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Ion G, Bostan M, Hardman WE, Putt McFarland M, Bleotu C, Radu N, Diaconu CC, Mihaila M, Caramihai MD, Hotnog CM. Nutrients Lowering Obesity-Linked Chemokines Blamable for Metastasis. Int J Mol Sci 2025; 26:2275. [PMID: 40076892 PMCID: PMC11899810 DOI: 10.3390/ijms26052275] [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: 01/28/2025] [Revised: 02/25/2025] [Accepted: 02/27/2025] [Indexed: 03/14/2025] Open
Abstract
Food intake is an essential contributor to both health and disease. Nutrients contribute to a beneficial metabolic equilibrium at the cellular level, preventing or delaying disease onset. Dietary intake contributes to obesity, and obesity supports further cancer and metastasis. Metastasis, a multifactorial and multistep process, is supported by the systemic inflammation of obesity. Spreading of the cancer cells requires the presence of a plethora of recruiter and regulator molecules. Molecules such as chemokines are provided at high levels by obesity-associated fat depots. Chemokine up-regulation in adipose tissue of obese individuals has been associated with different types of cancers such as breast, prostate, colon, liver, and stomach. Chemokines support all metastasis steps from invasion/migration to intravasation, circulation, extravasation, and ending with colonization. The obesity pool of chemokines supporting these processes includes CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL18, CCL19, CCL20, CXCL1, CXCL5, CXCL 8, CXCL10, and CXCL12. Keeping obesity under control can be beneficial in reducing the levels of pro-inflammatory chemokines and the risk of poor cancer outcome. Nutrients can help, support, and boost cancer treatment effects or jeopardize the treatment. Constituents with anti-inflammatory and anti-obesity properties such as polyphenols, organosulfur components, fatty acids, curcumin, and vitamin E have a proven beneficial effect in lowering obesity and its contribution to metastasis.
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Affiliation(s)
- Gabriela Ion
- Center of Immunology, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (G.I.); (C.M.H.)
| | - Marinela Bostan
- Center of Immunology, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (G.I.); (C.M.H.)
- Department of Immunology, ‘Victor Babes’ National Institute of Pathology, 050096 Bucharest, Romania
| | - Wanda Elaine Hardman
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA (M.P.M.)
| | - Margaret Putt McFarland
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA (M.P.M.)
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (C.B.); (C.C.D.)
- Research Institute of the University of Bucharest (ICUB), University of Bucharest, 060023 Bucharest, Romania
- The Academy of Romanian Scientist, 050711 Bucharest, Romania
| | - Nicoleta Radu
- Faculty of Biotechnology, University of Agronomic Sciences and Veterinary Medicine of Bucharest, 011464 Bucharest, Romania;
- Biotechnology Department, National Institute for Chemistry and Petrochemistry R&D of Bucharest, 060021 Bucharest, Romania
| | - Carmen Cristina Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (C.B.); (C.C.D.)
| | - Mirela Mihaila
- Center of Immunology, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (G.I.); (C.M.H.)
- Faculty of Pharmacy, Titu Maiorescu University, 040314 Bucharest, Romania
| | - Mihai Dan Caramihai
- Faculty of Automatic Control and Computer Science, National University of Science and Technology Politehnica Bucharest, 060042 Bucharest, Romania;
| | - Camelia Mia Hotnog
- Center of Immunology, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (G.I.); (C.M.H.)
- Department of Biochemistry and Biophysics, Faculty of Midwives and Nursing, University of Medicine and Pharmacy “Carol Davila” Bucharest, 050474 Bucharest, Romania
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Wang Y, Ding C, Wei X, Li Y, Yu X, Chen X, Sun J, Zhuang J, Cao S, Zhen P, Fang F, Zhang J, Wang J, Qian D, Pang Q. CCL4 and MIF: Prognostic Biomarkers for Evaluating the Chemoradiotherapy Response and Prognosis in Patients with ESCC. J Cancer 2025; 16:2015-2025. [PMID: 40092701 PMCID: PMC11905412 DOI: 10.7150/jca.104088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 01/25/2025] [Indexed: 03/19/2025] Open
Abstract
Background: Radiotherapy plays a central role in therapeutic strategy of local-advanced oesophageal squamous cell carcinoma. The aim of this study was to investigate cytokine profiles in serum of patients with ESCC and evaluate the potential utility of cytokine markers in predicting CRT response and prognostic prediction. Methods: CCL4, MIF and CXCL8 in the serum samples who were participating in a phase II clinical trial (NCT02959385) were determined. The association between these cytokines and CRT response as well as prognostic prediction were subsequently assessed in ESCC. Subsequently, the results were verified in ESCC tissue and in the Cancer Genome Atals (TCGA) database. Results: The expression of 120 cytokines were evaluated in serum of 4 ESCC patients with excellent CRT-response and 4 patients with CRT-resistance by cytokine microarrays. CCL3, CCL4, MIF, PLAUR and CXCL8 were screened. CCL4, MIF and CXCL8 were further detected by ELISA in other 60 patients enrolled in this study. Upregulation of CCL4, CXCL8 and MIF were observed in patients with excellent CRT-response. Elevated expression of CCL4 and MIF were closely associated with improved PFS and OS outcomes. Similar results were obtained in other 46 ESCC tumor tissues. 82 ESCC patients in TCGA database with increased CCL4 and MIF expression exhibited the favorable immunocyte infiltration and enriched immune response-related pathways, which indicates the preferable tumor immunogenicity. Conclusions: CCL4 and MIF are identified as dependable and prognostic biomarkers for evaluating the response to CRT and prognosis in patients with ESCC.
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Affiliation(s)
- Yuwen Wang
- Department of Radiation Oncology, Tianjin Cancer Hospital Airport Hospital, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Chunxue Ding
- Department of Radiation Oncology, Tianjin Cancer Hospital Airport Hospital, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Xiaoying Wei
- Department of Radiation Oncology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Yuting Li
- Department of Radiation Oncology, Department of Pathology, Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, China
| | - Xuyao Yu
- Department of Radiation Oncology, Tianjin Cancer Hospital Airport Hospital, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Xi Chen
- Department of Radiation Oncology, Tianjin Cancer Hospital Airport Hospital, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Jifeng Sun
- Department of Radiation Oncology, Tianjin Cancer Hospital Airport Hospital, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Junhong Zhuang
- Department of Radiation Oncology, Tianjin Cancer Hospital Airport Hospital, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Shuai Cao
- Department of Radiation Oncology, Tianjin Cancer Hospital Airport Hospital, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Peng Zhen
- Department of Radiation Oncology, Chifeng Tumor Hospital, Chifeng, China
| | - Fang Fang
- Department of Radiation Oncology, Chifeng Tumor Hospital, Chifeng, China
| | - Jiarui Zhang
- Department of Radiation Oncology, Chifeng Tumor Hospital, Chifeng, China
| | - Jun Wang
- Department of Radiation Oncology, Tianjin Cancer Hospital Airport Hospital, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Dong Qian
- Department of Radiation Oncology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Qingsong Pang
- Department of Radiation Oncology, Tianjin Cancer Hospital Airport Hospital, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
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Guo HW, Lai HJ, Long BQ, Xu LX, Wang EHC, Shapiro J, McElwee KJ. Increased CRHR1 expression on monocytes from patients with AA enables a pro-inflammatory response to corticotrophin-releasing hormone. Exp Dermatol 2024; 33:e15182. [PMID: 39367575 DOI: 10.1111/exd.15182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 08/19/2024] [Accepted: 09/06/2024] [Indexed: 10/06/2024]
Abstract
Stress may play a key role in alopecia areata (AA), though the exact interactions of stress with AA remain undefined. Corticotropin-releasing hormone (CRH), the proximal regulator of the stress axis, has been recognized as an immunomodulatory factor in tissues and peripheral blood mononuclear cells (PBMCs). We used multicolour flow cytometry to identify receptor CRHR1 expression on PBMC subsets in AA patients (n = 54) and controls (n = 66). We found that CRHR1 was primarily expressed by circulating monocytes. CRHR1 expression on monocytes was enhanced in AA compared with controls (3.17% vs. 1.44%, p = 0.002, chi-squared test). AA incidence was correlated to elevated CD14+ monocyte numbers (R = 0.092, p = 0.036) and markedly independently correlated with increased CRHR1 expression (R = 0.215, p = 0.027). High CRHR1 expression was significantly related to chronic AA (disease duration >1 year; p = 0.003, chi-squared test), and large lesion area (AA area >25%; p = 0.049, chi-squared test). We also observed enhanced percentages of active monocytes and reduced CD16+ CD3- NK cell numbers in AA patients' PBMCs (p = 0.010; 0.025, respectively). In vitro CRH treatment of PBMCs and human monocyte cell line THP-1 promoted CD86 upregulation. The findings imply that stress-related factors CRH and CRHR1 contribute to AA development and progression where higher CRHR1 expression is associated with chronic AA and larger lesions.
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Affiliation(s)
- Hong-Wei Guo
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Dermatology, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Hui-Jun Lai
- Department of Dermatology, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Bo-Quan Long
- Department of Dermatology, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Li-Xin Xu
- Flow Core Facility, Children and Family Research Institute, Vancouver, British Columbia, Canada
| | - Eddy Hsi Chun Wang
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jerry Shapiro
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada
- The Ronald O. Perelman Department of Dermatology, New York University Grossman School of Medicine, New York, New York, USA
| | - Kevin J McElwee
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada
- Centre for Skin Sciences, University of Bradford, Bradford, West Yorkshire, UK
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Chuma M, Uojima H, Toyoda H, Hiraoka A, Arase Y, Atsukawa M, Itokawa N, Okubo T, Tada T, Numata K, Morimoto M, Sugimori M, Nozaki A, Iwasaki S, Yasuda S, Koshiyama Y, Mishima Y, Tsuruya K, Tokoro C, Miura Y, Hidaka H, Kumada T, Kusano C, Kagawa T, Maeda S. Clinical significance of circulating biomarkers of immune-checkpoint molecules with atezolizumab plus bevacizumab therapy in unresectable hepatocellular carcinoma. Hepatol Int 2024; 18:1472-1485. [PMID: 38963640 DOI: 10.1007/s12072-024-10680-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 04/06/2024] [Indexed: 07/05/2024]
Abstract
BACKGROUND The aims of this study were to identify clinically significant biomarkers of a response to atezolizumab plus bevacizumab (ATZ + BV) therapy and to develop target strategies against unresectable hepatocellular carcinoma (u-HCC). METHOD We first investigated the potential of circulating tumor DNA (ctDNA) to serve as a biomarker for predicting the therapeutic outcome in 24 u-HCC patients treated with ATZ + BV therapy. Next, we analyzed levels of immune-related cytokines in blood samples from 134 u-HCC patients who received ATZ + BV. For this, serum immune-related molecules or cancer-immune cycle-related molecules that have been reported in HCC patient sera, namely CD274, LAG-3, CCL2, 4, 5, CXCL1, 9, 10, 12, 13, CX3CL1, CCR5, IFNγ and IL-6, 8 were measured using enzyme-linked immunosorbent assay. RESULTS More than 1% of variant read frequency (VRF) mutations were found in TP53, APC, PIK3CA and VHL, although with no correlation with treatment response. Among the 15 cytokines evaluated, CXCL9 and LAG-3 levels were significantly different between patients with objective response (OR), stable disease (SD), and progressive disease (PD) following ATZ + BV treatment. Receiver-operating characteristic curve analyses of CXCL9 (cut-off value: 419.1 pg/ml) and LAG-3 (cut-off value: 3736.3 pg/ml) indicated areas of 0.779 and 0.697, respectively, for differentiating PD from non-PD and OR from non-OR. In multivariate analysis of progression-free survival (PFS) and overall survival (OS), high serum CXCL9 (hazard ratio (HR) and 95% confidence interval (CI): 0.412 (0.251-0.677) (p = 0.0005) for PFS and 0.252 (0.125-0.508) (p = 0.0001) for OS), and low serum LAG-3 (HR and 95% CI 0.419 (0.249-0.705) (p = 0.0011) for PFS and 0.294 (0.140-0.617) (p = 0.0012) for OS) were independent positive predictive factors. CONCLUSION Although, as far as we examined, no ctDNA mutations in blood were found to be related to ATZ + BV treatment efficacy, serum CXCL9 and LAG-3 levels, which are related to the cancer-immune cycle, were associated with treatment efficacy and could be predictive markers of the efficacy of ATZ + BV treatment in HCC patients.
