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1
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Zheng C, Peng Y, Wang H, Wang Y, Liu L, Zhao Q. Identification and Validation of Ferroptosis-Related Subtypes and a Predictive Signature in Hepatocellular Carcinoma. Pharmgenomics Pers Med 2023; 16:39-58. [PMID: 36726530 PMCID: PMC9885776 DOI: 10.2147/pgpm.s397892] [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: 11/16/2022] [Accepted: 01/12/2023] [Indexed: 01/27/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world with an immunosuppressive Tumor microenvironment (TME). Ferroptosis plays an essential role in tumor proliferation, invasion, and metastasis. However, the relationship between ferroptosis and TME of HCC has remained elusive. Methods Differentially expressed ferroptosis-related genes (DE FRGs) between normal liver tissues and HCC tissues were obtained from The Cancer Genome Atlas (TCGA). On this basis, we identified the molecular subtypes mediated by DE FRGs and TME cell infiltration. Next, a predictive signature was established to quantity the ferroptosis-related characteristics by performing the least absolute shrinkage and selection operator Cox regression analyses. Univariate and multivariate COX analyses determined the independent prognostic factors. Finally, the expression stability of 3 ferroptosis-related signature genes was verified in cancer and paracancerous normal tissues of HCC. Results We identified three different molecular subtypes and found that the subtype with the better prognosis was associated with high enrichment of immune- and metabolic-related hallmark signaling pathways and high infiltration of immune cells in TME. The signature was considered to be an independent prognostic factor. We also found that the signature can reflect the infiltration characteristics of different immune cells in TME. Immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells, and type 17 T helper cells were significantly enriched in the high-risk group. The analysis data of immune checkpoints and tumor mutation load indicated that the signature had great potential in predicting Immunotherapy response and chemotherapeutic sensitivity. In addition, the overexpression of 3 ferroptosis-related signature genes was confirmed in HCC tissues and HCC cell lines. Ferroptosis inducer RSL3 inhibited the proliferation of HCC cells and was a potential cancer immunotherapy agent. Conclusion These findings enhanced our understanding of the regulatory mechanism of ferroptosis in HCC and provided new insights into evaluating prognosis and developing more effective Immunotherapy and chemotherapy strategies.
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Affiliation(s)
- Chunlan Zheng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, People’s Republic of China
| | - Yanan Peng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, People’s Republic of China
| | - Haizhou Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, People’s Republic of China
| | - Youwei Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, People’s Republic of China
| | - Lan Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, People’s Republic of China,Correspondence: Lan Liu; Qiu Zhao, Tel +86-027-67812888, Fax +86 027-67812892, Email ;
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, People’s Republic of China
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2
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Macedo C, Tran LM, Zahorchak AF, Dai H, Gu X, Ravichandran R, Mohanakumar T, Elinoff B, Zeevi A, Styn MA, Humar A, Lakkis FG, Metes DM, Thomson AW. Donor-derived regulatory dendritic cell infusion results in host cell cross-dressing and T cell subset changes in prospective living donor liver transplant recipients. Am J Transplant 2021; 21:2372-2386. [PMID: 33171019 PMCID: PMC8215622 DOI: 10.1111/ajt.16393] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 10/13/2020] [Accepted: 11/01/2020] [Indexed: 01/25/2023]
Abstract
Regulatory dendritic cells (DCreg) promote transplant tolerance following their adoptive transfer in experimental animals. We investigated the feasibility, safety, fate, and impact on host T cells of donor monocyte-derived DCreg infused into prospective, living donor liver transplant patients, 7 days before transplantation. The DCreg expressed a tolerogenic gene transcriptional profile, high cell surface programed death ligand-1 (PD-L1):CD86 ratios, high IL-10/no IL-12 productivity and poor ability to stimulate allogeneic T cell proliferation. Target DCreg doses (range 2.5-10 × 106 cells/kg) were achieved in all but 1 of 15 recipients, with no infusion reactions. Following DCreg infusion, transiently elevated levels of donor HLA and immunoregulatory PD-L1, CD39, and CD73 were detected in circulating small extracellular vesicles. At the same time, flow and advanced image stream analysis revealed intact DCreg and "cross-dressing" of host DCs in blood and lymph nodes. PD-L1 co-localization with donor HLA was observed at higher levels than with recipient HLA. Between DCreg infusion and transplantation, T-bethi Eomeshi memory CD8+ T cells decreased, whereas regulatory (CD25hi CD127- Foxp3+ ): T-bethi Eomeshi CD8+ T cell ratios increased. Thus, donor-derived DCreg infusion may induce systemic changes in host antigen-presenting cells and T cells potentially conducive to modulated anti-donor immune reactivity at the time of transplant.
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Affiliation(s)
- Camila Macedo
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Lillian M. Tran
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Alan F. Zahorchak
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Helong Dai
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Xinyan Gu
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | | | | | - Beth Elinoff
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Adriana Zeevi
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania,Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Mindi A. Styn
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Abhinav Humar
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Fadi G. Lakkis
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Diana M. Metes
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Angus W. Thomson
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
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3
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Yang Y, Yang L, Wang Y. [Immunotherapy for Lung Cancer: Mechanisms of Resistance and Response Strategy]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2021; 24:112-123. [PMID: 33626853 PMCID: PMC7936078 DOI: 10.3779/j.issn.1009-3419.2021.101.02] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inhibition of immune checkpoints is at the forefront of immunotherapy for lung cancer. However, a high percentage of lung cancer patients do not respond to these immunotherpy or their responses are transient, indicating the existence of immune resistance. Emerging evidence suggested that the interactions between cancer cells and immune system were continuous and dynamic. Here, we review how a range of cancer-cell-autonomous characteristics, tumor-microenvironment factors, and host-related influences account for heterogenous responses. Furthermore, with the identification of new targets of immunotherapy and development of immune-based combination therapy, we elucidate the methods might useful to overcome resistance.
