indispensable in immunity. These complex chemokine networks play pro-tumor roles or anti-tumor roles when produced by breast cancer cells in the tumor microenvironment. Additionally, chemokines have diverse roles when secreted by various immune cells in the tumor microenvironment of breast cancer, which can be roughly divided into immunosuppressive effects and immunostimulatory effects. Recently, targeting chemokine networks has been shown to have potential for use in treatment of metastatic malignancies, including bone-metastatic breast cancer. In this review, we focus on the role of chemokines networks in the biology of breast cancer and metastasis to the bone. We also discuss the therapeutic opportunities and future prospects of targeting chemokine networks, in combination with other current standard therapies, for the treatment of bone-metastatic breast cancer.
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Affiliation(s)
| | - Shihong Ren
- First People's Hospital of Wenling, Wenling, China
| | - Zhan Wang
- Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zenan Wang
- Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ning Zhu
- Hebei North University, Zhangjiakou, China
| | | | - Zhaoming Ye
- Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Bradshaw D, Gilleece Y, Verma S, Abramowicz I, Bremner S, Perry N. Protocol for a phase IV, open-label feasibility study investigating non-invasive markers of hepatic fibrosis in people living with HIV-1 and non-alcoholic fatty liver disease randomised to receiving optimised background therapy (OBT) plus maraviroc or OBT alone. BMJ Open 2020; 10:e035596. [PMID: 32636281 PMCID: PMC7342479 DOI: 10.1136/bmjopen-2019-035596] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION At least 30% of people living with HIV (PLWH) infection have non-alcoholic fatty liver disease (NAFLD), which has now become a leading cause of hepatic fibrosis and cirrhosis. Management is based largely on lifestyle modifications, which are difficult to achieve, and therapeutic options are urgently needed. Maraviroc (MVC), through antagonism of CCR5 receptors, may reduce hepatic fibrosis progression and could be an effective treatment for NAFLD. However, dosing is usually two times per day, unlike most currently recommended antiretroviral therapies. This study will investigate the feasibility and acceptability of addition of MVC to combination antiretroviral therapy in PLWH and NAFLD as a treatment for NAFLD. METHODS AND ANALYSIS This is a phase IV, randomised, open-label, non-invasive feasibility study. Sixty individuals with well-controlled HIV-1 and NAFLD will be recruited from UK HIV clinics and randomised 1:1 to receive either optimised background therapy (OBT) plus MVC or OBT alone. Follow-up will be every 24 weeks for 96 weeks. The primary outcome measures will include recruitment and retention rates, adverse events and adherence. Secondary outcomes will include changes in markers of hepatic fibrosis, including the Enhanced Liver Fibrosis score, median liver stiffness measurement and controlled attenuation parameter scores on Fibroscan, and quality of life assessments. Analyses will be performed according to intention-to-treat principles. For secondary outcomes, estimated differences and 95% CIs between the groups using a t-method will be presented for continuous variables and as exact 95% binomial CIs for categorical variables. ETHICS AND DISSEMINATION Ethical approval was obtained through the London Dulwich UK Research Ethics Committee (reference 17/LO/2093). Results will be disseminated both through community groups and peer-reviewed scientific literature.Trial registration number SRCTN31461655. EudraCT number 2017-004141-24; Pre-results.
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Affiliation(s)
- Daniel Bradshaw
- Brighton and Sussex University Hospitals NHS Trust, Brighton
| | - Yvonne Gilleece
- Brighton and Sussex University Hospitals NHS Trust, Brighton
| | - Sumita Verma
- Brighton and Sussex Medical School, Brighton, UK
| | | | | | - Nicky Perry
- Brighton and Sussex Medical School, Brighton, UK
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22
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Tsukamoto T. Hematopoietic Stem/Progenitor Cells and the Pathogenesis of HIV/AIDS. Front Cell Infect Microbiol 2020; 10:60. [PMID: 32154191 PMCID: PMC7047323 DOI: 10.3389/fcimb.2020.00060] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/06/2020] [Indexed: 12/13/2022] Open
Abstract
The interaction between human immunodeficiency virus (HIV) and hematopoietic stem/progenitor cells (HSPCs) has been of great interest. However, it remains unclear whether HSPCs can act as viral reservoirs. Many studies have reported the presence of latently infected HSPCs in the bone marrow of HIV-infected patients, whereas many other investigators have reported negative results. Hence, further evidence is required to elucidate this controversy. The other arm of HSPC investigations of HIV infection involves dynamics analysis in the early and late stages of infection to understand the impact on the pathogenesis of acquired immunodeficiency syndrome. Several recent studies have suggested reduced amounts and/or functional impairment of multipotent, myeloid, and lymphoid progenitors in HIV infection that may contribute to hematological manifestations, including anemia, pancytopenia, and T-cell depletion. In addition, ongoing and future studies on the senescence of HSPCs are expected to further the understanding of HIV pathogenesis. This mini review summarizes reports describing the basic aspects of hematopoiesis in response to HIV infection and offers insights into the association of HIV infection/exposure of the host HSPCs and hematopoietic potential.
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Affiliation(s)
- Tetsuo Tsukamoto
- Department of Immunology, Faculty of Medicine, Kindai University, Osaka, Japan
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23
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Siracusano G, Tagliamonte M, Buonaguro L, Lopalco L. Cell Surface Proteins in Hepatocellular Carcinoma: From Bench to Bedside. Vaccines (Basel) 2020; 8:vaccines8010041. [PMID: 31991677 PMCID: PMC7157713 DOI: 10.3390/vaccines8010041] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 01/16/2020] [Accepted: 01/22/2020] [Indexed: 12/20/2022] Open
Abstract
Cell surface proteins act as the go-between in carrying the information from the extracellular environment to the intracellular signaling proteins. However, these proteins are often deregulated in neoplastic diseases, including hepatocellular carcinoma. This review discusses several recent studies that have investigated the role of cell surface proteins in the occurrence and progression of HCC, highlighting the possibility to use them as biomarkers of the disease and/or targets for vaccines and therapeutics.
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Affiliation(s)
- Gabriel Siracusano
- Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy;
- Correspondence: ; Tel.: +39-022643-4957
| | - Maria Tagliamonte
- Cancer Immunoregulation Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori IRCCS, “Fondazione Pascale”, 80131 Naples, Italy; (M.T.); (L.B.)
| | - Luigi Buonaguro
- Cancer Immunoregulation Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori IRCCS, “Fondazione Pascale”, 80131 Naples, Italy; (M.T.); (L.B.)
| | - Lucia Lopalco
- Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy;
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Lefere S, Devisscher L, Tacke F. Targeting CCR2/5 in the treatment of nonalcoholic steatohepatitis (NASH) and fibrosis: opportunities and challenges. Expert Opin Investig Drugs 2020; 29:89-92. [PMID: 31952447 DOI: 10.1080/13543784.2020.1718106] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- Sander Lefere
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium
| | - Lindsey Devisscher
- Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medical Center, Berlin, Germany
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Abstract
As basic research into GPCR signaling and its association with disease has come into fruition, greater clarity has emerged with regards to how these receptors may be amenable to therapeutic intervention. As a diverse group of receptor proteins, which regulate a variety of intracellular signaling pathways, research in this area has been slow to yield tangible therapeutic agents for the treatment of a number of diseases including cancer. However, recently such research has gained momentum based on a series of studies that have sought to define GPCR proteins dynamics through the elucidation of their crystal structures. In this chapter, we define the approaches that have been adopted in developing better therapeutics directed against the specific parts of the receptor proteins, such as the extracellular and the intracellular domains, including the ligands and auxiliary proteins that bind them. Finally, we also briefly outline how GPCR-derived signaling transduction pathways hold great potential as additional targets.