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Affiliation(s)
- Makoto Chuma
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan.
| | - Haruki Uojima
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Yoshitake Arase
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Hospital, Tokyo, Japan
| | - Norio Itokawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Hospital, Tokyo, Japan
| | - Tomomi Okubo
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Toshifumi Tada
- Department of Gastroenterology, Himeji Red Cross Hospital, Himeji, Japan
| | - Kazushi Numata
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan
| | - Manabu Morimoto
- Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital, Yokohama, Japan
| | - Makoto Sugimori
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan
| | - Akito Nozaki
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan
| | - Shuichiro Iwasaki
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Yuichi Koshiyama
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Yusuke Mishima
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Kota Tsuruya
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Chikako Tokoro
- Division of Gastroenterology, Saiseikai Yokohamashi-Nanbu Hospital, Yokohama, Japan
| | - Yuki Miura
- Gastroenterology Division, Hadano Red Cross Hospital, Hadano, Japan
| | - Hisashi Hidaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Takashi Kumada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
- Faculty of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Chika Kusano
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Tatehiro Kagawa
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Hospital, Yokohama, Japan
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Jiang L, Meng Q, Liu L, Li W. A Comprehensive Review on Molecular Mechanisms, Treatments, and Brief Role of Natural Products in Hepatocellular Cancer. Nat Prod Commun 2024; 19. [DOI: 10.1177/1934578x241284873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Most initial liver cancers are hepatocellular carcinomas (HCC), which make up the vast majority of cases. Hepatitis B or C virus infection as well as alcohol consumption is among the key risk factors. The significance of the most intriguing soluble factors as indicators for early diagnosis and as suggested targets for therapy in light of the increasing challenges in precision medicine. The development of HCC is influenced by a complex combination between pro-inflammatory and anti-inflammatory cytokines and their signalling cascades. Recently,researchers are aims to assess the potential of a number of distinct molecular cascade/cascade including cytokines to function as key players with particular underlying etiologies. Increasing our knowledge of the signaling network that links retro differentiation and inflammationmay help us find novel therapeutic targets and develop combined therapies or treatments that work against tumors with a significant degree of heterogeneity. With nursing processes at its center, comprehensive nursing care is a new nursing paradigm that combines the benefits of primary and group nursin g as well as a perfect synthesis of many nursing metrics like nursing philosophy, nursing plan, and nursing quality evaluation. In order to treat patients with serious liver diseases like cancer, it can conduct nursing interventions item by item in accordance with the unique disease conditions of each patient and combine efficient therapeutic approaches with high-quality nursing modes. Dietary natural products, including fruits, vegetables, and spices, may prevent and treat liver cancer by inhibiting tumor growth, protecting the liver, and enhancing chemotherapy.
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Affiliation(s)
- Linlin Jiang
- Interventional Radiology, Harbin Medical University Cancer Hospital, Harbin Heilongjiang, China
| | - Qin Meng
- Department of Nursing, Huaian Hospital of Huaian City, Huaian Jiangsu,China
| | - Lixiu Liu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin Heilongjiang, China
| | - Weihang Li
- Interventional Radiology, Harbin Medical University Cancer Hospital, Harbin Heilongjiang, China
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CHEN R, YANG X, LIU Q, ZHANG S, MA L. [Research Progresses on the Effects of CCL4 on Immune Escape
in Tumor Microenvironment]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2024; 27:613-621. [PMID: 39318254 PMCID: PMC11425676 DOI: 10.3779/j.issn.1009-3419.2024.106.23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Indexed: 09/26/2024]
Abstract
Immunotherapy has become the cornerstone of current malignant tumor treatment. However, the response of different patients to immunotherapy is highly heterogeneous, and not all patients can benefit from it. There is an urgent need to find biomarkers that can effectively predict the efficacy of immunotherapy. C-C chemokine ligand 4 (CCL4) is a cytokine, belonging to the inflammatory CCL subfamily. It is mainly secreted by immune cells and tumor cells and shows low or no expression in normal tissues but abnormally high expression in various malignant tumor tissues. After binding to CCL4 and its receptor C-C chemokine receptor type 5 (CCR5), it can recruit and mediate immune cell migration, destroy the stability of the tumor microenvironment (TME), participate in carcinogenesis and promote the development of tumors. In the tumor immune microenvironment, CCL4 can mediate and recruit the directed migration of key immune cells such as monocytes, macrophages, natural killer (NK) cells, and T cells, which makes it a potentially important element affecting the efficacy of immunotherapy and has specific value. This paper reviews the research progresses of CCL4's effects on immune escape in TME, in order to provide clues and references for basic research and clinical diagnosis and treatment.
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Stayoussef M, Weili X, Habel A, Barbirou M, Bedoui S, Attia A, Omrani Y, Zouari K, Maghrebi H, Almawi WY, Bouhaouala-Zahar B, Larbi A, Yacoubi-Loueslati B. Altered expression of cytokines, chemokines, growth factors, and soluble receptors in patients with colorectal cancer, and correlation with treatment outcome. Cancer Immunol Immunother 2024; 73:169. [PMID: 38954024 PMCID: PMC11219625 DOI: 10.1007/s00262-024-03746-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 05/22/2024] [Indexed: 07/04/2024]
Abstract
Insofar as they play an important role in the pathogenesis of colorectal cancer (CRC), this study analyzes the serum profile of cytokines, chemokines, growth factors, and soluble receptors in patients with CRC and cancer-free controls as possible CRC signatures. Serum levels of 65 analytes were measured in patients with CRC and age- and sex-matched cancer-free controls using the ProcartaPlex Human Immune Monitoring 65-Plex Panel. Of the 65 tested analytes, 8 cytokines (CSF-3, IFN-γ, IL-12p70, IL-18, IL-20, MIF, TNF-α and TSLP), 8 chemokines (fractalkine, MIP-1β, BLC, Eotaxin-1, Eotaxin-2, IP-10, MIP-1a, MIP-3a), 2 growth factors (FGF-2, MMP-1), and 4 soluble receptors (APRIL, CD30, TNFRII, and TWEAK), were differentially expressed in CRC. ROC analysis confirmed the high association of TNF-α, BLC, Eotaxin-1, APRIL, and Tweak with AUC > 0.70, suggesting theranostic application. The expression of IFN-γ, IL-18, MIF, BLC, Eotaxin-1, Eotaxin-2, IP-10, and MMP1 was lower in metastatic compared to non-metastatic CRC; only AUC of MIF and MIP-1β were > 0.7. Moreover, MDC, IL-7, MIF, IL-21, and TNF-α are positively associated with tolerance to CRC chemotherapy (CT) (AUC > 0.7), whereas IL-31, Fractalkine, Eotaxin-1, and Eotaxin-2 were positively associated with resistance to CT. TNF-α, BLC, Eotaxin-1, APRIL, and Tweak may be used as first-line early detection of CRC. The variable levels of MIF and MIP-1β between metastatic and non-metastatic cases assign prognostic nature to these factors in CRC progression. Regarding tolerance to CT, MDC, IL-7, MIF, IL-21, and TNF-α are key when down-regulated or resistant to treatment is observed.
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Affiliation(s)
- M Stayoussef
- Laboratory of Mycology, Faculty of Sciences of Tunis (FST), Pathologies and Biomarkers (LR16ES05), University of Tunis El Manar (UTM), 1092, Tunis, Tunisia.
| | - X Weili
- Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Immunos Building, Singapore, 138648, Singapore
| | - A Habel
- Laboratory of Mycology, Faculty of Sciences of Tunis (FST), Pathologies and Biomarkers (LR16ES05), University of Tunis El Manar (UTM), 1092, Tunis, Tunisia
| | - M Barbirou
- Center for Biomedical Informatics, University of Missouri School of Medicine, Columbia, MO, USA
| | - S Bedoui
- Laboratory of Mycology, Faculty of Sciences of Tunis (FST), Pathologies and Biomarkers (LR16ES05), University of Tunis El Manar (UTM), 1092, Tunis, Tunisia
| | - A Attia
- Laboratory of Mycology, Faculty of Sciences of Tunis (FST), Pathologies and Biomarkers (LR16ES05), University of Tunis El Manar (UTM), 1092, Tunis, Tunisia
| | - Y Omrani
- Laboratory of Biomolecules, Venoms and Theranostic Applications, University of Tunis El Manar (UTM), Pasteur Institute of Tunis, 13 Place Pasteur, B.P. 74, 1002, Tunis, Tunisia
| | - K Zouari
- Department of Digestive Surgery, Fattouma Bourguiba Hospital, University of Monastir, Monastir, Tunisia
| | - H Maghrebi
- Faculty of Medicine of Tunis, University of Tunis El Manar (UTM), Tunis, Tunisia
| | - W Y Almawi
- Laboratory of Mycology, Faculty of Sciences of Tunis (FST), Pathologies and Biomarkers (LR16ES05), University of Tunis El Manar (UTM), 1092, Tunis, Tunisia
| | - B Bouhaouala-Zahar
- Laboratory of Biomolecules, Venoms and Theranostic Applications, University of Tunis El Manar (UTM), Pasteur Institute of Tunis, 13 Place Pasteur, B.P. 74, 1002, Tunis, Tunisia
- University of Tunis El Manar (UTM), Medical School of Tunis, Rue Djebal Lakhdar, 1006, Tunis, Tunisia
| | - A Larbi
- Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Immunos Building, Singapore, 138648, Singapore
- Department of Medicine, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC, Canada
| | - B Yacoubi-Loueslati
- Laboratory of Mycology, Faculty of Sciences of Tunis (FST), Pathologies and Biomarkers (LR16ES05), University of Tunis El Manar (UTM), 1092, Tunis, Tunisia
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Deng Q, Zhang X, Wan X, Zheng X, Wang H, Zhao J, Wang HQ, Yang W. The chemokine CCL20 can assist AFP in serological diagnosis of hepatocellular carcinoma. Heliyon 2024; 10:e26774. [PMID: 38439882 PMCID: PMC10909724 DOI: 10.1016/j.heliyon.2024.e26774] [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: 07/20/2023] [Revised: 12/28/2023] [Accepted: 02/20/2024] [Indexed: 03/06/2024] Open
Abstract
The chemokine 20 (CCL20) is a member of the CC chemokine family and plays a role in tumor immunity and autoimmune disease. This work investigated the value of CCL20 as a serum diagnostic marker for primary hepatocellular carcinoma (HCC). Based on the data of hepatocellular carcinoma patients in the TCGA database, the up-regulated genes encoding secretory proteins were analyzed in each pathological stage, and the candidate marker CCL20 gene was selected. Serum concentrations of CCL20 in patients with primary HCC, benign liver disease, and healthy subjects were analyzed by enzyme-linked immunosorbent assay (ELISA). The ROC curve evaluated the efficacy of CCL20 alone or in combination with AFP in the diagnosis of HCC. It was found the expression of CCL20 in HCC patients was significantly higher than that in the benign liver disease group and healthy controls (P < 0.05); The AUC of ROC curve to distinguish HCC patients from healthy controls was 0.859, the sensitivity was 73.42%, and the specificity was 86.84%. After combination with AFP, the AUC increased to 0.968, the sensitivity was 88.16%, and the specificity was 97.37%. Although CCL20 was increased in the serum of patients with benign liver diseases, combined with AFP, the AUC to distinguish HCC patients from non-HCC cohorts (benign liver disease group and healthy control group) was 0.902, with a sensitivity of 91.67% and a specificity of 75.26%. Collectively, serum CCL20 is closely related to the occurrence of HCC, and detection of serum CCL20 can assist AFP in improving the diagnostic sensitivity of HCC.