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Affiliation(s)
- Yaning Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lu Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yan Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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4
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Yin K, Xia X, Rui K, Wang T, Wang S. Myeloid-Derived Suppressor Cells: A New and Pivotal Player in Colorectal Cancer Progression. Front Oncol 2020; 10:610104. [PMID: 33384962 PMCID: PMC7770157 DOI: 10.3389/fonc.2020.610104] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) remains a devastating human malignancy with poor prognosis. Of the various factors, immune evasion mechanisms play pivotal roles in CRC progression and impede the effects of cancer therapy. Myeloid-derived suppressor cells (MDSCs) constitute an immature population of myeloid cells that are typical during tumor progression. These cells have the ability to induce strong immunosuppressive effects within the tumor microenvironment (TME) and promote CRC development. Indeed, MDSCs have been shown to accumulate in both tumor-bearing mice and CRC patients, and may therefore become an obstacle for cancer immunotherapy. Consequently, numerous studies have focused on the characterization of MDSCs and their immunosuppressive capacity, as well as developing novel approaches to suppress MDSCs function with different approaches. Current therapeutic strategies that target MDSCs in CRC include inhibition of their recruitment and alteration of their function, alone or in combination with other therapies including chemotherapy, radiotherapy and immunotherapy. Herein, we summarize the recent roles and mechanisms of MDSCs in CRC progression. In addition, a brief review of MDSC-targeting approaches for potential CRC therapy is presented.
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Affiliation(s)
- Kai Yin
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xueli Xia
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Ke Rui
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Tingting Wang
- Department of Laboratory Medicine, Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi Children's Hospital, Wuxi, China
| | - Shengjun Wang
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
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5
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Zhang Q, Huang H, Zheng F, Liu H, Qiu F, Chen Y, Liang CL, Dai Z. Resveratrol exerts antitumor effects by downregulating CD8 +CD122 + Tregs in murine hepatocellular carcinoma. Oncoimmunology 2020; 9:1829346. [PMID: 33150044 PMCID: PMC7588216 DOI: 10.1080/2162402x.2020.1829346] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 09/23/2020] [Accepted: 09/23/2020] [Indexed: 12/17/2022] Open
Abstract
CD4+Foxp3+ regulatory T cells (Tregs) in the tumor microenvironment restrain antitumor immunity, resulting in tumor aggression and poor survival in hepatocellular carcinoma (HCC). CD8+CD122+ Tregs have been previously shown to be more potent in immunosuppression than are CD4+Foxp3+ Tregs. Previous studies have demonstrated that resveratrol exerts its anti-cancer effects by downregulating CD4+Foxp3+ and M2-like macrophages, two key immunoregulatory cells that maintain the immunosuppressive tumor microenvironment. In this study, we found that resveratrol inhibited the tumor growth in a subcutaneous Hepa1-6 HCC model and decreased the frequency of CD8+CD122+ Tregs in the tumor as well as lymph nodes and spleen of the tumor-bearing mice. It also increased the percentage of IFN-γ-expressing CD8+ T cells in the tumor and peripheral lymphoid organs. The antitumor effects of resveratrol were partially reversed by the adoptive transfer of exogenous CD8+CD122+ Tregs into the tumor-bearing mice. Meanwhile, resveratrol treatment downregulated immunosuppressive cytokines, including TGF-β1 and interleukin-10, in the tumor while elevating antitumor cytokines, TNF-α and IFN-γ. It also inhibited the activation of STAT3 signaling in the tumor. As expected, resveratrol reduced the percentage of M2-like macrophages in the mice. Importantly, resveratrol suppressed orthotopic H22 tumor growth and decreased the frequency of CD8+CD122+ Tregs and M2-like macrophages in the tumor-bearing mice. Furthermore, our studies showed that resveratrol, at non-cytotoxic concentrations, inhibited CD8+CD122+ Treg differentiation from CD8+CD122- T cells in vitro. Thus, our studies unveiled a new immune mechanism underlying the immunosuppressive tumor microenvironment and demonstrated that resveratrol could help reverse it by diminishing CD8+CD122+ Tregs.
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Affiliation(s)
- Qunfang Zhang
- Section of Immunology & Joint Immunology Program, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China
| | - Haiding Huang
- Section of Immunology & Joint Immunology Program, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China
| | - Fang Zheng
- Section of Immunology & Joint Immunology Program, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China
| | - Huazhen Liu
- Section of Immunology & Joint Immunology Program, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China
| | - Feifei Qiu
- Section of Immunology & Joint Immunology Program, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China
| | - Yuchao Chen
- Section of Immunology & Joint Immunology Program, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China
| | - Chun-Ling Liang
- Section of Immunology & Joint Immunology Program, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China
| | - Zhenhua Dai
- Section of Immunology & Joint Immunology Program, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China
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6
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Yu SJ, Greten TF. Deciphering and Reversing Immunosuppressive Cells in the Treatment of Hepatocellular Carcinoma. JOURNAL OF LIVER CANCER 2020; 20:1-16. [PMID: 37383056 PMCID: PMC10035699 DOI: 10.17998/jlc.20.1.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/06/2019] [Accepted: 11/10/2019] [Indexed: 06/30/2023]
Abstract
Use of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) has been partially successful. However, most HCC patients do not respond to immunotherapy. HCC has been shown to induce several immune suppressor mechanisms in patients. These suppressor mechanisms include involvement of myeloid-derived suppressor cells, regulatory T-cells, functionally impaired dendritic cells (DCs), neutrophils, monocytes, and tumor associated macrophages. The accumulation of immunosuppressive cells may lead to an immunosuppressive tumor microenvironment as well as the dense fibrotic stroma which may contribute to immune tolerance. Our laboratory has been investigating different cellular mechanisms of immune suppression in HCC patients. In vitro as well as in vivo studies have demonstrated that abrogation of the suppressor cells enhances or unmasks tumor-specific antitumor immune responses. Two or three effective systemic therapies including ICIs and/or molecular targeted therapies and the addition of innovative combination therapies targeting immune suppressor cells may lead to increased immune recognition with a greater tumor response. We reviewed the literature for the latest research on immune suppressor cells in HCC, and here we provide a comprehensive summary of the recent studies in this field.
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Affiliation(s)
- Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Tim F. Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA
- NCI CCR Liver Cancer Program, Bethesda, USA
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7
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Han Q, Zhao H, Jiang Y, Yin C, Zhang J. HCC-Derived Exosomes: Critical Player and Target for Cancer Immune Escape. Cells 2019; 8:cells8060558. [PMID: 31181729 PMCID: PMC6627799 DOI: 10.3390/cells8060558] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 05/30/2019] [Accepted: 06/06/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver, and currently the second most common cause of cancer-related deaths worldwide with increasing incidence and poor prognosis. Exosomes are now considered as important mediators of host anti-tumor immune response as well as tumor cell immune escape. HCC-derived exosomes have been shown to attenuate the cytotoxicity of T-cells and NK cells, and promote the immuno-suppressive M2 macrophages, N2 neutrophils, and Bregs. These exosomes harbor several immune-related non-coding RNAs and proteins that drive immune-escape and tumor progression, and thus may serve as potential diagnostic biomarkers and therapeutic targets for HCC. In a previous study, we identified miR146a as an exosomal factor that promotes M2-polarization and suppresses the anti-HCC function of T-cells. In this review, we summarized the role of tumor-derived exosomes and their key components in mediating tumor immune escape during HCC development.