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Affiliation(s)
- Surinder M Soond
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russian Federation.
| | - Andrey A Zamyatnin
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russian Federation; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russian Federation.
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26
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Fantuzzi L, Tagliamonte M, Gauzzi MC, Lopalco L. Dual CCR5/CCR2 targeting: opportunities for the cure of complex disorders. Cell Mol Life Sci 2019; 76:4869-4886. [PMID: 31377844 PMCID: PMC6892368 DOI: 10.1007/s00018-019-03255-6] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 06/27/2019] [Accepted: 07/24/2019] [Indexed: 02/06/2023]
Abstract
The chemokine system mediates acute inflammation by driving leukocyte migration to damaged or infected tissues. However, elevated expression of chemokines and their receptors can contribute to chronic inflammation and malignancy. Thus, great effort has been taken to target these molecules. The first hint of the druggability of the chemokine system was derived from the role of chemokine receptors in HIV infection. CCR5 and CXCR4 function as essential co-receptors for HIV entry, with the former accounting for most new HIV infections worldwide. Not by chance, an anti-CCR5 compound, maraviroc, was the first FDA-approved chemokine receptor-targeting drug. CCR5, by directing leukocytes to sites of inflammation and regulating their activation, also represents an important player in the inflammatory response. This function is shared with CCR2 and its selective ligand CCL2, which constitute the primary chemokine axis driving the recruitment of monocytes/macrophages to inflammatory sites. Both receptors are indeed involved in the pathogenesis of several immune-mediated diseases, and dual CCR5/CCR2 targeting is emerging as a more efficacious strategy than targeting either receptor alone in the treatment of complex human disorders. In this review, we focus on the distinctive and complementary contributions of CCR5 and CCR2/CCL2 in HIV infection, multiple sclerosis, liver fibrosis and associated hepatocellular carcinoma. The emerging therapeutic approaches based on the inhibition of these chemokine axes are highlighted.
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Affiliation(s)
- Laura Fantuzzi
- National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy.
| | - Maria Tagliamonte
- Cancer Immunoregulation Unit, Istituto Nazionale Tumori- IRCCS-"Fond G. Pascale", Naples, Italy
| | | | - Lucia Lopalco
- Immunobiology of HIV Unit, Division Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.
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Mouse Models for Immunotherapy in Hepatocellular Carcinoma. Cancers (Basel) 2019; 11:cancers11111800. [PMID: 31731753 PMCID: PMC6896030 DOI: 10.3390/cancers11111800] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 11/01/2019] [Indexed: 12/13/2022] Open
Abstract
Liver cancer is one of the dominant causes of cancer-related mortality, and the survival rate of liver cancer is among the lowest for all cancers. Immunotherapy for hepatocellular carcinoma (HCC) has yielded some encouraging results, but the percentage of patients responding to single-agent therapies remains low. Therefore, potential directions for improved immunotherapies include identifying new immune targets and checkpoints and customizing treatment procedures for individual patients. The development of combination therapies for HCC is also crucial and urgent and, thus, further studies are required. Mice have been utilized in immunotherapy research due to several advantages, for example, being low in cost, having high success rates for inducing tumor growth, and so on. Moreover, immune-competent mice are used in immunotherapy research to clarify the role that the immune system plays in cancer growth. In this review paper, the advantages and disadvantages of mouse models for immunotherapy, the equipment that are used for monitoring HCC, and the cell strains used for inducing HCC are reviewed.
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Wiedemann GM, Röhrle N, Makeschin MC, Fesseler J, Endres S, Mayr D, Anz D. Peritumoural CCL1 and CCL22 expressing cells in hepatocellular carcinomas shape the tumour immune infiltrate. Pathology 2019; 51:586-592. [PMID: 31445808 DOI: 10.1016/j.pathol.2019.06.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 05/16/2019] [Accepted: 06/06/2019] [Indexed: 12/21/2022]
Abstract
Development, course of disease and prognosis of hepatocellular carcinomas (HCC) are strongly influenced by the immune system. Immunosuppressive regulatory T cells (Treg) have been shown to negatively impact disease progression and survival. To further understand the mechanisms of Treg attraction to HCC lesions, this study provides an analysis of Treg attracting chemokines in human HCC tissues. We analysed the expression of the Treg attracting chemokines CCL1 and CCL22 as well as the infiltration of FoxP3+ Treg and CD8+ T cells in paraffin-embedded tissue sections of 62 HCC patients. Expression of both chemokines was detected in 47 of 62 tissue slides. Chemokine expression was generally higher in tumour stroma and peritumoural liver tissue than in the tumour tissue itself. CD8+ T cells and FoxP3+ Treg were found at high levels in many tumour tissues. Intratumoural infiltration of Treg positively correlated with CCL22 levels in peritumoural liver tissue. In contrast, no correlation of Treg numbers and expression of CCL1 was detected. In summary, we describe here that the chemokines CCL1 and CCL22 are expressed in HCC tissues and, to a higher extent, in the stroma and peritumoural liver tissue. CCL22 may contribute to Treg recruitment and immunosuppression, whereas the role of CCL1 remains to be defined. It will be interesting to investigate the potential of these chemokines as drug targets for cancer therapy.
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Affiliation(s)
- Gabriela M Wiedemann
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Natascha Röhrle
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Marie-Christine Makeschin
- Pathologisches Institut, Medizinische Fakultät der Ludwig-Maximilians Universität München, Munich, Germany
| | - Julia Fesseler
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Stefan Endres
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Doris Mayr
- Pathologisches Institut, Medizinische Fakultät der Ludwig-Maximilians Universität München, Munich, Germany
| | - David Anz
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany; Department of Medicine II, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
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Fatima F, Saleem S, Hameed A, Haider G, Ali Zaidi SA, Kanwal M, Zehra S, Azhar A. Association analysis and allelic distribution of deletion in CC chemokine receptor 5 gene (CCR5Δ32) among breast cancer patients of Pakistan. Mol Biol Rep 2019; 46:2387-2394. [DOI: 10.1007/s11033-019-04699-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 02/12/2019] [Indexed: 12/17/2022]
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Ponziani FR, Bhoori S, Castelli C, Putignani L, Rivoltini L, Del Chierico F, Sanguinetti M, Morelli D, Paroni Sterbini F, Petito V, Reddel S, Calvani R, Camisaschi C, Picca A, Tuccitto A, Gasbarrini A, Pompili M, Mazzaferro V. Hepatocellular Carcinoma Is Associated With Gut Microbiota Profile and Inflammation in Nonalcoholic Fatty Liver Disease. Hepatology 2019; 69:107-120. [PMID: 29665135 DOI: 10.1002/hep.30036] [Citation(s) in RCA: 449] [Impact Index Per Article: 74.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 04/06/2018] [Indexed: 02/06/2023]
Abstract
The gut-liver axis plays a pivotal role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), which is the third leading cause of hepatocellular carcinoma (HCC) worldwide. However, the link between gut microbiota and hepatocarcinogenesis remains to be clarified. The aim of this study was to explore what features of the gut microbiota are associated with HCC in patients with cirrhosis and NAFLD. A consecutive series of patients with NAFLD-related cirrhosis and HCC (group 1, 21 patients), NAFLD-related cirrhosis without HCC (group 2, 20 patients), and healthy controls (group 3, 20 patients) was studied for gut microbiota profile, intestinal permeability, inflammatory status, and circulating mononuclear cells. We finally constructed a model depicting the most relevant correlations among these features, possibly involved in hepatocarcinogenesis. Patients with HCC showed increased levels of fecal calprotectin, while intestinal permeability was similar to patients with cirrhosis but without HCC. Plasma levels of interleukin 8 (IL8), IL13, chemokine (C-C motif) ligand (CCL) 3, CCL4, and CCL5 were higher in the HCC group and associated with an activated status of circulating monocytes. The fecal microbiota of the whole group of patients with cirrhosis showed higher abundance of Enterobacteriaceae and Streptococcus and a reduction in Akkermansia. Bacteroides and Ruminococcaceae were increased in the HCC group, while Bifidobacterium was reduced. Akkermansia and Bifidobacterium were inversely correlated with calprotectin concentration, which in turn was associated with humoral and cellular inflammatory markers. A similar behavior was also observed for Bacteroides. Conclusion: Our results suggest that in patients with cirrhosis and NAFLD the gut microbiota profile and systemic inflammation are significantly correlated and can concur in the process of hepatocarcinogenesis.