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Affiliation(s)
- Qingmei Deng
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- Medical Pathology Center, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China
| | - Xinhui Zhang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- Medical Pathology Center, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Xiaofeng Wan
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- Medical Pathology Center, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China
| | - Xin Zheng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Hongzhi Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- Medical Pathology Center, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Jingyu Zhao
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- Medical Pathology Center, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China
- Institutes of Physical Science and Information Technology, Anhui University, Hefei, 230601, China
| | - Hong-Qiang Wang
- Biological Molecular Information System Laboratory, Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Wulin Yang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- Medical Pathology Center, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
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9
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Cheng X, Tang Y, He Q, Song J, Wang K, Li H, Huang J, Wang W, Li J, Wang H, Tu M, Chen J, Yuan G, Kang S, Liu H, Zhang X, Luo W, Ji Y, Lan X, Zhou L, Lai Q, Luo X, Wu Q, Zhou D, Tan Y, Chen J, Zhang X. Spleen-dedicated stiffness measurement performed well to rule out high-risk varices in HBV-related hepatocellular carcinoma: Screening for high-risk varices in HCC. Aliment Pharmacol Ther 2024; 59:680-691. [PMID: 38155565 DOI: 10.1111/apt.17850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 11/06/2023] [Accepted: 12/14/2023] [Indexed: 12/30/2023]
Abstract
BACKGROUND Esophagogastroduodenoscopy (EGD) is required to screen for high-risk varices (HRV) in patients with hepatocellular carcinoma (HCC), especially since overall survival rates have dramatically improved with new systemic therapies. AIM To assess the Baveno VI and Baveno VII algorithms' ability to rule out HRV in hepatitis B virus (HBV)-related HCC METHODS: We prospectively enrolled consecutive patients with HBV related, compensated cirrhosis and newly diagnosed HCC who underwent liver stiffness measurement, spleen stiffness measurement (SSM) using a 100-Hz shear wave frequency, and EGD. RESULTS From September 2021 to August 2023, we enrolled 219 patients with HCC, with 107 (48.9%) Barcelona Clinic Liver Cancer (BCLC) A, 28 (12.8%) BCLC B and 84 (38.3%) BCLC C, respectively. HRV prevalence was 28.8% (63/219). Baveno VI criteria safely (HRV missing rate, 3.2%) avoided 27.4% unnecessary EGDs, while the Baveno VII algorithm avoided 49.3% with HRV missing rate at 7.9% (5/63). The SSM ≤40 kPa avoided 47.5% of EGDs safely (HRV missing rate, 4.8%), significantly better than the Baveno VI criteria (p < 0.001) and comparable to the Baveno VII algorithm (p = 0.390). The SSM ≤40 kPa safely avoided EGDs in patient subgroups within Milan criteria, with portal vein tumour thrombosis or BCLC B/C or candidates for systemic therapy. CONCLUSIONS We validated that the SSM ≤40 kPa using a 100-Hz probe could safely eliminate more unnecessary EGDs than the Baveno VI criteria in patients with HBV-related HCC. However, the efficacy of the Baveno VII algorithm in patients with HCC requires further investigation.
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Affiliation(s)
- Xiao Cheng
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yujun Tang
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qinjun He
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiankang Song
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kunyuan Wang
- Liver Tumor Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hui Li
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jing Huang
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weibin Wang
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Junying Li
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Haiyu Wang
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Minghan Tu
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinzhang Chen
- Liver Tumor Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guosheng Yuan
- Liver Tumor Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shuai Kang
- Liver Tumor Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hongyan Liu
- Liver Tumor Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyong Zhang
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wenfan Luo
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yali Ji
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoqin Lan
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ling Zhou
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qintao Lai
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoqin Luo
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qiaoping Wu
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Damei Zhou
- Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yingqi Tan
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinjun Chen
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Hepatology Unit, Department of Infectious Diseases, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaofeng Zhang
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Jung IR, Ahima RS, Kim SF. Time-Restricted Feeding Ameliorates Methionine-Choline Deficient Diet-Induced Steatohepatitis in Mice. Int J Mol Sci 2024; 25:1390. [PMID: 38338668 PMCID: PMC10855189 DOI: 10.3390/ijms25031390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/20/2024] [Accepted: 01/21/2024] [Indexed: 02/12/2024] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is an inflammatory form of non-alcoholic fatty liver disease (NAFLD), closely associated with disease progression, cirrhosis, liver failure, and hepatocellular carcinoma. Time-restricted feeding (TRF) has been shown to decrease body weight and adiposity and improve metabolic outcomes; however, the effect of TRF on NASH has not yet been fully understood. We had previously reported that inositol polyphosphate multikinase (IPMK) mediates hepatic insulin signaling. Importantly, we have found that TRF increases hepatic IPMK levels. Therefore, we investigated whether there is a causal link between TRF and IPMK in a mouse model of NASH, i.e., methionine- and choline-deficient diet (MCDD)-induced steatohepatitis. Here, we show that TRF alleviated markers of NASH, i.e., reduced hepatic steatosis, liver triglycerides (TG), serum alanine transaminase (ALT) and aspartate aminotransferase (AST), inflammation, and fibrosis in MCDD mice. Interestingly, MCDD led to a significant reduction in IPMK levels, and the deletion of hepatic IPMK exacerbates the NASH phenotype induced by MCDD, accompanied by increased gene expression of pro-inflammatory chemokines. Conversely, TRF restored IPMK levels and significantly reduced gene expression of proinflammatory cytokines and chemokines. Our results demonstrate that TRF attenuates MCDD-induced NASH via IPMK-mediated changes in hepatic steatosis and inflammation.
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Affiliation(s)
| | - Rexford S. Ahima
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University, Baltimore, MD 21218, USA;
| | - Sangwon F. Kim
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University, Baltimore, MD 21218, USA;
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11
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Puengel T, Tacke F. Role of Kupffer cells and other immune cells. SINUSOIDAL CELLS IN LIVER DISEASES 2024:483-511. [DOI: 10.1016/b978-0-323-95262-0.00024-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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12
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Kirchmeyer M, Gaigneaux A, Servais FA, Arslanow A, Casper M, Krawczyk M, Lammert F, Behrmann I. Altered profiles of circulating cytokines in chronic liver diseases (NAFLD/HCC): Impact of the PNPLA3I148M risk allele. Hepatol Commun 2023; 7:e0306. [PMID: 38015590 PMCID: PMC10667005 DOI: 10.1097/hc9.0000000000000306] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 09/02/2023] [Indexed: 11/29/2023] Open
Abstract
BACKGROUND Individuals carrying the risk variant p.I148M of patatin-like phospholipase domain-containing protein 3 (PNPLA3) have a higher susceptibility to fatty liver diseases and associated complications, including HCC, a cancer closely linked to chronic inflammation. Here, we assessed circulating cytokine profiles for patients with chronic liver diseases genotyped for PNPLA3. METHODS Serum concentrations of 22 cytokines were measured by multiplex sandwich-ELISA. The cohort comprised 123 individuals: 67 patients with NAFLD without cirrhosis (57 steatosis, 10 NASH), 24 patients with NAFLD with cirrhosis, 21 patients with HCC (15 cirrhosis), and 11 healthy controls. Receiver operator characteristic analyses were performed to assess the suitability of the cytokine profiles for the prediction of steatosis, cirrhosis, and HCC. RESULTS HGF, IL-6, and IL-8 levels were increased in patients, with ∼2-fold higher levels in patients with cirrhosis versus healthy, while platelet derived growth factor-BB (PDGF-BB) and regulated on activation, normal T cell expressed and secreted (RANTES) showed lower concentrations compared to controls. Migration inhibitory factor and monocyte chemoattractant protein-1 (MCP-1) were found at higher levels in NAFLD samples (maximum: NAFLD-cirrhosis) versus healthy controls and HCC samples. In receiver operator characteristic analyses, migration inhibitory factor, IL-8, IL-6, and monocyte chemoattractant protein-1 yielded high sensitivity scores for predicting noncirrhotic NAFLD (vs. healthy). The top combination to predict cirrhosis was HGF plus PDGF-BB. Migration inhibitory factor performed best to discriminate HCC from NAFLD; the addition of monokine induced gamma (MIG), RANTES, IL-4, macrophage colony-stimulating factor (M-CSF), or IL-17A as second parameters further increased the AUC values (> 0.9). No significant impact of the PNPLA3I148M allele on cytokine levels was observed in this cohort. CONCLUSIONS Cytokines have biomarker potential in patients with fatty liver, possibly suited for early HCC detection in patients with fatty liver. Patients carrying the PNPLA3 risk allele did not present significantly different levels of circulating cytokines.
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Affiliation(s)
- Mélanie Kirchmeyer
- Department of Life Sciences and Medicine, University of Luxembourg, Luxembourg
| | - Anthoula Gaigneaux
- Department of Life Sciences and Medicine, University of Luxembourg, Luxembourg
| | - Florence A. Servais
- Department of Life Sciences and Medicine, University of Luxembourg, Luxembourg
| | - Anita Arslanow
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
- Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Markus Casper
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
- Health Sciences, Hannover Medical School MHH, Hannover, Germany
| | - Iris Behrmann
- Department of Life Sciences and Medicine, University of Luxembourg, Luxembourg
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13
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Bessaad M, Habel A, Hadj Ahmed M, Xu W, Stayoussef M, Bouaziz H, Hachiche M, Mezlini A, Larbi A, Yaacoubi-Loueslati B. Assessing serum cytokine profiles in inflammatory breast cancer patients using Luminex® technology. Cytokine 2023; 172:156409. [PMID: 37918053 DOI: 10.1016/j.cyto.2023.156409] [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: 08/16/2023] [Revised: 10/03/2023] [Accepted: 10/23/2023] [Indexed: 11/04/2023]
Abstract
BACKGROUND Inflammatory breast cancer (IBC), accounts for the majority of deaths associated with breast tumors. Because this form is aggressive from its appearance and has a strong metastatic potential. The majority of patients are not diagnosed until late stages, highlighting the need for the development of novel diagnostic biomarkers. Immune mediators may affect IBC progression and metastasis installation. AIM OF THE STUDY Analysis of serum proteins to identify a panel of prognostic biomarkers for IBC. PATIENTS AND METHODS Serum levels of 65 analytes were determined in IBC and Non-IBC patients with the ProcartaPlex Human Immune Monitoring 65-Plex Panel. RESULTS Fifteen analytes: 5 cytokines (IL-8, IL-16, IL-21, IL-22 and MIF), 7 chemokines (Eotaxin, eotaxin-3, Fractalkine, IP-10, MIP-1α, MIP-1β and SDF-1α), One growth factors (FGF-2) and 2 soluble receptors (TNFRII and Tweak); were significantly differentially expressed between the two groups. ROC curves showed that twelve of them (IL-8, IL-16, IL-21, IL-22, MIF, MIP-1α, MIP-1β, SDF-1α, TNFRII, FGF-2, Eotaxin-3, and Fractalkine) had AUC values greater than 0.70 and thus had potential clinical utility. Moreover, seven cytokines: IL-8, IL-16, MIF, Eotaxin-3, MIP-1α, MIP-1β, and CD-30 are positively associated with patients who developed distant metastasis. Ten analytes: Eotaxin-3, Fractalkine, IL-16, IL-1α, IL-22, IL-8, MIF, MIP-1α, MIP-1β, and TNFRII are positively associated with patients who had Lymph-Nodes invasion. CONCLUSION This study has uncovered a set of 8 analytes (Eotaxin-3, Fractalkine, IL-16, IL-8, IL-22, MIF, MIP-1α, MIP-1β) that can be used as biomarkers of IBC, and can be utilized for early detection of IBC, preventing metastasis and lymph-Nodes invasion.
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Affiliation(s)
- Maryem Bessaad
- University of Tunis El Manar (UTM), Faculty of Sciences of Tunis (FST), Laboratory of Mycology, Pathologies and Biomarkers (LR16ES05), Tunisia
| | - Azza Habel
- University of Tunis El Manar (UTM), Faculty of Sciences of Tunis (FST), Laboratory of Mycology, Pathologies and Biomarkers (LR16ES05), Tunisia
| | - Mariem Hadj Ahmed
- University of Tunis El Manar (UTM), Faculty of Sciences of Tunis (FST), Laboratory of Mycology, Pathologies and Biomarkers (LR16ES05), Tunisia
| | - Weili Xu
- Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Immunos Building, Singapore 138648, Singapore
| | - Mouna Stayoussef
- University of Tunis El Manar (UTM), Faculty of Sciences of Tunis (FST), Laboratory of Mycology, Pathologies and Biomarkers (LR16ES05), Tunisia
| | - Hanen Bouaziz
- Salah Azaiez Oncology Institute, Avenue 9 April, 1006, Bab Saadoun, Tunis, Tunisia
| | - Monia Hachiche
- Salah Azaiez Oncology Institute, Avenue 9 April, 1006, Bab Saadoun, Tunis, Tunisia
| | - Amel Mezlini
- Salah Azaiez Oncology Institute, Avenue 9 April, 1006, Bab Saadoun, Tunis, Tunisia
| | - Anis Larbi
- Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Immunos Building, Singapore 138648, Singapore
| | - Besma Yaacoubi-Loueslati
- University of Tunis El Manar (UTM), Faculty of Sciences of Tunis (FST), Laboratory of Mycology, Pathologies and Biomarkers (LR16ES05), Tunisia.