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Affiliation(s)
- Qiuju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China.
| | - Huajun Zhao
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China.
| | - Yu Jiang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China.
| | - Chunlai Yin
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China.
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China.
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8
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Ogunwobi OO, Harricharran T, Huaman J, Galuza A, Odumuwagun O, Tan Y, Ma GX, Nguyen MT. Mechanisms of hepatocellular carcinoma progression. World J Gastroenterol 2019; 25:2279-2293. [PMID: 31148900 PMCID: PMC6529884 DOI: 10.3748/wjg.v25.i19.2279] [Citation(s) in RCA: 159] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 03/27/2019] [Accepted: 04/10/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells, immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.
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Affiliation(s)
- Olorunseun O Ogunwobi
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Trisheena Harricharran
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Jeannette Huaman
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Anna Galuza
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Oluwatoyin Odumuwagun
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Yin Tan
- Center for Asian Health, School of Medicine, Temple University, Philadelphia, PA 19140, United States
| | - Grace X Ma
- Center for Asian Health, School of Medicine, Temple University, Philadelphia, PA 19140, United States
| | - Minhhuyen T Nguyen
- Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA 19111, United States
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9
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Liu LZ, Zhang Z, Zheng BH, Shi Y, Duan M, Ma LJ, Wang ZC, Dong LQ, Dong PP, Shi JY, Zhang S, Ding ZB, Ke AW, Cao Y, Zhang XM, Xi R, Zhou J, Fan J, Wang XY, Gao Q. CCL15 Recruits Suppressive Monocytes to Facilitate Immune Escape and Disease Progression in Hepatocellular Carcinoma. Hepatology 2019; 69:143-159. [PMID: 30070719 DOI: 10.1002/hep.30134] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 06/05/2018] [Indexed: 12/12/2022]
Abstract
Chemokines play a key role in orchestrating the recruitment and positioning of myeloid cells within the tumor microenvironment. However, the tropism regulation and functions of these cells in hepatocellular carcinoma (HCC) are not completely understood. Herein, by scrutinizing the expression of all chemokines in HCC cell lines and tissues, we found that CCL15 was the most abundantly expressed chemokine in human HCC. Further analyses showed that CCL15 expression was regulated by genetic, epigenetic, and microenvironmental factors, and negatively correlated with patient clinical outcome. In addition to promoting tumor invasion in an autocrine manner, CCL15 specifically recruited CCR1+ cells toward HCC invasive margin, approximately 80% of which were CD14+ monocytes. Clinically, a high density of marginal CCR1+ CD14+ monocytes positively correlated with CCL15 expression and was an independent index for dismal survival. Functionally, these tumor-educated monocytes directly accelerated tumor invasion and metastasis through bursting various pro-tumor factors and activating signal transducer and activator of transcription 1/3, extracellular signal-regulated kinase 1/2, and v-akt murine thymoma viral oncogene homolog signaling in HCC cells. Meanwhile, tumor-derived CCR1+ CD14+ monocytes expressed significantly higher levels of programmed cell death-ligand 1, B7-H3, and T-cell immunoglobulin domain and mucin domain-3 that may lead to immune suppression. Transcriptome sequencing confirmed that tumor-infiltrating CCR1+ CD14+ monocytes were reprogrammed to upregulate immune checkpoints, immune tolerogenic metabolic enzymes (indoleamine and arginase), inflammatory/pro-angiogenic cytokines, matrix remodeling proteases, and inflammatory chemokines. Orthotopic animal models confirmed that CCL15-CCR1 axis forested an inflammatory microenvironment enriched with CCR1+ monocytes and led to increased metastatic potential of HCC cells. Conclusion: A complex tumor-promoting inflammatory microenvironment was shaped by CCL15-CCR1 axis in human HCC. Blockade of CCL15-CCR1 axis in HCC could be an effective anticancer therapy.
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Affiliation(s)
- Long-Zi Liu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Zhao Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Bo-Hao Zheng
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Yang Shi
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Men Duan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Li-Jie Ma
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Zhi-Chao Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Liang-Qing Dong
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Ping-Ping Dong
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie-Yi Shi
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Shu Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Zhen-Bin Ding
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Ai-Wu Ke
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Ya Cao
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China
| | - Xiao-Ming Zhang
- Key Laboratory of Molecular Virology & Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Ruibin Xi
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Xiao-Ying Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
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10
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Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression. Br J Cancer 2018; 120:16-25. [PMID: 30413826 PMCID: PMC6325125 DOI: 10.1038/s41416-018-0333-1] [Citation(s) in RCA: 588] [Impact Index Per Article: 84.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 10/18/2018] [Accepted: 10/23/2018] [Indexed: 12/21/2022] Open
Abstract
Under steady-state conditions, bone marrow-derived immature myeloid cells (IMC) differentiate into granulocytes, macrophages and dendritic cells (DCs). This differentiation is impaired under chronic inflammatory conditions, which are typical for tumour progression, leading to the accumulation of IMCs. These cells are capable of inducing strong immunosuppressive effects through the expression of various cytokines and immune regulatory molecules, inhibition of lymphocyte homing, stimulation of other immunosuppressive cells, depletion of metabolites critical for T cell functions, expression of ectoenzymes regulating adenosine metabolism, and the production of reactive species. IMCs are therefore designated as myeloid-derived suppressor cells (MDSCs), and have been shown to accumulate in tumour-bearing mice and cancer patients. MDSCs are considered to be a strong contributor to the immunosuppressive tumour microenvironment and thus an obstacle for many cancer immunotherapies. Consequently, numerous studies are focused on the characterisation of MDSC origin and their relationship to other myeloid cell populations, their immunosuppressive capacity, and possible ways to inhibit MDSC function with different approaches being evaluated in clinical trials. This review analyses the current state of knowledge on the origin and function of MDSCs in cancer, with a special emphasis on the immunosuppressive pathways pursued by MDSCs to inhibit T cell functions, resulting in tumour progression. In addition, we describe therapeutic strategies and clinical benefits of MDSC targeting in cancer.