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Affiliation(s)
- Francesca Romana Ponziani
- Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione IRCCS, Agostino Gemelli Hospital, Catholic University, Rome, Italy
| | - Sherrie Bhoori
- Hepato-Bilio-Pancreatic Surgery and Liver Transplantation, Fondazione IRCCS, Istituto Nazionale Tumori and University of Milan, Italy
| | - Chiara Castelli
- Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Lorenza Putignani
- Human Microbiome Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.,Parasitology Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Licia Rivoltini
- Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Maurizio Sanguinetti
- Microbiology Unit, Fondazione IRCCS, Agostino Gemelli Hospital, Catholic University, Rome, Italy
| | - Daniele Morelli
- Biochemistry Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Valentina Petito
- Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione IRCCS, Agostino Gemelli Hospital, Catholic University, Rome, Italy
| | - Sofia Reddel
- Human Microbiome Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Riccardo Calvani
- Department of Geriatrics, Neuroscience and Orthopedics, Fondazione IRCCS, Agostino Gemelli Hospital, Catholic University, Rome, Italy
| | - Chiara Camisaschi
- Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Anna Picca
- Department of Geriatrics, Neuroscience and Orthopedics, Fondazione IRCCS, Agostino Gemelli Hospital, Catholic University, Rome, Italy
| | - Alessandra Tuccitto
- Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Antonio Gasbarrini
- Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione IRCCS, Agostino Gemelli Hospital, Catholic University, Rome, Italy
| | - Maurizio Pompili
- Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione IRCCS, Agostino Gemelli Hospital, Catholic University, Rome, Italy
| | - Vincenzo Mazzaferro
- Hepato-Bilio-Pancreatic Surgery and Liver Transplantation, Fondazione IRCCS, Istituto Nazionale Tumori and University of Milan, Italy
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Suenaga M, Stintzing S, Cao S, Zhang W, Yang D, Ning Y, Okazaki S, Berger MD, Miyamoto Y, Schirripa M, Soni S, Barzi A, Heinemann V, Lenz HJ. Role of CCL5 and CCR5 gene polymorphisms in epidermal growth factor receptor signalling blockade in metastatic colorectal cancer: analysis of the FIRE-3 trial. Eur J Cancer 2019; 107:100-114. [PMID: 30554073 PMCID: PMC6367121 DOI: 10.1016/j.ejca.2018.11.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 11/10/2018] [Accepted: 11/10/2018] [Indexed: 12/28/2022]
Abstract
BACKGROUND Epidermal growth factor receptor signalling blockade increases CCL5 expression that regulates either the anti-tumour immune response or tumour progression. We investigated the potential role of CCL5/CCR5 axis in cetuximab-based treatment in metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS Genomic DNA was extracted from 491 samples of two different cohorts with KRAS wild-type mCRC from the FIRE-3 trial: an evaluation cohort of 244 patients receiving cetuximab plus FOLFIRI and a control cohort of 247 patients receiving bevacizumab plus FOLFIRI. Single-nucleotide polymorphisms (SNPs) of CCL5 and CCR5 genes were analysed by polymerase chain reaction-based direct sequencing. RESULTS Patients in the evaluation cohort with any CCL5 rs2280789G allele had shorter overall survival (OS) compared with those with the A/A variant (hazard ratio 1.56, P = 0.024). Patients carrying any CCR5 rs1799988T allele had a trend toward lower response rate than those with the C/C variant (68 vs. 81%, P = 0.078). In the analysis based on primary tumour location (left-sided [L]: right-sided [R]), remarkable differences in outcomes were observed between patients with L-CCR5 SNPs C/C variant (L-C/C), L-any T, R-T/T and R-any C as follows: median OS, 38.5, 30.6, 27.1 and 15.8 months, P < 0.001; response rate, 91, 66, 92 and 48%, P < 0.001. Median OS for CCL5 SNPs including L-A/A, L-any G, R-A/A and R-any G groups were 38.3, 21.7, 21.9 and 18.3 months, P < 0.001. The findings were not significant in the control cohort. CONCLUSION Genetic variants of CCL5 and CCR5 SNPs may predict outcomes in mCRC patients receiving cetuximab-based treatment depending on tumour location.
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Affiliation(s)
- Mitsukuni Suenaga
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
| | - Sebastian Stintzing
- Department of Medicine III, University Hospital, LMU Munich, Marchioninistrasse 15, 81377 Munich, Germany
| | - Shu Cao
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Dongyun Yang
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Yan Ning
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Satoshi Okazaki
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Martin D Berger
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Yuji Miyamoto
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Marta Schirripa
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Afsaneh Barzi
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Volker Heinemann
- Department of Medicine III, University Hospital, LMU Munich, Marchioninistrasse 15, 81377 Munich, Germany
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
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Suenaga M, Cao S, Zhang W, Yang D, Ning Y, Okazaki S, Berger MD, Miyamoto Y, Schirripa M, Soni S, Barzi A, Yamaguchi T, Lenz HJ. Genetic variants in CCL5 and CCR5 genes and serum VEGF-A levels predict efficacy of bevacizumab in metastatic colorectal cancer patients. Int J Cancer 2018; 144:2567-2577. [PMID: 30411783 DOI: 10.1002/ijc.31968] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 10/23/2018] [Accepted: 10/29/2018] [Indexed: 01/07/2023]
Abstract
Early VEGF-A reduction (EVR) by targeting abundant VEGF-A is a potential predictive marker of bevacizumab (BEV). The CCL5/CCR5 axis modulates VEGF-A production via endothelial progenitor cells migration. We tested whether genetic polymorphisms in the CCL5/CCR5 pathway could predict efficacy of BEV in patients with metastatic colorectal cancer (mCRC) in a first-line setting. Genomic DNA was extracted from 215 samples from three independent cohorts: 61 patients receiving FOLFOX+BEV (evaluation cohort); 83 patients receiving FOLFOX (control cohort); 71 patients receiving FOLFOX/XELOX+BEV (exploratory cohort) for validation and serum biochemistry assay (n = 48). Single nucleotide polymorphisms of genes in the CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Considering the unbalanced distribution of patient baseline characteristics between the evaluation and control cohorts, propensity score matching analysis was performed. Serum VEGF-A levels during treatment were measured using ELISA. Among the evaluation and control cohorts, patients with any CCL5 rs2280789 G allele had longer progression-free survival (PFS) and overall survival (OS) when receiving FOLFOX+BEV than FOLFOX (PFS: 19.8 vs. 11.0 months, HR 0.44, 95%CI: 0.24-0.83, p = 0.004; OS: 41.8 vs. 24.5 months, HR: 0.50, 95%CI: 0.26-0.95, p = 0.024). No significant difference was shown in patients with the A/A variant. In the exploratory cohort, CCL5 rs2280789 G alleles were associated with higher VEGF-A levels at baseline and a greater decrease in VEGF-A levels at day 14 compared to the A/A variant. CCL5 and CCR5 impact the angiogenic environment, and the genotypes in CCL5/CCR5 genes may identify specific populations who will benefit from BEV in first-line treatment for mCRC.