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Özkan A, Stolley DL, Cressman ENK, McMillin M, Yankeelov TE, Rylander MN. Vascularized Hepatocellular Carcinoma on a Chip to Control Chemoresistance through Cirrhosis, Inflammation and Metabolic Activity. SMALL STRUCTURES 2023; 4:2200403. [PMID: 38073766 PMCID: PMC10707486 DOI: 10.1002/sstr.202200403] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2024]
Abstract
Understanding the effects of inflammation and cirrhosis on the regulation of drug metabolism during the progression of hepatocellular carcinoma (HCC) is critical for developing patient-specific treatment strategies. In this work, we created novel three-dimensional vascularized HCC-on-a-chips (HCCoC), composed of HCC, endothelial, stellate, and Kupffer cells tuned to mimic normal or cirrhotic liver stiffness. HCC inflammation was controlled by tuning Kupffer macrophage numbers, and the impact of cytochrome P450-3A4 (CYP3A4) was investigated by culturing HepG2 HCC cells transfected with CYP3A4 to upregulate expression from baseline. This model allowed for the simulation of chemotherapeutic delivery methods such as intravenous injection and transcatheter arterial chemoembolization (TACE). We showed that upregulation of metabolic activity, incorporation of cirrhosis and inflammation, increase vascular permeability due to upregulated inflammatory cytokines leading to significant variability in chemotherapeutic treatment efficacy. Specifically, we show that further modulation of CYP3A4 activity of HCC cells by TACE delivery of doxorubicin provides an additional improvement to treatment response and reduces chemotherapy-associated endothelial porosity increase. The HCCoCs were shown to have utility in uncovering the impact of the tumor microenvironment (TME) during cancer progression on vascular properties, tumor response to therapeutics, and drug delivery strategies.
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Affiliation(s)
- Alican Özkan
- Department of Mechanical Engineering, The University of Texas, Austin, TX, 78712, United States
- Current address: Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, 02115, United States
| | - Danielle L Stolley
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030. United States
| | - Erik N K Cressman
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030. United States
| | - Matthew McMillin
- Department of Internal Medicine, The University of Texas at Austin, Dell Medical School
- Central Texas Veterans Health Care System, Austin, TX, 78712, United States
| | - Thomas E Yankeelov
- Department of Biomedical Engineering, The University of Texas, Austin, TX, 78712, United States
- Oden Institute for Computational Engineering and Sciences, The University of Texas, Austin, TX, 78712, United States
- Departments of Diagnostic Medicine, The University of Texas, Austin, TX, 78712, United States
- Department of Oncology, The University of Texas, Austin, TX, 78712, United States
- Livestrong Cancer Institutes, Dell Medical School, The University of Texas, Austin, TX, 78712, United States
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Marissa Nichole Rylander
- Department of Mechanical Engineering, The University of Texas, Austin, TX, 78712, United States
- Department of Biomedical Engineering, The University of Texas, Austin, TX, 78712, United States
- Oden Institute for Computational Engineering and Sciences, The University of Texas, Austin, TX, 78712, United States
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15
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Dong G, Fan F, He Y, Luo Y, Yu J, Liang P. T-Lymphocyte Gene-Regulated CCL5 and Its Association with Extrahepatic Metastasis in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2023; 10:1267-1279. [PMID: 37551333 PMCID: PMC10404438 DOI: 10.2147/jhc.s420836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 07/20/2023] [Indexed: 08/09/2023] Open
Abstract
BACKGROUND Extrahepatic metastasis in hepatocellular carcinoma (HCC) greatly limits the prognostic survival of HCC patients. Levels of preoperative peripheral lymphocyte subsets and cytokines in the serum for predicting extrahepatic spread of hepatocellular carcinoma are still not common in clinical practice. The aim of this study is to investigate the value and mechanisms of peripheral lymphocyte subsets and cytokines in predicting extrahepatic spread of HCC. METHODS We used a retrospective design to analyze data pertaining to a total of 380 patients with HCC who were examined for peripheral T-lymphocyte subsets before receiving microwave ablation. We performed Cox regression analysis to screen out independent risk factors and used pathology specimens from the patients and public databases of liver cancer to investigate the correlation between cytokines and intra-tumor immune cells. RESULTS The CD4low group had better metastasis-free 1-year, 3-year, and 5-year survival rates compared to the CD4high group (80% vs 69%, 67% vs 51%, and 57% vs 39%, respectively; HR 1.7 (1.2, 2.3), P = 0.0019). Similarly, the CD8high group had better metastasis-free 1-year, 3-year, and 5-year survival rates compared to the CD8low group (65% vs 78%, 46% vs 64%, and 34% vs 54%, respectively; HR 0.6 (0.4, 0.8), P < 0.001). Patients with the CD4high/CD8low phenotype had significantly worse metastasis-free survival times compared to other patients (HR 2.0 (1.5, 2.8), P < 0.001). Additionally, T lymphocyte-specific genes (CD4, CD8) were correlated with CCL5 expression, which was also positively correlated with the level of intra-tumoral infiltrating CD8 T cells and the prognosis of HCC patients. CONCLUSION Both CD4+ and CD8+ T lymphocyte subsets were independent risk factors for extrahepatic metastasis in HCC. Serum CCL5 levels could indicate the infiltration level of intra-tumoral CD8+ T cells and the risk of extrahepatic metastasis in HCC patients, aiding in patient risk stratification for metastasis.
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Affiliation(s)
- Guoping Dong
- Department of Interventional Ultrasound, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China
- Chinese PLA Medical School, Beijing, 100853, People’s Republic of China
| | - Fangying Fan
- Department of Interventional Ultrasound, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China
- Chinese PLA Medical School, Beijing, 100853, People’s Republic of China
| | - Yao He
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, People’s Republic of China
| | - Yanchun Luo
- Department of Interventional Ultrasound, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China
| | - Jie Yu
- Department of Interventional Ultrasound, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China
- Chinese PLA Medical School, Beijing, 100853, People’s Republic of China
| | - Ping Liang
- Department of Interventional Ultrasound, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China
- Chinese PLA Medical School, Beijing, 100853, People’s Republic of China
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Do XH, Le MT, Nguyen TH, Le TT, Nguyen XH, Mai TB, Hoang TMN, Than UTT. Detection of sFas, sCD137, and IL-27 Cytokines as Potential Biomarkers for Hepatocellular Carcinoma Diagnosis. J Hepatocell Carcinoma 2023; 10:783-793. [PMID: 37260529 PMCID: PMC10228584 DOI: 10.2147/jhc.s409649] [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: 02/22/2023] [Accepted: 05/14/2023] [Indexed: 06/02/2023] Open
Abstract
Purpose Hepatocellular carcinoma (HCC), a prevalent type of liver cancer, is mainly diagnosed in the advanced stage, leading to a high mortality rate. Recent advances have identified peripheral cytokines as a potential tool to predict disease outcomes and inform therapeutic decisions. Hence, in this study, we aim to build a predictive model for HCC based on serum levels of different cytokines. Patients and Methods We used immunoassay to quantify the concentrations of IL-27, MIP-1β, Perforin, sCD137, sFas, and TNF-α in the serum of 38 HCC patients and 15 healthy controls. Logistic regression was then used to construct classification models detecting HCC based on these cytokines. A nomogram of the best-performing model was generated to visualize HCC prediction. Results sFas and MIP-1β were found to be significantly higher in HCC patients compared to controls. Predictive models based on cytokine levels combining sFas, sCD137, and IL-27 performed the best in distinguishing HCC patients from healthy controls. This model has a bias-corrected area under the receiver operating characteristic (ROC) curve (AUC) of 0.948, a sensitivity of 92.11%, a specificity of 93.33%, and an accuracy of 0.925. Conclusion Our findings suggest that serum cytokines have the potential to be utilized in HCC screening to improve detection rates.
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Affiliation(s)
- Xuan-Hai Do
- Department of Practical and Experimental Surgery, Vietnam Military Medical University, Hanoi, Vietnam
| | - Mai Thi Le
- Center of Applied Sciences, Regenerative Medicine and Advance Technologies, Vinmec Healthcare System, Hanoi, Vietnam
- Faculty of Biology, VNU University of Science, Vietnam National University, Hanoi, Vietnam
| | - Thu Huyen Nguyen
- Center of Applied Sciences, Regenerative Medicine and Advance Technologies, Vinmec Healthcare System, Hanoi, Vietnam
| | - Thanh Thien Le
- Center of Applied Sciences, Regenerative Medicine and Advance Technologies, Vinmec Healthcare System, Hanoi, Vietnam
| | - Xuan-Hung Nguyen
- Center of Applied Sciences, Regenerative Medicine and Advance Technologies, Vinmec Healthcare System, Hanoi, Vietnam
- College of Health Sciences, VinUniversity, Hanoi, Vietnam
| | - Thanh Binh Mai
- Department of Gastroenterology, 108 Military Central Hospital, Hanoi, Vietnam
| | - Thi My Nhung Hoang
- Faculty of Biology, VNU University of Science, Vietnam National University, Hanoi, Vietnam
| | - Uyen Thi Trang Than
- Center of Applied Sciences, Regenerative Medicine and Advance Technologies, Vinmec Healthcare System, Hanoi, Vietnam
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17
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Shahini E, Pasculli G, Solimando AG, Tiribelli C, Cozzolongo R, Giannelli G. Updating the Clinical Application of Blood Biomarkers and Their Algorithms in the Diagnosis and Surveillance of Hepatocellular Carcinoma: A Critical Review. Int J Mol Sci 2023; 24:ijms24054286. [PMID: 36901717 PMCID: PMC10001986 DOI: 10.3390/ijms24054286] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/14/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
The most common primary liver cancer is hepatocellular carcinoma (HCC), and its mortality rate is increasing globally. The overall 5-year survival of patients with liver cancer is currently 10-20%. Moreover, because early diagnosis can significantly improve prognosis, which is highly correlated with tumor stage, early detection of HCC is critical. International guidelines advise using α-FP biomarker with/without ultrasonography for HCC surveillance in patients with advanced liver disease. However, traditional biomarkers are sub-optimal for risk stratification of HCC development in high-risk populations, early diagnosis, prognostication, and treatment response prediction. Since about 20% of HCCs do not produce α-FP due to its biological diversity, combining α-FP with novel biomarkers can enhance HCC detection sensitivity. There is a chance to offer promising cancer management methods in high-risk populations by utilizing HCC screening strategies derived from new tumor biomarkers and prognostic scores created by combining biomarkers with distinct clinical parameters. Despite numerous efforts to identify molecules as potential biomarkers, there is no single ideal marker in HCC. When combined with other clinical parameters, the detection of some biomarkers has higher sensitivity and specificity in comparison with a single biomarker. Therefore, newer biomarkers and models, such as the Lens culinaris agglutinin-reactive fraction of Alpha-fetoprotein (α-FP), α-FP-L3, Des-γ-carboxy-prothrombin (DCP or PIVKA-II), and the GALAD score, are being used more frequently in the diagnosis and prognosis of HCC. Notably, the GALAD algorithm was effective in HCC prevention, particularly for cirrhotic patients, regardless of the cause of their liver disease. Although the role of these biomarkers in surveillance is still being researched, they may provide a more practical alternative to traditional imaging-based surveillance. Finally, looking for new diagnostic/surveillance tools may help improve patients' survival. This review discusses the current roles of the most used biomarkers and prognostic scores that may aid in the clinical management of HCC patients.