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11
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Zhao T, Jia H, Cheng Q, Xiao Y, Li M, Ren W, Li C, Feng Y, Feng Z, Wang H, Zheng J. Nifuroxazide prompts antitumor immune response of TCL-loaded DC in mice with orthotopically-implanted hepatocarcinoma. Oncol Rep 2017; 37:3405-3414. [PMID: 28498414 DOI: 10.3892/or.2017.5629] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 04/13/2017] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis and high mortality. At present, vaccination with tumor cell lysate (TCL) loaded dendritic cells (DC) has been shown to be an effective therapy against HCC. However, the ability of promoting the specific T cell immune response is rather weak, influencing the antitumor response. Thus, it is necessary to find a strategy to improve the antitumor effect of TCL-loaded DC. Activation of signal transducer and activator of transcription 3 (STAT3) significantly inhibits antitumor immune response and DC maturity. Nifuroxazide, an antidiarrheal agent, has been proved to directly inhibit STAT3 activation. Thus, we investigated whether nifuroxazide could improve the antitumor immune response in mice vaccinated with TCL-loaded DC. The study provides the theoretical and experimental basis for developing an effective adjuvant for DC vaccine to treat HCC. Our results showed that the administration of nifuroxazide and DC-loaded TCL could significantly improve the survival rate, inhibit the tumor growth, and prompt the antitumor immune responses in mice with orthotopically implanted hepatocarcinomas, thus, possibly providing a new combination strategy to treat HCC.
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Affiliation(s)
- Tiesuo Zhao
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Huijie Jia
- Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Qian Cheng
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, Jiangsu 221002, P.R. China
| | - Yali Xiao
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Minming Li
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Wenjing Ren
- Department of Dermatology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Chen Li
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Yuchen Feng
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Zhiwei Feng
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Hui Wang
- Research Center for Immunology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Junnian Zheng
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, Jiangsu 221002, P.R. China
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12
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He C, Peng W, Li C, Wen TF. Thymalfasin, a promising adjuvant therapy in small hepatocellular carcinoma after liver resection. Medicine (Baltimore) 2017; 96:e6606. [PMID: 28422855 PMCID: PMC5406071 DOI: 10.1097/md.0000000000006606] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
There is limited information available concerning the effect of thymalfasin (Tα1) as an adjuvant therapy in hepatocellular carcinoma (HCC) patient who received liver resection. The present study aimed to evaluate whether Tα1 can improve the prognosis of small HCC patients after liver resection.A total of 206 patients with small HCC who underwent liver resection were analyzed in our retrospective cohort study. Patients were divided into 2 groups: group A (resection + Tα1, n = 44) and group B (resection, n = 162). Clinical data, overall survival (OS), and recurrence-free survival (RFS) were compared. Prognostic factors were identified using multivariate analysis.After a median follow-up of 47.0 months, 134 patients (65%) had recurrence, and 62 patients (30.09%) died. The 1, 3, and 5-year OS rate of patients in group A was 97.7%, 90.6%, and 82.9%, respectively, and 95.1%, 80.5%, and 62.9%, respectively, for patients in group B (P = .014). The 1, 3, and 5-year RFS rate of patients in group A was 70.5%, 56.8%, and 53.3%, respectively, and 65.8%, 41.3%, and 32.1%, respectively, for patients in group B (P = .015). Multivariate analysis indicated that Tα1 was an independent prognostic factor for both OS (P = .015, hazard ratio 0.349, 95% confidence interval 0.149-0.816) and RFS (P = .019, hazard ratio 0.564, 95% confidence interval 0.349-0.910).Tα1 as an adjuvant therapy after liver resection may improve the prognosis of small HCC patients after liver resection.
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13
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Li XF, Dai D, Song XY, Liu JJ, Zhu L, Zhu X, Ma W, Xu W. A different representation of natural T cells and natural killer cells between tumor-infiltrating and periphery lymphocytes in human hepatocellular carcinoma. Oncol Lett 2017; 13:3291-3298. [PMID: 28529568 DOI: 10.3892/ol.2017.5808] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 01/19/2017] [Indexed: 12/18/2022] Open
Abstract
Natural T cells [cluster of differentiation (CD) 3+CD56+] and natural killer (NK) cells (CD3-CD56+) are particularly abundant in the human liver and serve an important role in immune responses in the liver. The aim of the present study was to extensively determine the phenotypic and functional characteristics of natural T and NK cells in human hepatocellular carcinoma (HCC). Tumorous and non-tumorous tissue infiltrating lymphocytes (TILs and NILs, respectively) and peripheral blood mononuclear cells (PBMCs) from patients with hepatocellular carcinoma (HCC) were obtained to determine the frequency and phenotype of natural T/NK cells by a multicolor fluorescence activated cell sorting analysis. The abundance of natural T cells and NK cells was decreased in TILs vs. NILs (natural T cells, 6.315±1.002 vs. 17.16±1.804; NK cells, 6.324±1.559 vs. 14.52±2.336, respectively). However such results were not observed in PBMCs from HCC patients vs. that of healthy donors. Notably, a substantial fraction of the natural T cells (21.96±5.283) in TILs acquired forkhead box P3 (FOXP3) expression, and the FOXP3+ natural T cells lost the expression of interferon-γ and perforin. Conversely, being similar to the conventional FOXP3+ regulatory T cells, the FOXP3+ natural T cells assumed a specific phenotype that was characteristic of CD25+, CD45RO+ and cytotoxic T-lymphocyte-associated protein 4+. Consistent with the phenotypic conversion, the present functional results indicate that FOXP3 expression in natural T cells contributes to the acquisition of a potent immunosuppressive capability. In conclusion, the present study describes a different representation of natural T cells and NK cells in local tumor tissues and in the periphery blood of patients with HCC, and identified a new type of FOXP3-expressing natural T cell spontaneously arising in the TILs of HCC.