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Affiliation(s)
- Mitsukuni Suenaga
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA.,Gastroenterology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shu Cao
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Wu Zhang
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Dongyun Yang
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Yan Ning
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Satoshi Okazaki
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Martin D Berger
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Yuji Miyamoto
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Marta Schirripa
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Shivani Soni
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Afsaneh Barzi
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Toshiharu Yamaguchi
- Gastroenterology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Heinz-Josef Lenz
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
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Karatayli E, Hall RA, Weber SN, Dooley S, Lammert F. Effect of alcohol on the interleukin 6-mediated inflammatory response in a new mouse model of acute-on-chronic liver injury. Biochim Biophys Acta Mol Basis Dis 2018; 1865:298-307. [PMID: 30447270 DOI: 10.1016/j.bbadis.2018.11.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 11/09/2018] [Accepted: 11/13/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS ACLF is usually associated with a precipitant in the setting of a chronically damaged liver. We aim to combine a mouse model with a pre-injured liver (Abcb4/Mdr2-/-) with a recently standardized ethanol feeding model to dissect alcohol-related inflammatory responses in this model. METHOD Ten (n = 64) and 15 (n = 64) week old wild-type (WT) C57BL/6 J and Abcb4-/- knock-out (KO) mice were either fed control (WT/Cont and KO/Cont groups) or liquid ethanol diet (5% v/v) followed by an ethanol binge (4 mg/kg) (WT/EtOH and KO/EtOH groups). Hepatic mRNA levels of IL6, IFN-G, IL-1B, TGFB1, TNF-A, CCL2, HGF, CRP, RANTES, PNPLA3 and COL3A1 were evaluated using the 2-ΔΔCt method. IL6 and HGF plasma levels were quantified by ELISA. RESULTS Older mice in KO/EtOH group displayed higher IL6 expressions compared to KO/Cont, WT/EtOH and WT/Cont groups of the same age, whereas HGF did not differ. Significant over-expression of CCL2 also corresponded to the same group. Males in KO/EtOH group exhibited higher IL6 expression than females. Lipid droplets were observed in about 80% of mice challenged with ethanol. There was a profound downregulation in PNPLA3 and RANTES levels after ethanol exposure. Mean size of the LDs was inversely correlated with hepatic PNPLA3 levels. CONCLUSION We propose a novel promising approach to model alcohol-related ACLI. Acute inflammatory IL6-driven response might help transition from a stable chronic state to a progressive liver damage in Abcb4-/- mice. Repression of PNPLA3 resulted in a notable expansion in size of lipid droplets, indicating lipid remodeling in this model.
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Affiliation(s)
- Ersin Karatayli
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
| | - Rabea A Hall
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Susanne N Weber
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Steven Dooley
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
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Pérez-Martínez L, Ochoa-Callejero L, Rubio-Mediavilla S, Narro J, Bernardo I, Oteo JA, Blanco JR. Maraviroc improves hepatic triglyceride content but not inflammation in a murine nonalcoholic fatty liver disease model induced by a chronic exposure to high-fat diet. Transl Res 2018; 196:17-30. [PMID: 29421523 DOI: 10.1016/j.trsl.2018.01.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 12/19/2017] [Accepted: 01/16/2018] [Indexed: 01/11/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the general population. Its severity ranges from simple steatosis to cirrhosis. C-C chemokine ligand type 5 or RANTES (Regulated upon Activation, Normal T-cell Expressed, and Secreted) plays an important role in the progression of hepatic inflammation and fibrosis. Our objective was to examine the preventive and therapeutic effects of maraviroc (MVC), a C-C chemokine receptor 5 antagonist, on liver pathology in an NAFLD mouse model. A total of 60 male C57BL/6 mice were randomly assigned to 1 of 4 groups: (1) high-fat diet (HFD) group or control group, (2) preventive group (HFD group plus MVC in drinking water since the beginning of the study), (3) early-therapeutic group (HFD group plus MVC in drinking starting at week 24 of the study), and (4) late-therapeutic group (HFD group plus MVC in drinking water starting at week 36 of the study). All mice were sacrificed at week 48. The hepatic triglyceride concentration in the HFD group was significantly higher than that in the groups treated with MVC at any time. Gene expression associated with lipogenesis (diacylglycerol acyltransferase 2 and proliferator-activated receptor-γ), insulin resistance (insulin receptor substrate-2), and β-oxidation (carnitine palmitoyltransferase 1A and acyl-CoA oxidase) was significantly reduced in all the groups treated with MVC. In summary, the beneficial effect of MVC on hepatic steatosis is maintained throughout the study.
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Affiliation(s)
- Laura Pérez-Martínez
- Infectious Diseases Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain
| | | | | | - Judit Narro
- Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain
| | - Iván Bernardo
- Biomedical Diagnostic Service, Hospital San Pedro, Logroño, Spain
| | - José-Antonio Oteo
- Infectious Diseases Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain
| | - José-Ramón Blanco
- Infectious Diseases Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain.
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Ram AK, Pottakat B, Vairappan B. Increased systemic zonula occludens 1 associated with inflammation and independent biomarker in patients with hepatocellular carcinoma. BMC Cancer 2018; 18:572. [PMID: 29776350 PMCID: PMC5960107 DOI: 10.1186/s12885-018-4484-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 05/08/2018] [Indexed: 02/08/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a frequent type of primary liver cancer, and its prevalence is increasing worldwide. Indeed, the underlying molecular mechanism is not well understood. Previous studies have shown evidence that tight junction (TJ) components were correlated with carcinogenesis and tumor development. Our aims were to determine the serum levels of tight junction protein Zonula Occludens (ZO)-1 and an inflammatory marker such as high-sensitive C-reactive protein (hs-CRP) in HCC patients compared to healthy volunteers and also to identify the association between ZO-1 and inflammation in HCC. Methods Thirty HCC patients and 30 healthy volunteers were recruited in the current study. Clinical data regarding child class, BCLC staging, the number of lesions, tumor size, absence or presence of metastasis, cirrhosis and hepatitis infection were also collected in HCC patients. Plasma ZO-1 and serum hsCRP were analyzed by EIA and ELISA respectively and biochemical parameters by autoanalyser (AU680 Beckman Coulter, USA). Furthermore, hepatic ZO-1 protein expression and tissue localization were examined. Results Compared to healthy individuals, the serum levels of bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP) were elevated significantly (P < 0.0001) whilst serum albumin level was significantly (P < 0.0001) decreased in HCC patients. Furthermore, tight junction protein ZO-1 concentration was significantly elevated in HCC patients compared to control subjects (648 ± 183.8 vs. 396.4 ± 135.8 pg/ml, respectively; P < 0.0001). Serum hsCRP level was also significantly increased in HCC patients compared to control subjects (17.25 ± 3.57 vs. 5.54 ± 2.62 mg/L, respectively; P < 0.0001). Moreover, decreased protein expression of ZO-1 was found in liver tissue obtained from HCC patients. Conclusion Our findings show for the first time that the systemic concentration of ZO-1 was significantly elevated in HCC patients and is positively correlated with inflammatory markers. Thus, the current study showing evidence that inflammation promotes plasma ZO-1 concentration and raises the possibility that it could be used as a potential diagnostic biomarker for HCC progression. Electronic supplementary material The online version of this article (10.1186/s12885-018-4484-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Amit Kumar Ram
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Puducherry, 605006, India
| | - Biju Pottakat
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India
| | - Balasubramaniyan Vairappan
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Puducherry, 605006, India.