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Affiliation(s)
- Endrit Shahini
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
- Correspondence: ; Tel.: +39-0804994249
| | - Giuseppe Pasculli
- National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
| | - Antonio Giovanni Solimando
- Guido Baccelli Unit of Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area-(DiMePRe-J), University of Bari “A. Moro”, 70121 Bari, Italy
| | | | - Raffaele Cozzolongo
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
| | - Gianluigi Giannelli
- Scientific Director, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
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18
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Monavarian M, Elhaw AT, Tang PW, Javed Z, Shonibare Z, Scalise CB, Arend R, Jolly MK, Sewell-Loftin MK, Hempel N, Mythreye K. Emerging perspectives on growth factor metabolic relationships in the ovarian cancer ascites environment. Semin Cancer Biol 2022; 86:709-719. [PMID: 35259492 PMCID: PMC9441472 DOI: 10.1016/j.semcancer.2022.03.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/02/2022] [Accepted: 03/03/2022] [Indexed: 02/07/2023]
Abstract
The ascites ecosystem in ovarian cancer is inhabited by complex cell types and is bathed in an environment rich in cytokines, chemokines, and growth factors that directly and indirectly impact metabolism of cancer cells and tumor associated cells. This milieu of malignant ascites, provides a 'rich' environment for the disease to thrive, contributing to every aspect of advanced ovarian cancer, a devastating gynecological cancer with a significant gap in targeted therapeutics. In this perspective we focus our discussions on the 'acellular' constituents of this liquid malignant tumor microenvironment, and how they influence metabolic pathways. Growth factors, chemokines and cytokines are known modulators of metabolism and have been shown to impact nutrient uptake and metabolic flexibility of tumors, yet few studies have explored how their enrichment in malignant ascites of ovarian cancer patients contributes to the metabolic requirements of ascites-resident cells. We focus here on TGF-βs, VEGF and ILs, which are frequently elevated in ovarian cancer ascites and have all been described to have direct or indirect effects on metabolism, often through gene regulation of metabolic enzymes. We summarize what is known, describe gaps in knowledge, and provide examples from other tumor types to infer potential unexplored roles and mechanisms for ovarian cancer. The distribution and variation in acellular ascites components between patients poses both a challenge and opportunity to further understand how the ascites may contribute to disease heterogeneity. The review also highlights opportunities for studies on ascites-derived factors in regulating the ascites metabolic environment that could act as a unique signature in aiding clinical decisions in the future.
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Affiliation(s)
- Mehri Monavarian
- Division of Molecular Cellular Pathology, Department of Pathology, O'Neal Comprehensive Cancer Center, University of Alabama Heersink School of Medicine, Birmingham, AL, USA
| | - Amal Taher Elhaw
- Division of Hematology Oncology, Department of Medicine, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh PA 15213, USA
| | - Priscilla W Tang
- Division of Hematology Oncology, Department of Medicine, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh PA 15213, USA
| | - Zaineb Javed
- Division of Hematology Oncology, Department of Medicine, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh PA 15213, USA
| | - Zainab Shonibare
- Division of Molecular Cellular Pathology, Department of Pathology, O'Neal Comprehensive Cancer Center, University of Alabama Heersink School of Medicine, Birmingham, AL, USA
| | - Carly Bess Scalise
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama School of Medicine, Birmingham, AL, USA
| | - Rebecca Arend
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama School of Medicine, Birmingham, AL, USA
| | - Mohit Kumar Jolly
- Center for Biosystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
| | - Mary Kathryn Sewell-Loftin
- Department of Biomedical Engineering, O'Neal Comprehensive Cancer Center, University of Alabama School of Medicine, Birmingham, AL, USA
| | - Nadine Hempel
- Division of Hematology Oncology, Department of Medicine, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh PA 15213, USA.
| | - Karthikeyan Mythreye
- Division of Molecular Cellular Pathology, Department of Pathology, O'Neal Comprehensive Cancer Center, University of Alabama Heersink School of Medicine, Birmingham, AL, USA.
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19
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Chemokines and NSCLC: Emerging role in prognosis, heterogeneity, and therapeutics. Semin Cancer Biol 2022; 86:233-246. [PMID: 35787939 DOI: 10.1016/j.semcancer.2022.06.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 06/15/2022] [Accepted: 06/24/2022] [Indexed: 12/11/2022]
Abstract
Lung cancer persists to contribute to one-quarter of cancer-associated deaths. Among the different histologies, non-small cell lung cancer (NSCLC) alone accounts for 85% of the cases. The development of therapies involving immune checkpoint inhibitors and angiogenesis inhibitors has increased patients' survival probability and reduced mortality rates. Developing targeted therapies against essential genetic alterations also translates to better treatment strategies. But the benefits still seem farfetched due to the development of drug resistance and refractory tumors. In this review, we have highlighted the interplay of different tumor microenvironment components, essentially discussing the chemokine families (CC, CXC, C, and CX3C) that regulate the tumor biology in NSCLC and promote tumor growth, metastasis, and associated heterogeneity. The development of therapeutics and prognostic markers is a complex and multipronged approach. However, some essential chemokines can act as critical players for being considered potential prognostic markers and therapeutic targets.
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20
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Jia W, Zhang T, Yao Q, Li J, Nie Y, Lei X, Mao Z, Wang Y, Shi W, Song W. Tertiary Lymphatic Structures in Primary Hepatic Carcinoma: Controversy Cannot Overshadow Hope. Front Immunol 2022; 13:870458. [PMID: 35844587 PMCID: PMC9278517 DOI: 10.3389/fimmu.2022.870458] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Tertiary lymphoid structures (TLSs) are organized aggregates of immune cells found in the tumor microenvironment. TLS can influence primary hepatic carcinoma (PHC) occurrence and have an active role in cancer. TLS can promote or inhibit the growth of PHC depending on their location, and although available findings are controversial, they suggest that TLS have a protective role in PHC tissues and a non-protective role in paracancerous tissues. In addition, the cellular composition of TLS can also influence the outcome of PHC. As an immunity marker, TLS can act as a marker of immunotherapy to predict its effect and help to identify patients who will respond well to immunotherapy. Modulation of TLS formation through the use of chemokines/cytokines, immunotherapy, or induction of high endothelial vein to interfere with tumor growth has been studied extensively in PHC and other cancers. In addition, new tools such as genetic interventions, cellular crosstalk, preoperative radiotherapy, and advances in materials science have been shown to influence the prognosis of malignant tumors by modulating TLS production. These can also be used to develop PHC treatment.
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Affiliation(s)
- Weili Jia
- Xi’an Medical University, Xi’an, China
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Tianchen Zhang
- Xi’an Medical University, Xi’an, China
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Qianyun Yao
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Jianhui Li
- Xi’an Medical University, Xi’an, China
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Ye Nie
- Xi’an Medical University, Xi’an, China
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Xinjun Lei
- Xi’an Medical University, Xi’an, China
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Zhenzhen Mao
- Xi’an Medical University, Xi’an, China
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Yanfang Wang
- Xi’an Medical University, Xi’an, China
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Wen Shi
- Xi’an Medical University, Xi’an, China
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Wenjie Song
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
- *Correspondence: Wenjie Song,
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21
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Tapmeier TT, Howell JH, Zhao L, Papiez BW, Schnabel JA, Muschel RJ, Gal A. Evolving polarisation of infiltrating and alveolar macrophages in the lung during metastatic progression of melanoma suggests CCR1 as a therapeutic target. Oncogene 2022; 41:5032-5045. [PMID: 36241867 PMCID: PMC9652148 DOI: 10.1038/s41388-022-02488-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 09/16/2022] [Accepted: 09/26/2022] [Indexed: 12/30/2022]
Abstract
Metastatic tumour progression is facilitated by tumour associated macrophages (TAMs) that enforce pro-tumour mechanisms and suppress immunity. In pulmonary metastases, it is unclear whether TAMs comprise tissue resident or infiltrating, recruited macrophages; and the different expression patterns of these TAMs are not well established. Using the mouse melanoma B16F10 model of experimental pulmonary metastasis, we show that infiltrating macrophages (IM) change their gene expression from an early pro-inflammatory to a later tumour promoting profile as the lesions grow. In contrast, resident alveolar macrophages (AM) maintain expression of crucial pro-inflammatory/anti-tumour genes with time. During metastatic growth, the pool of macrophages, which initially contains mainly alveolar macrophages, increasingly consists of infiltrating macrophages potentially facilitating metastasis progression. Blocking chemokine receptor mediated macrophage infiltration in the lung revealed a prominent role for CCR2 in Ly6C+ pro-inflammatory monocyte/macrophage recruitment during metastasis progression, while inhibition of CCR2 signalling led to increased metastatic colony burden. CCR1 blockade, in contrast, suppressed late phase pro-tumour MR+Ly6C- monocyte/macrophage infiltration accompanied by expansion of the alveolar macrophage compartment and accumulation of NK cells, leading to reduced metastatic burden. These data indicate that IM has greater plasticity and higher phenotypic responsiveness to tumour challenge than AM. A considerable difference is also confirmed between CCR1 and CCR2 with regard to the recruited IM subsets, with CCR1 presenting a potential therapeutic target in pulmonary metastasis from melanoma.
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Affiliation(s)
- Thomas T. Tapmeier
- grid.4991.50000 0004 1936 8948CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ UK ,grid.1002.30000 0004 1936 7857Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168 Australia ,grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168 Australia
| | - Jake H. Howell
- grid.12477.370000000121073784School of Applied Sciences, University of Brighton, Brighton, BN2 4GJ UK
| | - Lei Zhao
- grid.440144.10000 0004 1803 8437Shandong Cancer Hospital and Institute, Shandong Cancer Hospital Affiliated to Shandong First Medical University, Jinan, 250117 China
| | - Bartlomiej W. Papiez
- Li Ka Shing Centre for Health Information and Discovery, Big Data Institute, Oxford, OX3 7LF UK
| | - Julia A. Schnabel
- grid.13097.3c0000 0001 2322 6764School of Biomedical Imaging and Imaging Sciences, King’s College London, London, SE1 7EU UK ,grid.4567.00000 0004 0483 2525Helmholtz Center Munich – German Center for Environmental Health, 85764 Neuherberg, Germany ,grid.6936.a0000000123222966Faculty of Informatics and Institute for Advanced Study, Technical University of Munich, 85748 Garching, Germany
| | - Ruth J. Muschel
- grid.4991.50000 0004 1936 8948CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ UK
| | - Annamaria Gal
- grid.4991.50000 0004 1936 8948CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ UK ,grid.12477.370000000121073784School of Applied Sciences, University of Brighton, Brighton, BN2 4GJ UK
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22
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Cao P, Ma B, Sun D, Zhang W, Qiu J, Qin L, Xue X. hsa_circ_0003410 promotes hepatocellular carcinoma progression by increasing the ratio of M2/M1 macrophages through the miR-139-3p/CCL5 axis. Cancer Sci 2021; 113:634-647. [PMID: 34890089 PMCID: PMC8819332 DOI: 10.1111/cas.15238] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 11/22/2021] [Accepted: 11/29/2021] [Indexed: 12/15/2022] Open
Abstract
Noncoding RNAs have been verified to regulate the infiltration of macrophages to accelerate tumor biological progression, however the regulation of macrophages by circular RNAs in hepatocellular carcinoma (HCC) remains unresolved. Using high‐throughput RNA sequencing, we demonstrated that hsa_circ_0003410 was clearly upregulated in HCC. 5‐Ethynyl‐2′‐deoxyuridine and transwell assays showed that hsa_circ_0003410 facilitated the proliferation and migration of HCC cells in vitro. We knocked down the expression of hsa_circ_0003410 in HepG2 cells and performed next‐generation sequencing to determine possible target genes of hsa_circ_0003410. Kyoto Encyclopedia of Genes and Genomes analysis revealed that different genes were mainly enriched in immune‐related pathways. Mechanistically, we identified CCL5 as the target gene of hsa_circ_0003410. RNA‐FISH showed the co‐expression of hsa_circ_0003410 and CCL5. Western blot and ELISA also verified that hsa_circ_0003410 could upregulate the expression of CCL5 protein. Flow cytometry and immunofluorescence assays indicated that CCL5 activated and recruited M2 macrophages and increased the ratio of M2/M1 macrophages to promote the progression of HCC. Animal experiments in vitro also confirmed our results. Taken together, our experiments revealed that noncoding RNAs play a critical role in the HCC microenvironment and can be considered as markers for the diagnosis and prognosis of HCC.