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Affiliation(s)
- Xiao-Feng Li
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Hexi, Tianjin 300060, P.R. China.,National Clinical Research Center of Cancer, Hexi, Tianjin 300060, P.R. China.,Key Laboratory of Cancer Prevention and Therapy, Hexi, Tianjin 300060, P.R. China
| | - Dong Dai
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Hexi, Tianjin 300060, P.R. China.,National Clinical Research Center of Cancer, Hexi, Tianjin 300060, P.R. China.,Key Laboratory of Cancer Prevention and Therapy, Hexi, Tianjin 300060, P.R. China
| | - Xiu-Yu Song
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Hexi, Tianjin 300060, P.R. China.,National Clinical Research Center of Cancer, Hexi, Tianjin 300060, P.R. China.,Key Laboratory of Cancer Prevention and Therapy, Hexi, Tianjin 300060, P.R. China
| | - Jian-Jing Liu
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Hexi, Tianjin 300060, P.R. China.,National Clinical Research Center of Cancer, Hexi, Tianjin 300060, P.R. China.,Key Laboratory of Cancer Prevention and Therapy, Hexi, Tianjin 300060, P.R. China
| | - Lei Zhu
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Hexi, Tianjin 300060, P.R. China.,National Clinical Research Center of Cancer, Hexi, Tianjin 300060, P.R. China.,Key Laboratory of Cancer Prevention and Therapy, Hexi, Tianjin 300060, P.R. China
| | - Xiang Zhu
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Hexi, Tianjin 300060, P.R. China.,National Clinical Research Center of Cancer, Hexi, Tianjin 300060, P.R. China.,Key Laboratory of Cancer Prevention and Therapy, Hexi, Tianjin 300060, P.R. China
| | - Wenchao Ma
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Hexi, Tianjin 300060, P.R. China.,National Clinical Research Center of Cancer, Hexi, Tianjin 300060, P.R. China.,Key Laboratory of Cancer Prevention and Therapy, Hexi, Tianjin 300060, P.R. China
| | - Wengui Xu
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Hexi, Tianjin 300060, P.R. China.,National Clinical Research Center of Cancer, Hexi, Tianjin 300060, P.R. China.,Key Laboratory of Cancer Prevention and Therapy, Hexi, Tianjin 300060, P.R. China
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14
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Liu XL, Wang LJ, Zhang S, Li MG, Yu H, Jiang YY, Wang XB, Yang ZY. Characteristics of CD4 + and CD8 + T cells in peripheral blood of patients with HBV-related primary liver cancer of Qi-Yin deficiency type. Shijie Huaren Xiaohua Zazhi 2016; 24:4264-4271. [DOI: 10.11569/wcjd.v24.i31.4264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To observe the traditional Chinese medicine (TCM) syndrome distribution in the occurrence and progression of hepatitis B virus-related primary liver cancer (HBV-PLC) and compare the changes of T and B cells among different HBV-PLC syndromes.
METHODS The laboratory characteristics and TCM syndromes of 67 HBV-PLV patients, 55 liver cirrhosis (LC) patients and 40 chronic hepatitis B (CHB) patients were collected at Beijing Ditan Hospital Affiliated to Capital Medical University. The distributions of CD3+ T, CD4+ T, CD8+ T and CD3-CD19+ B cells in peripheral blood of all patients were detected by flow cytometry.
RESULTS Compared with CHB and LC patients, the percentage of HBV-PLC patients of Qi and Yin deficiency type increased, but that of liver depression and spleen deficiency type declined. In terms of Child, Okuda, and BCLC stages of liver cancer, the early stage was mostly associated with liver depression and spleen deficiency, while the advanced stage was mainly associated with Qi and Yin deficiency. Compared with HBV-PLC patients with liver depression and spleen deficiency type, TBIL, DBIL, PT, PTA and the percentage of B cells increased in patients with Qi and Yin deficiency (P < 0.001), while A/G, CHE, the numbers and percentages of T and CD8+ cells, and the number of CD4+ cells significantly decreased (P < 0.05) in patients with Qi and Yin deficiency. The numbers of T, CD4+ T, CD8+ T and B cells were less in the LC and HBV-PLC patients of Qi and Yin deficiency type than in CHB patients of the same type (P < 0.05) .
CONCLUSION The TCM syndrome changes from liver depression and spleen deficiency to Qi and Yin deficiency in the occurrence and progression of HBV-PLC. HBV-PLC patients with Qi and Yin deficiency have worse liver function, lower anti-tumor immune response and poorer prognosis compared with patients with other types.
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15
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Rapisarda V, Loreto C, Malaguarnera M, Ardiri A, Proiti M, Rigano G, Frazzetto E, Ruggeri MI, Malaguarnera G, Bertino N, Malaguarnera M, Catania VE, Di Carlo I, Toro A, Bertino E, Mangano D, Bertino G. Hepatocellular carcinoma and the risk of occupational exposure. World J Hepatol 2016; 8:573-90. [PMID: 27168870 PMCID: PMC4858622 DOI: 10.4254/wjh.v8.i13.573] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 04/01/2016] [Accepted: 04/14/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The main risk factors for HCC are alcoholism, hepatitis B virus, hepatitis C virus, nonalcoholic steatohepatitis, obesity, type 2 diabetes, cirrhosis, aflatoxin, hemochromatosis, Wilson's disease and hemophilia. Occupational exposure to chemicals is another risk factor for HCC. Often the relationship between occupational risk and HCC is unclear and the reports are fragmented and inconsistent. This review aims to summarize the current knowledge regarding the association of infective and non-infective occupational risk exposure and HCC in order to encourage further research and draw attention to this global occupational public health problem.