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Peng WT, Sun WY, Li XR, Sun JC, Du JJ, Wei W. Emerging Roles of G Protein-Coupled Receptors in Hepatocellular Carcinoma. Int J Mol Sci 2018; 19:ijms19051366. [PMID: 29734668 PMCID: PMC5983678 DOI: 10.3390/ijms19051366] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 04/24/2018] [Accepted: 04/26/2018] [Indexed: 12/13/2022] Open
Abstract
Among a great variety of cell surface receptors, the largest superfamily is G protein-coupled receptors (GPCRs), also known as seven-transmembrane domain receptors. GPCRs can modulate diverse signal-transduction pathways through G protein-dependent or independent pathways which involve β-arrestins, G protein receptor kinases (GRKs), ion channels, or Src kinases under physiological and pathological conditions. Recent studies have revealed the crucial role of GPCRs in the tumorigenesis and the development of cancer metastasis. We will sum up the functions of GPCRs—particularly those coupled to chemokines, prostaglandin, lysophosphatidic acid, endothelin, catecholamine, and angiotensin—in the proliferation, invasion, metastasis, and angiogenesis of hepatoma cells and the development of hepatocellular carcinoma (HCC) in this review. We also highlight the potential avenues of GPCR-based therapeutics for HCC.
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Affiliation(s)
- Wen-Ting Peng
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Wu-Yi Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Xin-Ran Li
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Jia-Chang Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Jia-Jia Du
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
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Collino A, Termanini A, Nicoli P, Diaferia G, Polletti S, Recordati C, Castiglioni V, Caruso D, Mitro N, Natoli G, Ghisletti S. Sustained activation of detoxification pathways promotes liver carcinogenesis in response to chronic bile acid-mediated damage. PLoS Genet 2018; 14:e1007380. [PMID: 29734330 PMCID: PMC5957449 DOI: 10.1371/journal.pgen.1007380] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 05/17/2018] [Accepted: 04/26/2018] [Indexed: 01/14/2023] Open
Abstract
Chronic inflammation promotes oncogenic transformation and tumor progression. Many inflammatory agents also generate a toxic microenvironment, implying that adaptive mechanisms must be deployed for cells to survive and undergo transformation in such unfavorable contexts. A paradigmatic case is represented by cancers occurring in pediatric patients with genetic defects of hepatocyte phosphatidylcholine transporters and in the corresponding mouse model (Mdr2-/- mice), in which impaired bile salt emulsification leads to chronic hepatocyte damage and inflammation, eventually resulting in oncogenic transformation. By combining genomics and metabolomics, we found that the transition from inflammation to cancer in Mdr2-/- mice was linked to the sustained transcriptional activation of metabolic detoxification systems and transporters by the Constitutive Androstane Receptor (CAR), a hepatocyte-specific nuclear receptor. Activation of CAR-dependent gene expression programs coincided with reduced content of toxic bile acids in cancer nodules relative to inflamed livers. Treatment of Mdr2-/- mice with a CAR inhibitor blocked cancer progression and caused a partial regression of existing tumors. These results indicate that the acquisition of resistance to endo- or xeno-biotic toxicity is critical for cancers that develop in toxic microenvironments.
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Affiliation(s)
- Agnese Collino
- Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy
| | | | - Paola Nicoli
- Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy
| | - Giuseppe Diaferia
- Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy
| | | | - Camilla Recordati
- Mouse & Animal Pathology Laboratory, Fondazione Filarete, Milan, Italy
| | | | - Donatella Caruso
- DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - Nico Mitro
- DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - Gioacchino Natoli
- Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- Humanitas University, Pieve Emanuele, Milan, Italy
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Colucci G, D'Ambrosio R, Galmozzi E, Maggioni M, De Nicola S, Aghemo A, Colombo M. Chemokine Receptor 5 Has No Major Role in the Severity of Hepatitis C Virus-Related Liver Damage. Viral Immunol 2018; 31:358-361. [PMID: 29664712 DOI: 10.1089/vim.2017.0190] [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] [Indexed: 12/17/2022] Open
Abstract
Total or partial inactivation of the chemokine 5 (CC5) pathway, as caused by the CC5 receptor Δ32 deletion (CCR5Δ32), may result in a profound manipulation of immune surveillance with significant consequences on the course and response to therapy of diverse human infections, including HIV. It has been postulated that in chronic hepatitis C (CHC), such a deregulation of CC5 pathway may compromise T cell-dependent antiviral immune responses, which in turn may favor viral persistence. To test this hypothesis, we investigated a cohort of 100 patients with CHC in whom 12 heterozygous and 1 homozygous CCR5Δ32 mutations were detected compared to 8 and none in 98 healthy controls (13% vs. 8.2%, p = 0.36). As patients with and without CCR5Δ32 mutations were similar in terms of histological activity (p = 0.84) and fibrosis stage (p = 0.20) as well as CCR5 tissue expression, we reasonably exclude that this CCR5 mutation is significantly involved in the pathogenesis of CHC and may be a potential therapeutic target. However, deleted patients showed a significantly higher response to pegylated interferon-alfa (PEG-IFN), suggesting that a dormant immune system is more readily primed by immunostimulation.
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Affiliation(s)
- Giuseppe Colucci
- 1 Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano , Milan, Italy
| | - Roberta D'Ambrosio
- 1 Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano , Milan, Italy
| | - Enrico Galmozzi
- 1 Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano , Milan, Italy
| | - Marco Maggioni
- 2 Department of Pathology, IRCCS Ca' Granda Ospedale Maggiore Policlinico , Università degli Studi di Milano, Milan, Italy
| | - Stella De Nicola
- 3 Division of Hepatology and Gastroenterology, AAST Grande Ospedale Metropolitano Niguarda , Milan, Italy
| | - Alessio Aghemo
- 4 Division of Medicine and Hepatology, Humanitas Research Hospital , Rozzano, Italy
| | - Massimo Colombo
- 5 Traslational Research Center in Hepatology , Humanitas Research Hospital, Rozzano, Italy
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Pandey P, Rahman M, Bhatt PC, Beg S, Paul B, Hafeez A, Al-Abbasi FA, Nadeem MS, Baothman O, Anwar F, Kumar V. Implication of nano-antioxidant therapy for treatment of hepatocellular carcinoma using PLGA nanoparticles of rutin. Nanomedicine (Lond) 2018; 13:849-870. [DOI: 10.2217/nnm-2017-0306] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Aim: The present work describes the development of poly(lactic co-glycolic acid) (PLGA) nanoparticles (NPs) of rutin (RT) for the treatment of hepatocellular carcinoma in rats. Materials & methods: RT-loaded PLGA NPs (RT-PLGA-NPs) were prepared by double emulsion evaporation method. Further these are optimized by Box–Behnken design. PLGA NPs were evaluated for size, polydispersity index, drug-loading capacity, entrapment, gastric stability, in vitro drug release, in vivo preclinical studies and biochemical studies. Results: Preclinical evaluation of RT-PLGA-NPs for anticancer activity through oral route exhibited significant improvement in hepatic, hematologic and renal biochemical parameters. Highly superior activity was observed in regulating oxidative stress and inflammatory markers, antioxidant enzymes, cytokines and inflammatory mediators and their role on plasma membrane ATPases responsible for destruction in liver tissues. Conclusion: Histopathological evaluation indicated reduced incidence of hepatic nodules, necrosis formation, infiltration of inflammatory cells, blood vessel inflammation and cell swelling with RT-PLGA-NP treatment along with considerable downregulation in the levels of proinflammatory cytokines.