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Affiliation(s)
- Pei Cao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Bo Ma
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ding Sun
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Weigang Zhang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Junyi Qiu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lei Qin
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaofeng Xue
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
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23
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Song MA, Seffernick AE, Archer KJ, Mori KM, Park SY, Chang L, Ernst T, Tiirikainen M, Peplowska K, Wilkens LR, Le Marchand L, Lim U. Race/ethnicity-associated blood DNA methylation differences between Japanese and European American women: an exploratory study. Clin Epigenetics 2021; 13:188. [PMID: 34635168 PMCID: PMC8507376 DOI: 10.1186/s13148-021-01171-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Racial/ethnic disparities in health reflect a combination of genetic and environmental causes, and DNA methylation may be an important mediator. We compared in an exploratory manner the blood DNA methylome of Japanese Americans (JPA) versus European Americans (EUA). METHODS Genome-wide buffy coat DNA methylation was profiled among healthy Multiethnic Cohort participant women who were Japanese (JPA; n = 30) or European (EUA; n = 28) Americans aged 60-65. Differentially methylated CpGs by race/ethnicity (DM-CpGs) were identified by linear regression (Bonferroni-corrected P < 0.1) and analyzed in relation to corresponding gene expression, a priori selected single nucleotide polymorphisms (SNPs), and blood biomarkers of inflammation and metabolism using Pearson or Spearman correlations (FDR < 0.1). RESULTS We identified 174 DM-CpGs with the majority of hypermethylated in JPA compared to EUA (n = 133), often in promoter regions (n = 48). Half (51%) of the genes corresponding to the DM-CpGs were involved in liver function and liver disease, and the methylation in nine genes was significantly correlated with gene expression for DM-CpGs. A total of 156 DM-CpGs were associated with rs7489665 (SH2B1). Methylation of DM-CpGs was correlated with blood levels of the cytokine MIP1B (n = 146). We confirmed some of the DM-CpGs in the TCGA adjacent non-tumor liver tissue of Asians versus EUA. CONCLUSION We found a number of differentially methylated CpGs in blood DNA between JPA and EUA women with a potential link to liver disease, specific SNPs, and systemic inflammation. These findings may support further research on the role of DNA methylation in mediating some of the higher risk of liver disease among JPA.
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Affiliation(s)
- Min-Ae Song
- Division of Environmental Health Science, College of Public Health, The Ohio State University, 404 Cunz Hall, 1841 Neil Ave., Columbus, OH, 43210, USA.
| | - Anna Eames Seffernick
- Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, OH, USA
| | - Kellie J Archer
- Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, OH, USA
| | - Kellie M Mori
- Division of Environmental Health Science, College of Public Health, The Ohio State University, 404 Cunz Hall, 1841 Neil Ave., Columbus, OH, 43210, USA
| | - Song-Yi Park
- Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA
| | - Linda Chang
- School of Medicine, University of Maryland, Baltimore, MD, USA
| | - Thomas Ernst
- School of Medicine, University of Maryland, Baltimore, MD, USA
| | - Maarit Tiirikainen
- Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA
| | - Karolina Peplowska
- Genomics and Bioinformatics Shared Resources, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA
| | - Lynne R Wilkens
- Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA
| | - Loïc Le Marchand
- Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA
| | - Unhee Lim
- Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA
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24
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Rico Montanari N, Anugwom CM, Boonstra A, Debes JD. The Role of Cytokines in the Different Stages of Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13194876. [PMID: 34638361 PMCID: PMC8508513 DOI: 10.3390/cancers13194876] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/23/2021] [Accepted: 09/27/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Non-homeostatic cytokine expression during hepatocellular carcinogenesis, together with simple and inexpensive cytokine detection techniques, has opened up its use as potential biomarkers, from cancer detection to prognosis. However, carcinogenic programs during cancer progression are not linear. Therefore, cytokines with prognostic potential in one stage may not be relevant in another. Here, we reviewed cytokines with clinical potential in different settings during hepatocellular carcinoma progression. Abstract Hepatocellular carcinoma (HCC) is the primary form of liver cancer and a leading cause of cancer-related death worldwide. Early detection remains the most effective strategy in HCC management. However, the spectrum of underlying liver diseases preceding HCC, its genetic complexity, and the lack of symptomatology in early stages challenge early detection. Regardless of underlying etiology, unresolved chronic inflammation is a common denominator in HCC. Hence, many inflammatory molecules, including cytokines, have been investigated as potential biomarkers to predict different stages of HCC. Soluble cytokines carry cell-signaling functions and are easy to detect in the bloodstream. However, its biomarkers’ role remains limited due to the dysregulation of immune parameters related to the primary liver process and their ability to differentiate carcinogenesis from the underlying disease. In this review, we discuss and provide insight on cytokines with clinical relevance for HCC differentiating those implicated in tumor formation, early detection, advanced disease, and response to therapy.
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Affiliation(s)
- Noe Rico Montanari
- Department of Medicine, Division of Gastroenterology & Division of Infectious Disease, University of Minnesota, Minneapolis, MN 55455, USA; (N.R.M.); (C.M.A.)
- Department of Gastroenterology and Hepatology, Erasmus MC, 3015 CE Rotterdam, The Netherlands;
| | - Chimaobi M. Anugwom
- Department of Medicine, Division of Gastroenterology & Division of Infectious Disease, University of Minnesota, Minneapolis, MN 55455, USA; (N.R.M.); (C.M.A.)
- Health Partners Digestive Care, Saint Paul, MN 55130, USA
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC, 3015 CE Rotterdam, The Netherlands;
| | - Jose D. Debes
- Department of Medicine, Division of Gastroenterology & Division of Infectious Disease, University of Minnesota, Minneapolis, MN 55455, USA; (N.R.M.); (C.M.A.)
- Department of Gastroenterology and Hepatology, Erasmus MC, 3015 CE Rotterdam, The Netherlands;
- Correspondence:
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25
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Zhou D, Luan J, Huang C, Li J. Tumor-Associated Macrophages in Hepatocellular Carcinoma: Friend or Foe? Gut Liver 2021; 15:500-516. [PMID: 33087588 PMCID: PMC8283292 DOI: 10.5009/gnl20223] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/21/2020] [Accepted: 08/22/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and it has diverse etiologies with multiple mechanisms. The diagnosis of HCC typically occurs at advanced stages when there are limited therapeutic options. Hepatocarcinogenesis is considered a multistep process, and hepatic macrophages play a critical role in the inflammatory process leading to HCC. Emerging evidence has shown that tumor-associated macrophages (TAMs) are crucial components defining the HCC immune microenvironment and represent an appealing option for disrupting the formation and development of HCC. In this review, we summarize the current knowledge of the polarization and function of TAMs in the pathogenesis of HCC, as well as the mechanisms underlying TAM-related anti-HCC therapies. Eventually, novel insights into these important aspects of TAMs and their roles in the HCC microenvironment might lead to promising TAM-focused therapeutic strategies for HCC.
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Affiliation(s)
- Dexi Zhou
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, China.,Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, China.,School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Jiajie Luan
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, China.,Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, China.,School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Cheng Huang
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei, China
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Li X, Han QC, Yu C, Luo YC, Wang F, Sun XH, Gao YQ, Tan WF, Xia Q. C-C chemokine hepatocellular carcinoma motif ligand 5-deficiency promotes hepatocellular carcinoma progression by affecting B cell recruitment. J Dig Dis 2021; 22:433-441. [PMID: 33978316 DOI: 10.1111/1751-2980.12997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 04/12/2021] [Accepted: 05/10/2021] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To evaluate the expression of C-C motif chemokine ligand 5 (CCL5) in hepatocellular carcinoma (HCC) and to explore its role in regulating the immune microenvironment and the related mechanism in tumor immunity. METHODS The mRNA expression level of CCL5 in HCC and adjacent non-cancerous tissues was measured by quantitative polymerase chain reaction and the protein expression was examined by immunohistochemistry. Serum CCL5 expression was measured by an enzyme-linked immunosorbent assay (ELISA). C57BL/6 wild-type (WT) and Ccl5-knockout (Ccl5-/- ) mice were utilized to conduct the diethylnitrosamine-induced HCC model. The immune cell population was determined by flow cytometry, and peripheral serum immunoglobulin M (IgM) level was quantified by ELISA. RESULTS CCL5 expression was low in HCC tissue and peripheral blood compared with adjacent non-cancerous tissues or controls, and its expression was correlated with the overall survival, cancer recurrence and distant metastasis. In the HCC mouse model, liver-to-body weight ratio was of the Ccl5-/- group were higher than that of the WT group. Moreover, compared with the WT mice, the number of B cells in the tumor tissue of the Ccl5-/- mice was lower, while there were no significant differences in the other immune cell populations. Furthermore, serum IgM level of the Ccl5-/- mice was significantly lower than that of the WT mice. CONCLUSION CCL5 expression is decreased in HCC tissues. CCL5 deficiency reduces B cell recruitment and decreases IgM secretion in HCC, potentially leading to tumor progression.
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Affiliation(s)
- Xiang Li
- Department of Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Qiu Cheng Han
- Department of Ultrasound, Shuguang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Chang Yu
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Yi Chun Luo
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Fang Wang
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Xue Hua Sun
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Yue Qiu Gao
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Wei Feng Tan
- Department of Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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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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Pan X, Kaminga AC, Wen SW, Liu A. Chemokines in hepatocellular carcinoma: a meta-analysis. Carcinogenesis 2021; 41:1682-1694. [PMID: 33300549 DOI: 10.1093/carcin/bgaa106] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 09/17/2020] [Accepted: 10/08/2020] [Indexed: 12/17/2022] Open
Abstract
Accumulating evidence suggests that chemokines may play an important role in the formation and mediating of the immune microenvironment of hepatocellular carcinoma (HCC). The purpose of this meta-analysis was to explore the differences in blood or tissues chemokines concentrations between HCC patients and controls. Online databases, namely PubMed, Web of Science, Embase and Cochrane Library, were systematically searched for relevant articles published on or before 15 January 2020. Standardized mean differences (SMDs) with corresponding 95% confidence intervals of the chemokines concentrations were calculated as group differences between the HCC patients and the controls. Sixty-five studies met the inclusion criteria for the meta-analysis. Altogether they consisted of 26 different chemokines compared between 5828 HCC patients and 4909 controls; and 12 different chemokines receptors compared between 2053 patients and 2285 controls. The results of meta-analysis indicated that concentrations of CCL20, CXCL8 and CXCR4 in the HCC patients were significantly higher than those in the controls (SMD of 6.18, 1.81 and 1.04, respectively). Therefore, higher concentration levels of CCL20, CXCL8 and CXCR4 may indicate the occurrence of HCC Future research should explore the putative mechanisms underlying this linkage. Meanwhile, attempts can be made to replicate the existing findings in prospective cohort populations and explore the cause-and-effect relationships pertaining to this linkage in order to develop new diagnostic and therapeutic strategies for HCC.