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Affiliation(s)
- Venerando Rapisarda
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Carla Loreto
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Michele Malaguarnera
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Annalisa Ardiri
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Maria Proiti
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Giuseppe Rigano
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Evelise Frazzetto
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Maria Irene Ruggeri
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Giulia Malaguarnera
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Nicoletta Bertino
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Mariano Malaguarnera
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Vito Emanuele Catania
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Isidoro Di Carlo
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Adriana Toro
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Emanuele Bertino
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Dario Mangano
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Gaetano Bertino
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
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16
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Li X, Peng J, Pang Y, Yu S, Yu X, Chen P, Wang W, Han W, Zhang J, Yin Y, Zhang Y. Identification of a FOXP3(+)CD3(+)CD56(+) population with immunosuppressive function in cancer tissues of human hepatocellular carcinoma. Sci Rep 2015; 5:14757. [PMID: 26437631 PMCID: PMC4594002 DOI: 10.1038/srep14757] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 08/28/2015] [Indexed: 12/29/2022] Open
Abstract
The liver resident lymphoid population is featured by the presence of a large number of CD3+CD56+ cells referred as natural T cells. In human hepatocellular carcinoma (HCC) patients, the natural T cells were found to be sharply decreased in tumor (5.871 ± 3.553%) versus non-tumor (14.02 ± 6.151%) tissues. More intriguingly, a substantial fraction of the natural T cells (22.76 ± 18.61%) assumed FOXP3 expression. These FOXP3-expressing CD3+CD56+ cells lost the expression of IFN-γ and perforin, which are critical for the effector function of natural T cells. On the other hand, they acquired surface expression of CD25 and CTLA-4 typically found in regulatory T (Treg) cells. Consistent with the phenotypic conversion, they imposed an inhibitory effect on anti-CD3-induced proliferation of naive T cells. Further studies demonstrated that transforming growth factor β1 (TGF-β1) could effectively induce FOXP3 expression in CD3+CD56+ cells and the cells were thus endowed with a potent immunosuppressive capacity. Finally, Kaplan-Meier analysis revealed that the relative abundance of FOXP3-expressing CD3+CD56+ cells in tumor tissues was significantly correlated with the survival of HCC patients. In conclusion, the present study identified a new type of regulatory immune cells whose emergence in liver cancer tissues may contribute to tumor progression.
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Affiliation(s)
- Xiaofeng Li
- Department of Immunology, Peking University Health Science Center, Beijing 100191, China.,Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Jirun Peng
- Center of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Yanli Pang
- Department of Immunology, Peking University Health Science Center, Beijing 100191, China
| | - Sen Yu
- Department of Immunology, Peking University Health Science Center, Beijing 100191, China
| | - Xin Yu
- Center of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Pengcheng Chen
- Center of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Wenzhen Wang
- Center of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Wenling Han
- Department of Immunology, Peking University Health Science Center, Beijing 100191, China
| | - Jun Zhang
- Department of Immunology, Peking University Health Science Center, Beijing 100191, China
| | - Yanhui Yin
- Department of Immunology, Peking University Health Science Center, Beijing 100191, China
| | - Yu Zhang
- Department of Immunology, Peking University Health Science Center, Beijing 100191, China
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17
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Ehling J, Tacke F. Role of chemokine pathways in hepatobiliary cancer. Cancer Lett 2015; 379:173-83. [PMID: 26123664 DOI: 10.1016/j.canlet.2015.06.017] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 06/09/2015] [Indexed: 12/17/2022]
Abstract
Persistent hepatic inflammation resulting from hepatitis B or C virus infections (HBV or HCV, respectively), obesity-associated non-alcoholic steatohepatitis (NASH) or alcohol abuse is a hallmark feature of chronic liver diseases and appears to be an essential prerequisite of hepatocarcinogenesis. The inflammatory processes in the liver are regulated by various chemokines, which orchestrate the interaction between parenchymal liver cells, Kupffer cells (resident macrophages), hepatic stellate cells (HSC), endothelial cells, and infiltrating immune cells. In consequence, these cellular interactions result in the re-modeling of the hepatic microenvironment toward a pro-inflammatory, pro-fibrotic, pro-angiogenic and thus pre-neoplastic milieu. Once developed, liver neoplasms provoke pro- and anti-tumor immune responses that are also critically regulated through differential activation of chemokine pathways. With respect to hepatobiliary cancers, including hepatocellular carcinoma (HCC), gallbladder cancer and cholangiocellular carcinoma (cholangiocarcinoma), together belonging to the highest causes of cancer-related deaths worldwide, this review article will give an overview of chemokine pathways involved in both the establishment of a pro-tumorigenic microenvironment as well as the development and progression of hepatobiliary cancer. Pharmaceutical targeting of chemokine pathways is a promising approach to treat or even prevent hepatobiliary cancer.
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Affiliation(s)
- Josef Ehling
- Department of Experimental Molecular Imaging, Helmholtz Institute for Biomedical Engineering, Medical Faculty, RWTH University, Aachen, Germany
| | - Frank Tacke
- Department of Medicine III, Medical Faculty, RWTH University, Aachen, Germany.
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18
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Bertino G, Demma S, Ardiri A, Proiti M, Malaguarnera G, Bertino N, Malaguarnera M, Malaguarnera M. The immune system in hepatocellular carcinoma and potential new immunotherapeutic strategies. BIOMED RESEARCH INTERNATIONAL 2015; 2015:731469. [PMID: 25893197 PMCID: PMC4393929 DOI: 10.1155/2015/731469] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 12/11/2014] [Accepted: 12/12/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND Hepatocellular carcinoma is a major health problem worldwide and the third most common cause of cancer-related death. HCC treatment decisions are complex and dependent upon tumor staging. Several molecular targeted agents have been evaluated in clinical trials in advanced HCC. Despite of only modest objective response rates according to the Response Evaluation Criteria in Solid Tumors, several studies showed encouraging results in terms of prolongation of the time to progression, disease stabilization, and survival. Cellular immunotherapy would improve the immune state and has potential in enhancing the therapeutic outcome for HCC patients. MATERIALS AND METHODS A search of the literature was made using cancer literature, the PubMed, Scopus, and Web of Science (WOS) database for the following keywords: "hepatocellular carcinoma," "molecular hepatocarcinogenesis," "targeted therapy," "molecular immunological targets," "tumour-associated antigens," "Tregs," "MDSCs," "immunotherapy." DISCUSSION AND CONCLUSION Treatment strategies combining blockade of immunoregulatory cell types such as Tregs and MDSCs and of inhibitory receptors, with vaccine-induced activation of TAA-specific T cells, may be necessary to achieve the most effective therapeutic antitumour activity in HCC. In the future, new therapeutic options will be represented by a blend of immunotherapy-like vaccines and T-cell modulators, supplemented by molecularly targeted inhibitors of tumor signaling pathways.