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Affiliation(s)
- Preeti Pandey
- Natural Product Drug Discovery Laboratory, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad-211007, UP, India
| | - Mahfoozur Rahman
- Department of Pharmaceutical Sciences, Shalom Institute of Health & Allied Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad-211007, UP, India
| | - Prakash Chandra Bhatt
- Centre for Advanced Research in Pharmaceutical Sciences, Microbial & Pharmaceutical Biotechnology Laboratory, Faculty of Pharmacy, Jamia Hamdard, New Delhi-110062, India
| | - Sarwar Beg
- Product Development Research, Jubilant Generics Limited, Noida-201301, UP, India
| | - Basudev Paul
- Product Development Research, Jubilant Generics Limited, Noida-201301, UP, India
| | - Abdul Hafeez
- Glocal School of Pharmacy, Glocal University, Saharanpur, UP, India
| | - Fahad A Al-Abbasi
- Department of Biochemistry, Cancer Metabolism & Epigenetic Unit, Faculty of Science, Center of Innovation in Personalized Medicine, Cancer & Mutagenesis Unit, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Muhammad Shahid Nadeem
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Othman Baothman
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Firoz Anwar
- Department of Biochemistry, Cancer Metabolism & Epigenetic Unit, Faculty of Science, Center of Innovation in Personalized Medicine, Cancer & Mutagenesis Unit, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Vikas Kumar
- Natural Product Drug Discovery Laboratory, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad-211007, UP, India
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Effects of the rare elements lanthanum and cerium on the growth of colorectal and hepatic cancer cell lines. Toxicol In Vitro 2018; 46:9-18. [DOI: 10.1016/j.tiv.2017.09.024] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 09/01/2017] [Accepted: 09/22/2017] [Indexed: 12/20/2022]
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de Oliveira CE, Gasparoto TH, Pinheiro CR, Amôr NG, Nogueira MRS, Kaneno R, Garlet GP, Lara VS, Silva JS, Cavassani KA, Campanelli AP. CCR5-Dependent Homing of T Regulatory Cells to the Tumor Microenvironment Contributes to Skin Squamous Cell Carcinoma Development. Mol Cancer Ther 2017; 16:2871-2880. [DOI: 10.1158/1535-7163.mct-17-0341] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 08/14/2017] [Accepted: 09/07/2017] [Indexed: 11/16/2022]
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Cellular and molecular targets for the immunotherapy of hepatocellular carcinoma. Mol Cell Biochem 2017; 437:13-36. [PMID: 28593566 DOI: 10.1007/s11010-017-3092-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023]
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Lanton T, Shriki A, Nechemia-Arbely Y, Abramovitch R, Levkovitch O, Adar R, Rosenberg N, Paldor M, Goldenberg D, Sonnenblick A, Peled A, Rose-John S, Galun E, Axelrod JH. Interleukin 6-dependent genomic instability heralds accelerated carcinogenesis following liver regeneration on a background of chronic hepatitis. Hepatology 2017; 65:1600-1611. [PMID: 28027584 DOI: 10.1002/hep.29004] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 11/23/2016] [Accepted: 12/11/2016] [Indexed: 01/05/2023]
Abstract
UNLABELLED Liver cancer, which typically develops on a background of chronic liver inflammation, is now the second leading cause of cancer mortality worldwide. For patients with liver cancer, surgical resection is a principal treatment modality that offers a chance of prolonged survival. However, tumor recurrence after resection, the mechanisms of which remain obscure, markedly limits the long-term survival of these patients. We have shown that partial hepatectomy in multidrug resistance 2 knockout (Mdr2-/- ) mice, a model of chronic inflammation-associated liver cancer, significantly accelerates hepatocarcinogenesis. Here, we explore the postsurgical mechanisms that drive accelerated hepatocarcinogenesis in Mdr2-/- mice by perioperative pharmacological inhibition of interleukin-6 (IL6), which is a crucial liver regeneration priming cytokine. We demonstrate that inhibition of IL6 signaling dramatically impedes tumorigenesis following partial hepatectomy without compromising survival or liver mass recovery. IL6 blockade significantly inhibited hepatocyte cell cycle progression while promoting a hypertrophic regenerative response, without increasing apoptosis. Mdr2-/- mice contain hepatocytes with a notable persistent DNA damage response (γH2AX, 53BP1) due to chronic inflammation. We show that liver regeneration in this microenvironment leads to a striking increase in hepatocytes bearing micronuclei, a marker of genomic instability, which is suppressed by IL6 blockade. CONCLUSION Our findings indicate that genomic instability derived during the IL6-mediated liver regenerative response within a milieu of chronic inflammation links partial hepatectomy to accelerated hepatocarcinogenesis; this suggests a new therapeutic approach through the usage of an anti-IL6 treatment to extend the tumor-free survival of patients undergoing surgical resection. (Hepatology 2017;65:1600-1611).
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Affiliation(s)
| | | | | | - Rinat Abramovitch
- Goldyne Savad Institute of Gene Therapy.,Magnetic Resonance Imaging/Magnetic Resonance Spectroscopy Laboratory, Human Biology Research Center
| | | | | | | | | | | | - Amir Sonnenblick
- Sharett Institute of Oncology, Hadassah Medical Center, Jerusalem, Israel
| | | | - Stefan Rose-John
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
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Mohs A, Kuttkat N, Reißing J, Zimmermann HW, Sonntag R, Proudfoot A, Youssef SA, de Bruin A, Cubero FJ, Trautwein C. Functional role of CCL5/RANTES for HCC progression during chronic liver disease. J Hepatol 2017; 66:743-753. [PMID: 28011329 DOI: 10.1016/j.jhep.2016.12.011] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 12/07/2016] [Accepted: 12/08/2016] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS During liver inflammation, triggering fibrogenesis and carcinogenesis immune cells play a pivotal role. In the present study we investigated the role of CCL5 in human and in murine models of chronic liver inflammation leading to hepatocellular carcinoma (HCC) development. METHODS CCL5 expression and its receptors were studied in well-defined patients with chronic liver disease (CLD) and in two murine inflammation based HCC models. The role of CCL5 in inflammation, fibrosis, tumor initiation and progression was analyzed in different cell populations of NEMOΔhepa/CCL5-/- animals and after bone marrow transplantation (BMT). For therapeutic intervention Evasin-4 was injected for 24h or 8weeks. RESULTS In CLD patients, CCL5 and its receptor CCR5 are overexpressed - an observation confirmed in the Mdr2-/- and NEMOΔhepa model. CCL5 deletion in NEMOΔhepa mice diminished hepatocyte apoptosis, compensatory proliferation and fibrogenesis due to reduced immune cell infiltration. Especially, CD45+/Ly6G+ granulocytes, CD45+/CD11b+/Gr1.1+/F4/80+ pro-inflammatory monocytes, CD4+ and CD8+ T cells were decreased. One year old NEMOΔhepa/CCL5-/- mice displayed smaller and less malignant tumors, characterized by reduced proliferative capacity and less pronounced angiogenesis. We identified hematopoietic cells as the main source of CCL5, while CCL5 deficiency did not sensitise NEMOΔhepa hepatocytes towards TNFα induced apoptosis. Finally, therapeutic intervention with Evasin-4 over a period of 8weeks ameliorated liver disease progression. CONCLUSION We identified an important role of CCL5 in human and functionally in mice with disease progression, especially HCC development. A novel approach to inhibit CCL5 in vivo thus appears encouraging for patients with CLD. LAY SUMMARY Our present study identifies the essential role of the chemoattractive cytokine CCL5 for liver disease progression and especially hepatocellular carcinoma development in men and mice. Finally, the inhibition of CCL5 appears to be encouraging for therapy of human chronic liver disease.