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Affiliation(s)
- Xiongfeng Pan
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Atipatsa C Kaminga
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China.,Department of Mathematics and Statistics, Mzuzu University, Mzuzu, Malawi
| | - Shi Wu Wen
- OMNI Research Group, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Obstetrics and Gynaecology, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada.,School of Epidemiology and Public Health, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada
| | - Aizhong Liu
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
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Colli A, Nadarevic T, Miletic D, Giljaca V, Fraquelli M, Štimac D, Casazza G. Abdominal ultrasound and alpha-foetoprotein for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease. Cochrane Database Syst Rev 2021; 4:CD013346. [PMID: 33855699 PMCID: PMC8078581 DOI: 10.1002/14651858.cd013346.pub2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) occurs mostly in people with chronic liver disease and ranks sixth in terms of global instances of cancer, and fourth in terms of cancer deaths for men. Despite that abdominal ultrasound (US) is used as an initial test to exclude the presence of focal liver lesions and serum alpha-foetoprotein (AFP) measurement may raise suspicion of HCC occurrence, further testing to confirm diagnosis as well as staging of HCC is required. Current guidelines recommend surveillance programme using US, with or without AFP, to detect HCC in high-risk populations despite the lack of clear benefits on overall survival. Assessing the diagnostic accuracy of US and AFP may clarify whether the absence of benefit in surveillance programmes could be related to under-diagnosis. Therefore, assessment of the accuracy of these two tests for diagnosing HCC in people with chronic liver disease, not included in surveillance programmes, is needed. OBJECTIVES Primary: the diagnostic accuracy of US and AFP, alone or in combination, for the diagnosis of HCC of any size and at any stage in adults with chronic liver disease, either in a surveillance programme or in a clinical setting. Secondary: to assess the diagnostic accuracy of abdominal US and AFP, alone or in combination, for the diagnosis of resectable HCC; to compare the diagnostic accuracy of the individual tests versus the combination of both tests; to investigate sources of heterogeneity in the results. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic-Test-Accuracy Studies Register, Cochrane Library, MEDLINE, Embase, LILACS, Science Citation Index Expanded, until 5 June 2020. We applied no language or document-type restrictions. SELECTION CRITERIA Studies assessing the diagnostic accuracy of US and AFP, independently or in combination, for the diagnosis of HCC in adults with chronic liver disease, with cross-sectional and case-control designs, using one of the acceptable reference standards, such as pathology of the explanted liver, histology of resected or biopsied focal liver lesion, or typical characteristics on computed tomography, or magnetic resonance imaging, all with a six-months follow-up. DATA COLLECTION AND ANALYSIS We independently screened studies, extracted data, and assessed the risk of bias and applicability concerns, using the QUADAS-2 checklist. We presented the results of sensitivity and specificity, using paired forest-plots, and tabulated the results. We used a hierarchical meta-analysis model where appropriate. We presented uncertainty of the accuracy estimates using 95% confidence intervals (CIs). We double-checked all data extractions and analyses. MAIN RESULTS We included 373 studies. The index-test was AFP (326 studies, 144,570 participants); US (39 studies, 18,792 participants); and a combination of AFP and US (eight studies, 5454 participants). We judged at high-risk of bias all but one study. Most studies used different reference standards, often inappropriate to exclude the presence of the target condition, and the time-interval between the index test and the reference standard was rarely defined. Most studies with AFP had a case-control design. We also had major concerns for the applicability due to the characteristics of the participants. As the primary studies with AFP used different cut-offs, we performed a meta-analysis using the hierarchical-summary-receiver-operating-characteristic model, then we carried out two meta-analyses including only studies reporting the most used cut-offs: around 20 ng/mL or 200 ng/mL. AFP cut-off 20 ng/mL: for HCC (147 studies) sensitivity 60% (95% CI 58% to 62%), specificity 84% (95% CI 82% to 86%); for resectable HCC (six studies) sensitivity 65% (95% CI 62% to 68%), specificity 80% (95% CI 59% to 91%). AFP cut-off 200 ng/mL: for HCC (56 studies) sensitivity 36% (95% CI 31% to 41%), specificity 99% (95% CI 98% to 99%); for resectable HCC (two studies) one with sensitivity 4% (95% CI 0% to 19%), specificity 100% (95% CI 96% to 100%), and one with sensitivity 8% (95% CI 3% to 18%), specificity 100% (95% CI 97% to 100%). US: for HCC (39 studies) sensitivity 72% (95% CI 63% to 79%), specificity 94% (95% CI 91% to 96%); for resectable HCC (seven studies) sensitivity 53% (95% CI 38% to 67%), specificity 96% (95% CI 94% to 97%). Combination of AFP (cut-off of 20 ng/mL) and US: for HCC (six studies) sensitivity 96% (95% CI 88% to 98%), specificity 85% (95% CI 73% to 93%); for resectable HCC (two studies) one with sensitivity 89% (95% CI 73% to 97%), specificity of 83% (95% CI 76% to 88%), and one with sensitivity 79% (95% CI 54% to 94%), specificity 87% (95% CI 79% to 94%). The observed heterogeneity in the results remains mostly unexplained, and only in part referable to different cut-offs or settings (surveillance programme compared to clinical series). The sensitivity analyses, excluding studies published as abstracts, or with case-control design, showed no variation in the results. We compared the accuracy obtained from studies with AFP (cut-off around 20 ng/mL) and US: a direct comparison in 11 studies (6674 participants) showed a higher sensitivity of US (81%, 95% CI 66% to 90%) versus AFP (64%, 95% CI 56% to 71%) with similar specificity: US 92% (95% CI 83% to 97%) versus AFP 89% (95% CI 79% to 94%). A direct comparison of six studies (5044 participants) showed a higher sensitivity (96%, 95% CI 88% to 98%) of the combination of AFP and US versus US (76%, 95% CI 56% to 89%) with similar specificity: AFP and US 85% (95% CI 73% to 92%) versus US 93% (95% CI 80% to 98%). AUTHORS' CONCLUSIONS In the clinical pathway for the diagnosis of HCC in adults, AFP and US, singularly or in combination, have the role of triage-tests. We found that using AFP, with 20 ng/mL as a cut-off, about 40% of HCC occurrences would be missed, and with US alone, more than a quarter. The combination of the two tests showed the highest sensitivity and less than 5% of HCC occurrences would be missed with about 15% of false-positive results. The uncertainty resulting from the poor study quality and the heterogeneity of included studies limit our ability to confidently draw conclusions based on our results.
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Affiliation(s)
- Agostino Colli
- Department of Transfusion Medicine and Haematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Tin Nadarevic
- Department of Radiology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Damir Miletic
- Department of Radiology , Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Vanja Giljaca
- Department of Gastroenterology, Heart of England NHS Foundation Trust, Birmingham, UK
| | - Mirella Fraquelli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca´ Granda - Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Davor Štimac
- Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Giovanni Casazza
- Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università degli Studi di Milano, Milan, Italy
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Debes JD, Romagnoli PA, Prieto J, Arrese M, Mattos AZ, Boonstra A. Serum Biomarkers for the Prediction of Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13071681. [PMID: 33918270 PMCID: PMC8038187 DOI: 10.3390/cancers13071681] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 03/22/2021] [Accepted: 03/28/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of global cancer death. Major etiologies of HCC relate to chronic viral infections as well as metabolic conditions. The survival rate of people with HCC is very low and has been attributed to late diagnosis with limited treatment options. Combining ultrasound and the biomarker alpha-fetoprotein (AFP) is currently one of the most widely used screening combinations for HCC. However, the clinical utility of AFP is controversial, and the frequency and operator-dependence of ultrasound lead to a variable degree of sensitivity and specificity across the globe. In this review, we summarize recent developments in the search for non-invasive serum biomarkers for early detection of HCC to improve prognosis and outcome for patients. We focus on tumor-associated protein markers, immune mediators (cytokines and chemokines), and micro-RNAs in serum or circulating extracellular vesicles and examine their potential for clinical application.
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Affiliation(s)
- José D. Debes
- Department of Gastroenterology and Hepatology, Erasmus MC Rotterdam, 3015 CE Rotterdam, The Netherlands
- Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
- Correspondence: (J.D.D.); (A.B.)
| | - Pablo A. Romagnoli
- Centro de Investigaciones en Medicina Translacional “Severo Amuchastegui” (CIMETSA), Instituto Universitario de Ciencias Biomédicas de Córdoba (IUCBC), Córdoba 5016, Argentina;
| | - Jhon Prieto
- Centro de Enfermedades Hepaticas y Digestivas, Bogota CS412, Colombia;
| | - Marco Arrese
- Department of Gastroenterology, Escuela de Medicina, & Centro de Envejecimiento y Regeneración (CARE), Pontificia Universidad Católica de Chile, Santiago 8330077, Chile;
| | - Angelo Z. Mattos
- Graduate Program in Medicine: Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porte Alegre 90050-170, Brazil;
| | - André Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC Rotterdam, 3015 CE Rotterdam, The Netherlands
- Correspondence: (J.D.D.); (A.B.)
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Bozic T, Sersa G, Kranjc Brezar S, Cemazar M, Markelc B. Gene electrotransfer of proinflammatory chemokines CCL5 and CCL17 as a novel approach of modifying cytokine expression profile in the tumor microenvironment. Bioelectrochemistry 2021; 140:107795. [PMID: 33789177 DOI: 10.1016/j.bioelechem.2021.107795] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/22/2021] [Accepted: 02/23/2021] [Indexed: 11/19/2022]
Abstract
The effectiveness of immunotherapy highly correlates with the degree and the type of infiltrated immune cells in the tumor tissue. Treatments based on modifying the immune cell infiltrate of the tumor microenvironment are thus gaining momentum. Therefore, the aim of our study was to investigate the effects of gene therapy with two proinflammatory chemokines CCL5 and CCL17 on inflammatory cytokine expression profile and immune cell infiltrate in two murine breast tumor models, 4T1 and E0771, and two murine colon tumor models, CT26 and MC38. In vitro, lipofection of plasmid DNA encoding CCL5 or CCL17 resulted in changes in the cytokine expression profile similar to control plasmid DNA, implying that the main driver of these changes was the entry of foreign DNA into the cell's cytosol. In vivo, gene electrotransfer resulted in high expression levels of both Ccl5 and Ccl17 transgenes in the 4T1 and CT26 tumor models. Besides a minor increase in the survival of the treated mice, the therapy also resulted in increased expression of Cxcl9 and Ifnγ, potent activators of the immune system, in CT26 tumors. However, this was not recapitulated in changes of TME, implying that a further refinement of the dosing schedule is needed.
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Affiliation(s)
- T Bozic
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia
| | - G Sersa
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia; Faculty of Health Sciences, University of Ljubljana, Zdravstvena pot 5, SI-1000 Ljubljana, Slovenia
| | - S Kranjc Brezar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia
| | - M Cemazar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia; Faculty of Health Sciences, University of Primorska, Polje 42, SI-6310 Izola, Slovenia.
| | - B Markelc
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia; Faculty of Health Sciences, University of Ljubljana, Zdravstvena pot 5, SI-1000 Ljubljana, Slovenia.
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32
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Wang CC, Tseng KC, Tzeng IS, Kao JH. The impact of cytokine change after hepatitis C virus clearance by direct antiviral agents on the risk of hepatocellular carcinoma. J Formos Med Assoc 2020; 120:965-973. [PMID: 33129621 DOI: 10.1016/j.jfma.2020.10.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/30/2020] [Accepted: 10/16/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/PURPOSE De novo and early recurrent hepatocellular carcinoma (HCC) have been observed in clinical practice after direct antiviral agents (DAA) treatment. The study aims to investigate the change of cytokines and growth factors after hepatitis C virus (HCV) clearance by DAAs and their impact on the risk of HCC development. METHODS The chronic hepatitis C (CHC) patients with or without HCC who received DAA treatment were prospectively enrolled. The cytokines and growth factors were measured using Bio-Plex Pro™ Human Cytokine 27-plex Assay before and 12 weeks off DAA treatment. RESULTS A total of 37 patients were enrolled for final analysis. There were 11 males (29.7%) and 26 females (70.3%). The mean age was 67.39 ± 10.48 years. 11 (29.7%) patients were HCV-related HCC patients. The HCV genotype included genotype 2 in 26 patients and genotype 1b in 10 patients, and genotype 6 in 1. Among them, 35 (94.6%) patients achieved sustained virologic response (SVR). Two patients with HCC failed to DAA treatment. In HCV-related HCC patients, serum IP-10 level significantly declined after HCV clearance, but no difference in five growth factors including G-CSF, GM-CSF, basic FGF, PDGF-BB, and VEGF. Several cytokines including IP-10 significantly declined after HCV clearance in CHC patients. CONCLUSION This study showed only serum IP-10 level, a risk factor of HCC, was significantly declined after HCV clearance and no change in the markers of growth factors in HCV-related HCC patients, suggesting no promotion of HCC using DAA treatment for HCV-related HCC patients.