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Affiliation(s)
- Gaetano Bertino
- Department of Medical and Pediatric Sciences, Hepatology Unit, University of Catania, Policlinic, Via S. Sofia No. 78, 95123 Catania, Italy
| | - Shirin Demma
- Department of Medical and Pediatric Sciences, Hepatology Unit, University of Catania, Policlinic, Via S. Sofia No. 78, 95123 Catania, Italy
| | - Annalisa Ardiri
- Department of Medical and Pediatric Sciences, Hepatology Unit, University of Catania, Policlinic, Via S. Sofia No. 78, 95123 Catania, Italy
| | - Maria Proiti
- Department of Medical and Pediatric Sciences, Hepatology Unit, University of Catania, Policlinic, Via S. Sofia No. 78, 95123 Catania, Italy
| | - Giulia Malaguarnera
- Research Centre “The Great Senescence”, University of Catania, Cannizzaro Hospital, Via Messina No. 829, 95100 Catania, Italy
| | - Nicoletta Bertino
- Faculty of Pharmacy, University of Catania, Viale Andrea Doria No. 6, 95123 Catania, Italy
- Faculty of Pharmacy, University of Catania, University of Catania Policlinic, Via S. Sofia No. 78, 95123 Catania, Italy
| | - Mariano Malaguarnera
- Department of Medical and Pediatric Science, Research Centre “The Great Senescence”, University of Catania, Cannizzaro Hospital, Via Messina No. 829, 95100 Catania, Italy
| | - Michele Malaguarnera
- Research Centre “The Great Senescence”, University of Catania, Cannizzaro Hospital, Via Messina No. 829, 95100 Catania, Italy
- International Ph.D. Program in Neuropharmacology, University of Catania, Cannizzaro Hospital, Via Messina No. 829, 95100 Catania, Italy
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19
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De Re V, Caggiari L, De Zorzi M, Repetto O, Zignego AL, Izzo F, Tornesello ML, Buonaguro FM, Mangia A, Sansonno D, Racanelli V, De Vita S, Pioltelli P, Vaccher E, Beretta M, Mazzaro C, Libra M, Gini A, Zucchetto A, Cannizzaro R, De Paoli P. Genetic diversity of the KIR/HLA system and susceptibility to hepatitis C virus-related diseases. PLoS One 2015; 10:e0117420. [PMID: 25700262 PMCID: PMC4336327 DOI: 10.1371/journal.pone.0117420] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 12/21/2014] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND The variability in the association of host innate immune response to Hepatitis C virus (HCV) infection requires ruling out the possible role of host KIR and HLA genotypes in HCV-related disorders: therefore, we therefore explored the relationships between KIR/HLA genotypes and chronic HCV infection (CHC) as they relate to the risk of HCV-related hepatocarcinoma (HCC) or lymphoproliferative disease progression. METHODS AND FINDINGS We analyzed data from 396 HCV-positive patients with CHC (n = 125), HCC (118), and lymphoproliferative diseases (153), and 501 HCV-negative patients. All were HIV and HBV negative. KIR-SSO was used to determine the KIR typing. KIR2DL5 and KIR2DS4 variants were performed using PCR and GeneScan analysis. HLA/class-I genotyping was performed using PCR-sequence-based typing. The interaction between the KIR gene and ligand HLA molecules was investigated. Differences in frequencies were estimated using Fisher's exact test, and Cochran-Armitage trend test. The non-random association of KIR alleles was estimated using the linkage disequilibrium test. We found an association of KIR2DS2/KIR2DL2 genes, with the HCV-related lymphoproliferative disorders. Furthermore, individuals with a HLA-Bw6 KIR3DL1+ combination of genes showed higher risk of developing lymphoma than cryoglobulinemia. KIR2DS3 gene was found to be the principal gene associated with chronic HCV infection, while a reduction of HLA-Bw4 + KIR3DS1+ was associated with an increased risk of developing HCC. CONCLUSIONS Our data highlight a role of the innate-system in developing HCV-related disorders and specifically KIR2DS3 and KIR2D genes demonstrated an ability to direct HCV disease progression, and mainly towards lymphoproliferative disorders. Moreover the determination of KIR3D/HLA combination of genes direct the HCV progression towards a lymphoma rather than an hepatic disease. In this contest IFN-α therapy, a standard therapy for HCV-infection and lymphoproliferative diseases, known to be able to transiently enhance the cytotoxicity of NK-cells support the role of NK cells to counterstain HCV-related and lymphoproliferative diseases.
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Affiliation(s)
- Valli De Re
- Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy
| | - Laura Caggiari
- Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy
| | - Mariangela De Zorzi
- Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy
| | - Ombretta Repetto
- Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy
| | - Anna Linda Zignego
- Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Francesco Izzo
- Hepatobiliary Unit, National Cancer Institute “Fondazione Pascale”, Naples, Italy
| | - Maria Lina Tornesello
- Molecular Biology and Viral Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy
| | - Franco Maria Buonaguro
- Molecular Biology and Viral Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy
| | - Alessandra Mangia
- Liver, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
| | - Domenico Sansonno
- Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Vito Racanelli
- Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Salvatore De Vita
- Medical and Biological Sciences, University Hospital Santa Maria della Misericordia, Udine, Italy
| | - Pietro Pioltelli
- Hematology and Transplant Unit, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
| | - Emanuela Vaccher
- Medical Oncology, Centro di riferimento oncologico, Aviano, Pordenone, Italy
| | | | - Cesare Mazzaro
- Medical Oncology, Centro di riferimento oncologico, Aviano, Pordenone, Italy
| | - Massimo Libra
- Biomedical Sciences, University of Catania, Catania, Italy
| | - Andrea Gini
- Epidemiology and Biostatistics, CRO National Cancer Institute, Aviano, Pordenone, Italy
| | - Antonella Zucchetto
- Epidemiology and Biostatistics, CRO National Cancer Institute, Aviano, Pordenone, Italy
| | - Renato Cannizzaro
- Gastroenterology, CRO National Cancer Institute, Aviano, Pordenone, Italy
| | - Paolo De Paoli
- Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy
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Wang XF, Korangy F. Intrahepatic landscape of regulatory T-cell subsets in chronically HCV-infected patients with cirrhosis and HCC. Hepatology 2014; 60:1461-2. [PMID: 24954163 DOI: 10.1002/hep.27271] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Accepted: 06/13/2014] [Indexed: 12/29/2022]
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Bertino G, Demma S, Ardiri A, Proiti M, Malaguarnera G, Bertino N, Malaguarnera M, Malaguarnera M. Hepatocellular carcinoma: novel molecular targets in carcinogenesis for future therapies. BIOMED RESEARCH INTERNATIONAL 2014; 2014:203693. [PMID: 25089265 PMCID: PMC4096380 DOI: 10.1155/2014/203693] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 05/29/2014] [Accepted: 05/30/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma is one of the most common and lethal malignant tumors worldwide. Over the past 15 years, the incidence of HCC has more than doubled. Due to late diagnosis and/or advanced underlying liver cirrhosis, only limited treatment options with marginal clinical benefit are available in up to 70% of patients. During the last decades, no effective conventional cytotoxic systemic therapy was available contributing to the dismal prognosis in patients with HCC. A better knowledge of molecular hepatocarcinogenesis provides today the opportunity for targeted therapy. MATERIALS AND METHODS A search of the literature was made using cancer literature, the PubMed, Scopus, and Web of Science (WOS) database for the following keywords: "hepatocellular carcinoma," "molecular hepatocarcinogenesis," "targeted therapy," and "immunotherapy." DISCUSSION AND CONCLUSION Treatment decisions are complex and dependent upon tumor staging, presence of portal hypertension, and the underlying degree of liver dysfunction. The knowledge of molecular hepatocarcinogenesis broadened the horizon for patients with advanced HCC. During the last years, several molecular targeted agents have been evaluated in clinical trials in advanced HCC. In the future, new therapeutic options will be represented by a blend of immunotherapy-like vaccines and T-cell modulators, supplemented by molecularly targeted inhibitors of tumor signaling pathways.