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MESH Headings
- Animals
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/immunology
- Chemokine CCL5/antagonists & inhibitors
- Chemokine CCL5/deficiency
- Chemokine CCL5/genetics
- Chemokine CCL5/metabolism
- Disease Progression
- Hematopoiesis/immunology
- Hepatitis, Chronic/complications
- Hepatitis, Chronic/genetics
- Hepatitis, Chronic/immunology
- Humans
- Liver Cirrhosis/etiology
- Liver Cirrhosis/immunology
- Liver Cirrhosis/pathology
- Liver Neoplasms/etiology
- Liver Neoplasms/genetics
- Liver Neoplasms/immunology
- Liver Neoplasms, Experimental/etiology
- Liver Neoplasms, Experimental/immunology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, CCR5/metabolism
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Affiliation(s)
- Antje Mohs
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - Nadine Kuttkat
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - Johanna Reißing
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | | | - Roland Sonntag
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - Amanda Proudfoot
- Merck Serono Geneva Research Centre, Case postale 54, chemin des Mines 9, Geneva CH-1211 20, Switzerland
| | - Sameh A Youssef
- Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3508 TB Utrecht, The Netherlands
| | - Alain de Bruin
- Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3508 TB Utrecht, The Netherlands; University Medical Center Groningen, Department of Pediatrics, University of Groningen, NL-9713 Groningen, The Netherlands
| | | | - Christian Trautwein
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
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MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C. Nat Commun 2016; 7:12757. [PMID: 27630043 PMCID: PMC5027609 DOI: 10.1038/ncomms12757] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 07/29/2016] [Indexed: 02/08/2023] Open
Abstract
Cirrhosis likely shares common pathophysiological pathways despite arising from a variety of liver diseases. A recent GWAS identified rs641738, a polymorphism in the MBOAT7 locus, as being associated with the development of alcoholic cirrhosis. Here we explore the role of this variant on liver inflammation and fibrosis in two cohorts of patients with chronic hepatitis C. In 2,051 patients, rs641738 associated with severe hepatic inflammation and increased risk of fibrosis, as well as fast fibrosis progression. At functional level, rs641738 associated with MBOAT7 transcript and protein levels in liver and blood, and with serum inflammatory, oxidative stress and macrophage activation markers. MBOAT7 was expressed in immune cell subsets, implying a role in hepatic inflammation. We conclude that the MBOAT7 rs641738 polymorphism is a novel risk variant for liver inflammation in hepatitis C, and thereby for liver fibrosis. Chronic Hepatitis C infection is associated with a broad spectrum of liver pathologies, ranging from inflammation to fibrosis and liver cancer. Here Thabet et al. identified a polymorphism in the gene MBOAT7 that is associated with increased hepatic inflammation and higher risk of fibrosis development and progression.
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Akahoshi K, Tanaka S, Mogushi K, Shimada S, Matsumura S, Akiyama Y, Aihara A, Mitsunori Y, Ban D, Ochiai T, Kudo A, Arii S, Tanabe M. Expression of connective tissue growth factor in the livers of non-viral hepatocellular carcinoma patients with metabolic risk factors. J Gastroenterol 2016; 51:910-22. [PMID: 26739296 DOI: 10.1007/s00535-015-1159-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 12/21/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND The incidence of hepatocellular carcinoma (HCC) associated with metabolic risk factors, such as diabetes and obesity, has been increasing. However, the underlying mechanism that links these diseases remains unclear. METHODS We performed genome-wide expression analysis of human liver tissues of non-viral HCC patients with or without metabolic risk factors. The upregulated genes that associated with diabetes and obesity were investigated by in vitro and in vivo experiments, and immunohistochemistry of human liver tissues was performed. RESULTS Among the upregulated genes, connective tissue growth factor (CTGF) expression was induced to a greater extent by combined glucose and insulin administration to human hepatoma cells. Genome-wide expression analysis revealed upregulation of a chemokine network in CTGF-overexpressing hepatoma cells, which displayed an increased ability to induce in vitro activation of macrophages, and in vivo infiltration of liver macrophages. Immunohistochemistry of human liver tissues validated the correlations between CTGF expression and diabetes or obesity as well as activation of liver macrophages in patients with non-viral HCC. Recurrence-free survival was significantly poorer in the CTGF-positive patients compared with the CTGF-negative patients (p = 0.002). Multivariate analysis determined that CTGF expression (HR 2.361; 95 % CI 1.195-4.665; p = 0.013) and vascular invasion (HR 2.367; 95 % CI 1.270-4.410; p = 0.007) were independent prognostic factors for recurrence of non-viral HCC. CONCLUSIONS Our data suggest that CTGF could be involved in oncogenic pathways promoting non-viral HCC associated with metabolic risk factors via induction of liver inflammation and is expected to be a novel HCC risk biomarker and potential therapeutic target.
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Affiliation(s)
- Keiichi Akahoshi
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.,Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. .,Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
| | - Kaoru Mogushi
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Shu Shimada
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Satoshi Matsumura
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshimitsu Akiyama
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Arihiro Aihara
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yusuke Mitsunori
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Daisuke Ban
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takanori Ochiai
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Atsushi Kudo
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shigeki Arii
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Minoru Tanabe
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
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Cholecystectomy is associated with higher risk of early recurrence and poorer survival after curative resection for early stage hepatocellular carcinoma. Sci Rep 2016; 6:28229. [PMID: 27320390 PMCID: PMC4913319 DOI: 10.1038/srep28229] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 05/31/2016] [Indexed: 02/07/2023] Open
Abstract
Although cholecystectomy has been reported to be associated with increased risk of developing hepatocellular carcinoma (HCC), the association between cholecystectomy and prognosis of HCC patients underwent curative resection has never been examined. Through retrospective analysis of the data of 3933 patients underwent curative resection for HCC, we found that cholecystectomy was an independent prognostic factor for recurrence-free survival (RFS) of patients at early stage (BCLC stage 0/A) (p = 0.020, HR: 1.29, 95% CI: 1.04-1.59), and the 1-, 3-, 5-year RFS rates for patients at early stage were significantly worse in cholecystectomy group than in non-cholecystectomy group (80.5%, 61.8%, 52.0% vs 88.2%, 68.8%, 56.8%, p = 0.033). The early recurrence rate of cholecystectomy group was significantly higher than that of non-cholecystectomy group for patients at early stage (59/47 vs 236/333, p = 0.007), but not for patients at advanced stage (BCLC stage C) (p = 0.194). Multivariate analyses showed that cholecystectomy was an independent risk factor for early recurrence (p = 0.005, HR: 1.52, 95% CI: 1.13-2.03) of early stage HCC, but not for late recurrence (p = 0.959). In conclusion, cholecystectomy is an independent predictor for early recurrence and is associated with poorer RFS of early stage HCC. Removal of normal gallbladder during HCC resection may be avoided for early stage patients.
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Halama N, Zoernig I, Berthel A, Kahlert C, Klupp F, Suarez-Carmona M, Suetterlin T, Brand K, Krauss J, Lasitschka F, Lerchl T, Luckner-Minden C, Ulrich A, Koch M, Weitz J, Schneider M, Buechler MW, Zitvogel L, Herrmann T, Benner A, Kunz C, Luecke S, Springfeld C, Grabe N, Falk CS, Jaeger D. Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients. Cancer Cell 2016; 29:587-601. [PMID: 27070705 DOI: 10.1016/j.ccell.2016.03.005] [Citation(s) in RCA: 379] [Impact Index Per Article: 42.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Revised: 01/27/2016] [Accepted: 03/11/2016] [Indexed: 11/24/2022]
Abstract
The immune response influences the clinical course of colorectal cancer (CRC). Analyzing the invasive margin of human CRC liver metastases, we identified a mechanism of immune cell exploitation by tumor cells. While two distinct subsets of myeloid cells induce an influx of T cells into the invasive margin via CXCL9/CXCL10, CCL5 is produced by these T cells and stimulates pro-tumoral effects via CCR5. CCR5 blockade in patient-derived functional in vitro organotypic culture models showed a macrophage repolarization with anti-tumoral effects. These anti-tumoral effects were then confirmed in a phase I trial with a CCR5 antagonist in patients with liver metastases of advanced refractory CRC. Mitigation of tumor-promoting inflammation within the tumor tissue and objective tumor responses in CRC were observed.
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Affiliation(s)
- Niels Halama
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, 69120 Heidelberg, Germany; Institute for Immunology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
| | - Inka Zoernig
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Anna Berthel
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, 69120 Heidelberg, Germany
| | - Christoph Kahlert
- Department of Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany; Department of Surgery, University Hospital Dresden, 01307 Dresden, Germany
| | - Fee Klupp
- Department of Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Meggy Suarez-Carmona
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Thomas Suetterlin
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, 69120 Heidelberg, Germany
| | - Karsten Brand
- Institute for Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Juergen Krauss
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Felix Lasitschka
- Institute for Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Tina Lerchl
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, 69120 Heidelberg, Germany
| | - Claudia Luckner-Minden
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Alexis Ulrich
- Department of Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Moritz Koch
- Department of Surgery, University Hospital Dresden, 01307 Dresden, Germany
| | - Juergen Weitz
- Department of Surgery, University Hospital Dresden, 01307 Dresden, Germany
| | - Martin Schneider
- Department of Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Markus W Buechler
- Department of Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Laurence Zitvogel
- INSERM U1015, Institut Gustave Roussy (IGR), 94805 Villejuif, France
| | - Thomas Herrmann
- Department of Internal Medicine I, Klinikum Idar-Oberstein, 55743 Idar Oberstein, Germany
| | - Axel Benner
- Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Christina Kunz
- Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Stephan Luecke
- Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Christoph Springfeld
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Niels Grabe
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, 69120 Heidelberg, Germany
| | - Christine S Falk
- Institute of Transplant Immunology, Integrated Research and Treatment Center Transplantation, Hannover Medical School, 30625 Hannover, Germany
| | - Dirk Jaeger
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, 69120 Heidelberg, Germany
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Crespo M, Navarro J, Moreno S, Sanz J, Márquez M, Zamora J, Ocampo A, Iribaren JA, Rivero A, Llibre JM. Hepatic safety of maraviroc in HIV-1-infected patients with hepatitis C and/or B co-infection. The Maraviroc Cohort Spanish Group. Enferm Infecc Microbiol Clin 2016; 35:493-498. [PMID: 27061975 DOI: 10.1016/j.eimc.2016.02.029] [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: 12/18/2015] [Revised: 02/22/2016] [Accepted: 02/28/2016] [Indexed: 10/22/2022]
Abstract
INTRODUCTION Limited data is available regarding the hepatic safety of maraviroc in patients co-infected with HIV and HCV and/or HBV. Our objective was to compare the hepatic safety profile and fibrosis progression in HIV-mono-infected patients and co-infected with HCV and/or HBV treated with maraviroc. METHODS Retrospective multicentre cohort study of HIV-infected patients receiving treatment with a maraviroc-containing regimen in 27 hospitals in Spain. RESULTS A total of 667 patients were analyzed, of whom 313 were co-infected with HCV (n=282), HBV (n=14), or both (n=17). Maraviroc main indications were salvage therapy (52%) and drug toxicity (20%). Grade 3-4 hypertransaminasaemia (AST/ALT >5 times ULN) per 100 patient-years of maraviroc exposure, was 5.84 (95% CI, 4.04-8.16) and 1.23 (95% CI, 0.56-2.33) in co-infected and HIV-mono-infected patients, respectively (incidence rate ratio, 4.77; 95% CI, 2.35-10.5). However, the degree of aminotransferase abnormalities remained stable throughout the study in both groups, and no significant between-group differences were seen in the cumulative proportion of patients showing an increase in AST/ALT levels greater than 3.5 times baseline levels. No between-group differences were seen in liver fibrosis over time. With a maraviroc median exposure of 20 months (IQR, 12-41), two patients (0.3%) discontinued maraviroc because of grade 4 hepatitis, and other 2 died due to complications associated to end-stage-liver disease. CONCLUSIONS Maraviroc-containing regimens showed a low incidence of hepatitis in a large Spanish cohort of HIV-infected patients, including more than 300 patients co-infected with HCV and/or HBV. Co-infection did not influence the maximum liver enzyme level or the fibrosis progression throughout the study.
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Affiliation(s)
- Manuel Crespo
- Hospital Universitari Vall d'Hebrón, Universitat Autònoma de Barcelona, Spain; Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.
| | - Jordi Navarro
- Hospital Universitari Vall d'Hebrón, Universitat Autònoma de Barcelona, Spain; Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain
| | | | - Jesus Sanz
- Hospital Universitario La Princesa, Madrid, Spain
| | - Manuel Márquez
- Hospital Clínico Universitario Virgen de la Victoria, Málaga, Spain
| | - Javier Zamora
- Hospital Ramón y Cajal-IRYCIS, Madrid, Spain; CIBER Epidemiology and Public Heath, Spain; Barts and the London School of Medicine, Queen Mary University London, UK
| | | | | | | | - Josep M Llibre
- Hospital Universitari Germans Trias i Pujol, Badalona; Universitat Autònoma de Barcelona, Spain
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50
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Zhu F, Li X, Chen S, Zeng Q, Zhao Y, Luo F. Tumor-associated macrophage or chemokine ligand CCL17 positively regulates the tumorigenesis of hepatocellular carcinoma. Med Oncol 2016; 33:17. [PMID: 26781124 DOI: 10.1007/s12032-016-0729-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Accepted: 01/04/2016] [Indexed: 02/07/2023]
Abstract
Alternatively activated macrophages (M2) can secrete chemokines, such as chemokine ligand 17 (CCL17), and are associated with promoting tumorigenesis of hepatocellular carcinoma (HCC). This study aimed at investigating the potential role of M2 and CCL17 in progression of HCC. The levels of CCL17 expression in 90 HCC samples were characterized by tissue microarray and stratified for the postsurgical survival. MHCC97L cells were co-cultured with classically activated M1, M2 or CCL17-silencing M2(ccl17mute) or treated with conditional medium (CM) from these cells or CCL17 in vitro. The wound healing, invasion, viability and apoptosis of MHCC97L cells in vitro and tumor growth in vivo were determined. The stemness of MHCC97L cells was examined by sphere formation, flow cytometry and Western blot. The relative expression levels of epithelial-mesenchymal transition (EMT) factors and the Wnt/β-catenin signaling were determined. Higher levels of intratumoral CCL17 expression were significantly associated with clinical pathological characteristics of HCC and with poorer overall survival rates in HCC patients (P < 0.05). High levels of CCR4 were detected in MHCC97L cells. Treatment with the CM from M2 or with CCL17 significantly enhanced the wound healing process, invasion and proliferation of MHCC97L cells in vitro. Co-implantation MHCC97L cells with M2 significantly promoted the growth of MHCC97L tumors in vivo. Co-culture with M2 or treatment with CCL17 enhanced the stemness, EMT process, the TGF-β1 and Wnt/β-catenin signaling in MHCC97L cells. CCL17 promotes the tumorigenesis of HCC and may be a potential biomarker and target for HCC prognosis and therapy.
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Affiliation(s)
- Fangyu Zhu
- Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Xiangnan Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Siyu Chen
- Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Qiu Zeng
- Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Yu Zhao
- Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Fang Luo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China.
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