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Affiliation(s)
- Gaetano Bertino
- Hepatology Unit, Department of Medical and Pediatric Sciences, University of Catania, Policlinic, Via Santa Sofia No. 78, 95123 Catania, Italy
| | - Shirin Demma
- Hepatology Unit, Department of Medical and Pediatric Sciences, University of Catania, Policlinic, Via Santa Sofia No. 78, 95123 Catania, Italy
| | - Annalisa Ardiri
- Hepatology Unit, Department of Medical and Pediatric Sciences, University of Catania, Policlinic, Via Santa Sofia No. 78, 95123 Catania, Italy
| | - Maria Proiti
- Hepatology Unit, Department of Medical and Pediatric Sciences, University of Catania, Policlinic, Via Santa Sofia No. 78, 95123 Catania, Italy
| | - Giulia Malaguarnera
- Research Centre “The Great Senescence”, University of Catania, Via Messina No. 829, 95126 Catania, Italy
| | - Nicoletta Bertino
- Faculty of Pharmacy, University of Catania, Viale Andrea Doria No. 6, 95123 Catania, Italy
| | - Michele Malaguarnera
- Research Centre “The Great Senescence”, University of Catania, Via Messina No. 829, 95126 Catania, Italy
| | - Mariano Malaguarnera
- Research Centre “The Great Senescence”, University of Catania, Via Messina No. 829, 95126 Catania, Italy
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Bertino G, Di Carlo I, Ardiri A, Calvagno GS, Demma S, Malaguarnera G, Bertino N, Malaguarnera M, Toro A, Malaguarnera M. Systemic therapies in hepatocellular carcinoma: present and future. Future Oncol 2014; 9:1533-48. [PMID: 24106903 DOI: 10.2217/fon.13.171] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is now the third leading cause of cancer deathsworldwide and is generally presented at an advanced stage, limiting patients' quality of life. The conventional cytotoxic systemic therapy has proved to be ineffective in HCC, since its induction several decades ago. Today it is possible to use our knowledge of molecular hepatocarcinogenesis to provide a targeted therapy. Sorafenib has demonstrated large improvements in overall survival in HCC. This review describes the molecular mechanisms and potential therapeutic targets, focusing on sorafenib, sunitinib, tivantinib, antiangiogenic agents, and current and future immunotherapies. Thus, it will be necessary in the future to classify HCCs into subgroups according to their genomic and proteomic profiling. The identification of key molecules/receptors/signaling pathways and the assessment of their relevance as potential targets will be the main future challenge potentially influencing response to therapy. Defining molecular targeted agents that are effective for a specific HCC subgroup will hopefully lead to personalized therapy.
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Affiliation(s)
- Gaetano Bertino
- Hepatology Unit - Department of Medical & Pediatric Science, University of Catania Policlinic, Via S Sofia 78, 95123, Catania, Italy
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Mossanen JC, Tacke F. Role of lymphocytes in liver cancer. Oncoimmunology 2013; 2:e26468. [PMID: 24498546 PMCID: PMC3906418 DOI: 10.4161/onci.26468] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Revised: 09/10/2013] [Accepted: 09/11/2013] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) typically occurs in patients with chronic inflammatory liver diseases, such as viral hepatitis or (non-)alcoholic steatohepatitis. Inflammation appears indeed as a crucial factor in hepatocarcinogenesis. Nevertheless, sophisticated animal models and studies of human samples revealed that the HCC also elicits antitumor immune responses. Patrolling and infiltrating lymphocytes (e.g., NKT and T cells, respectively) can exert decisive functions in the transition from chronic hepatic inflammation to cancer as well as in antitumor immune responses. An improved understanding of the cellular and molecular mechanisms whereby inflammation promotes or restricts hepatocarcinogenesis will open new avenues for therapeutic approaches to liver cancer.
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Affiliation(s)
- Jana C Mossanen
- Department of Medicine III; RWTH-University Hospital Aachen; Aachen, Germany
| | - Frank Tacke
- Department of Medicine III; RWTH-University Hospital Aachen; Aachen, Germany
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Zhang GL, Zhao W. Recent progress in understanding the effect of interventional therapy for hepatic carcinoma on immune function. Shijie Huaren Xiaohua Zazhi 2012; 20:3225-3230. [DOI: 10.11569/wcjd.v20.i33.3225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is a common highly malignant tumor in China, with a high rate of recurrence and metastasis. The body's immune function is closely related with the occurrence and development of liver cancer, and low immunological function is an important reason why hepatic carcinoma is hard to cure and tend to recur and metastasize. At present, surgery-based comprehensive therapy plays a dominant role in the treatment of hepatic carcinoma; however, the majority of patients had lost their opportunities for surgical treatment when a definitive diagnosis was established. Interventional therapy is regarded as the first choice of nonsurgical treatment for hepatic carcinoma. Interventional therapy can not only result in coagulative tumor necrosis but also promote apoptosis of tumor cells. The body's immune function can be enhanced to improve the anti-tumor ability by interventional therapy, especially the cellular immune function. As a result, the metastasis and recurrence of hepatic carcinoma may be inhibited. The purpose of this article is to review the progress in understanding the effect of interventional therapy for hepatic carcinoma on immune function.
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