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Affiliation(s)
- Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Kuo-Chih Tseng
- Department of Gastroenterology, Da-Lin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - I-Shiang Tzeng
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
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Karin N. The Development and Homing of Myeloid-Derived Suppressor Cells: From a Two-Stage Model to a Multistep Narrative. Front Immunol 2020; 11:557586. [PMID: 33193327 PMCID: PMC7649122 DOI: 10.3389/fimmu.2020.557586] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 09/03/2020] [Indexed: 12/12/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSC) represent a heterogeneous population of immature myeloid cells. Under normal conditions, they differentiate into macrophages, dendritic cells, and granulocytes. Under pathological conditions, such as chronic inflammation, or cancer, they tend to maintain their immature state as immature myeloid cells that, within the tumor microenvironment, become suppressor cells and assist tumor escape from immune eradication. MDSC are comprised of two major subsets: monocytic MDSC (M-MDSC) and polymorphonuclear MDSC (PMN-MDSC). Monocytic myeloid cells give rise to monocytic cells, whereas PMN-MDSC share similarities with neutrophils. Based on their biological activities, a two-stage model that includes the mobilization of the periphery as myeloid cells and their activation within the tumor microenvironment converting them into suppressor cells was previously suggested by D. Gabrilovich. From the migratory viewpoint, we are suggesting a more complex setup. It starts with crosstalk between the tumor site and the hematopoietic stem and progenitor cells (HSPCs) at the bone marrow (BM) and secondary lymphatic organs, resulting in rapid myelopoiesis followed by mobilization to the blood. Although myelopoiesis is coordinated by several cytokines and transcription factors, mobilization is selectively directed by chemokine receptors and may differ between M-MDSC and PMN-MDSC. These myeloid cells may then undergo further expansion at these secondary lymphatic organs and then home to the tumor site. Finally, selective homing of T cell subsets has been associated with retention at the target organs directed by adhesion molecules or chemokine receptors. The possible relevance to myeloid cells is still speculative but is discussed.
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Affiliation(s)
- Nathan Karin
- Department of Immunology, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
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Yamashita S, Kato A, Akatsuka T, Sawada T, Asai T, Koyama N, Okita K. Clinical relevance of increased serum preneoplastic antigen in hepatitis C-related hepatocellular carcinoma. World J Gastroenterol 2020; 26:1463-1473. [PMID: 32308347 PMCID: PMC7152515 DOI: 10.3748/wjg.v26.i13.1463] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 03/06/2020] [Accepted: 03/19/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The prognosis of hepatocellular carcinoma (HCC) patients remains poor despite advances in treatment modalities and diagnosis. It is important to identify useful markers for the early detection of HCC in patients. Preneoplastic antigen (PNA), originally reported in a rat carcinogenesis model, is increased in the tissues and serum of HCC patients.
AIM To determine the diagnostic value of PNA for discriminating HCC and to characterize PNA-positive HCC.
METHODS Patients with hepatitis C virus (HCV)-related hepatic disorders were prospectively enrolled in this study, which included patients with hepatitis, with cirrhosis, and with HCC. A novel enzyme-linked immunosorbent assay was developed to measure serum PNA concentrations in patients.
RESULTS Serum PNA concentrations were measured in 89 controls and 141 patients with HCV infections (50 hepatitis, 44 cirrhosis, and 47 HCC). Compared with control and non-HCC patients, PNA was increased in HCC. On receiver operating characteristic curve analysis, the sensitivity of PNA was similar to the HCC markers des-γ-carboxy-prothrombin (DCP) and α-fetoprotein (AFP), but the specificity of PNA was lower. There was no correlation between PNA and AFP and a significant but weak correlation between PNA and DCP in HCC patients. Importantly, the correlations with biochemical markers were completely different for PNA, AFP, and DCP; glutamyl transpeptidase was highly correlated with PNA, but not with AFP or DCP, and was significantly higher in PNA-high patients than in PNA-low patients with HCV-related HCC.
CONCLUSION PNA may have the potential to diagnose a novel type of HCC in which glutamyl transpeptidase is positively expressed but AFP or DCP is weakly or negatively expressed.
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Affiliation(s)
- Satoyoshi Yamashita
- Department of Gastroenterology and Hepatology, Japan Community Health Care Organization Shimonoseki Medical Center, Shimonoseki, Yamaguchi 7500061, Japan
| | - Akira Kato
- Department of Gastroenterology and Hepatology, Japan Community Health Care Organization Shimonoseki Medical Center, Shimonoseki, Yamaguchi 7500061, Japan
| | - Toshitaka Akatsuka
- Department of Physiology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Saitama 3500495, Japan
| | - Takashi Sawada
- Research and Development Division, Sekisui Medical Company Limited, Ryugasaki, Ibaraki 3010852, Japan
| | - Tomohide Asai
- Research and Development Division, Sekisui Medical Company Limited, Ryugasaki, Ibaraki 3010852, Japan
| | - Noriyuki Koyama
- Clinical Research Department, Eidia Company Limited, Chiyoda-ku, Tokyo 1010032, Japan
- Eisai Company Limited, Shinjuku-ku, Tokyo 1620812, Japan
| | - Kiwamu Okita
- Department of Internal Medicine, Shunan Memorial Hospital, Kudamatsu, Yamaguchi 7440033, Japan
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Liu G, Yang ZF, Zhou PY, Zhou C, Guan RY, Sun BY, Fan J, Zhou J, Yi Y, Qiu SJ. ROR-α-1 inhibits the proliferation, invasion, and migration of hepatocellular carcinoma MHCC97H via downregulation of chemokine CXCL5. Cytokine 2020; 129:155004. [PMID: 32058275 DOI: 10.1016/j.cyto.2020.155004] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 01/14/2020] [Accepted: 01/22/2020] [Indexed: 12/17/2022]
Abstract
Hepatocarcinogenesis is a complicated process that is affected by a variety of microenvironmental factors, such as secretory chemokines and cell-extracellular matrix (ECM). Retinoic acid receptor-related orphan receptor (ROR)-α has been shown to attenuate tumor invasiveness by inducing suppressive cell microenvironment, and its low expression was associated with a worse prognosis in HCC patients. In the present study, we attempted to investigate the role and mechanism of the dominant transcript of ROR-α, ROR-α-1, in HCC development and progression. Among the four transcripts (ROR-α-1/-2/-3/-4), overexpression of ROR-α-1 dramatically suppressed the capacity of MHCC97H cells to proliferate, migrate and invade. We analyzed the differentially expressed genes in ROR-α-1-overexpressed and non-overexpressed MHCC97H cells, performed Gene Ontology (GO) enrichment analysis on these differentially-expressed genes, and found out that factors involved in the tumor microenvironment and ECM are related to the anti-tumor effects of ROR-α-1. Among these factors, chemokine CXCL5 was significantly downregulated by ROR-α-1 overexpression. Overexpression of ROR-α-1 remarkably inhibited the capacity of HCC cells to proliferate, migrate, invade, and downregulated the protein levels of β-catenin, c-Myc, Cyclin D1, and N-cadherin, suggesting the tumor-suppressive role of ROR-α-1 in MHCC97H cells. Moreover, overexpression of CXCL5 dramatically attenuated the suppressive effects of cell proliferation, migration and invasion induced by ROR-α-1 overexpression in MHCC97H, suggesting that ROR-α-1 exerts its anti-tumor effects via downregulating CXCL5. In conclusion, we demonstrate the tumor-suppressive role of ROR-α-1 in MHCC97H cells and that ROR-α-1 might play a tumor-suppressive role via regulation of chemokine CXCL5.
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Affiliation(s)
- Gao Liu
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Zhang-Fu Yang
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Pei-Yun Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Cheng Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Ruo-Yu Guan
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Bao-Ye Sun
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Yong Yi
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China.
| | - Shuang-Jian Qiu
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China.
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Nischalke HD, Lutz P, Bartok E, Krämer B, Langhans B, Frizler R, Berg T, Hampe J, Buch S, Datz C, Stickel F, Hartmann G, Strassburg CP, Nattermann J, Spengler U. The PNPLA3 I148M variant promotes lipid-induced hepatocyte secretion of CXC chemokines establishing a tumorigenic milieu. J Mol Med (Berl) 2019; 97:1589-1600. [PMID: 31637480 DOI: 10.1007/s00109-019-01836-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 09/05/2019] [Accepted: 09/20/2019] [Indexed: 02/07/2023]
Abstract
The I148M variant of the Patatin-like phospholipase domain-containing 3 (PNPLA3) protein is associated with an increased risk for liver inflammation and hepatocellular carcinoma (HCC), but the underlying mechanism is unknown. We hypothesized that enhanced CXC chemokine secretion mediates hepatic inflammation that accelerates development of HCC. Expandable primary human (upcyte®) hepatocytes and human PLC/PRF/5 hepatoma cells were lentivirally transduced with both PNPLA3 I148M variants and stimulated with lipids. Cytokine levels in culture supernatant and patient sera (n = 80) were analyzed by ELISA. Supernatants were assessed in transmigration experiments, tube formation, and proliferation assays. In vitro, lipid stimulation of transduced hepatocytes dose-dependently induced the production of interleukin-8 and CXCL1 in hepatocytes carrying the PNPLA3 148M variant. In line, sera from PNPLA3 148M-positive patients with alcoholic liver cirrhosis contained higher levels of interleukin-8 and CXCL1 than patients with wild-type PNPLA3. Supernatants from lipid-stimulated hepatocytes with the PNPLA3 148M variant induced enhanced migration of white blood cells, angiogenesis, and cell proliferation in comparison with supernatants from wild-type hepatocytes via CXC receptors 1 and 2. Increased production of interleukin-8 and CXCL1 by hepatocytes carrying the PNPLA3 148M variant contributes to a pro-inflammatory and tumorigenic milieu in patients with alcoholic liver disease. KEY MESSAGES: The PNPLA3 148M variant is associated with cirrhosis and hepatocellular carcinoma. Lipid stimulation of hepatocytes with this variant induces IL-8 and CXCL1. Supernatants from hepatocytes with this variant promote migration and angiogenesis. Sera from patients with this variant contained enhanced levels of IL-8 and CXCL1. The PNPLA3 148M variant contributes to a tumorigenic milieu via IL-8 and CXCL1.
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Affiliation(s)
- Hans Dieter Nischalke
- Department of Internal Medicine I, University Hospital, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
| | - Philipp Lutz
- Department of Internal Medicine I, University Hospital, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Eva Bartok
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Bonn, Germany
| | - Benjamin Krämer
- Department of Internal Medicine I, University Hospital, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Bettina Langhans
- Department of Internal Medicine I, University Hospital, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Regina Frizler
- Department of Internal Medicine I, University Hospital, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Thomas Berg
- Department of Gastroenterology, University Hospital Leipzig, Leipzig, Germany
| | - Jochen Hampe
- Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany
| | - Stephan Buch
- Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany
| | - Christian Datz
- Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Salzburg, Austria
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital of Zürich, Zürich, Switzerland
| | - Gunther Hartmann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Bonn, Germany
| | - Christian P Strassburg
- Department of Internal Medicine I, University Hospital, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University Hospital, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University Hospital, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
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Cai D, Xu Y, Ding R, Qiu K, Zhang R, Wang H, Huang L, Xie X, Yan H, Deng Y, Lin X, Shao J, Luo X, Duan C. Extensive serum biomarker analysis in patients with non-small-cell lung carcinoma. Cytokine 2019; 126:154868. [PMID: 31629110 DOI: 10.1016/j.cyto.2019.154868] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 07/21/2019] [Accepted: 09/28/2019] [Indexed: 01/16/2023]
Abstract
Lung cancer is a common malignant disease, nearly 2.09 million new patients occurred last year. Approximately 85% of the patients are classified as non-small-cell lung cancer (NSCLC). It is therefore important to identify new diagnostic and prognostic biomarkers for the early detection of this disease. The presented study identifies biomarkers in the serum of NSCLC patients. The expression of 274 cytokines was measured by a novel antibody array methodology and ELISA was applied to validate the array results. The levels of MIP-1 α, IL-8, MIP-1 β, Resistin, GDF-15, HGF, CA125, FLRG, VCAM-1, DKK-3, sTNF-R1, CTACK, Acrp30, CXCL-16 and LYVE-1 were significantly higher in serum from NSCLC patients, while the level of TIMP-2 and IGFBP-6 were lower. More importantly, the validation supported the result of the antibody array. The result of the antibody array indicates that these cytokines might be novel auxiliary biomarkers in the diagnosis and prognosis of NSCLC.
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Affiliation(s)
- Donghao Cai
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Ying Xu
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Rui Ding
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Kaifeng Qiu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Department of Pharmacy, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Ruihua Zhang
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Han Wang
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Lisi Huang
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Xiaoying Xie
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Haiyan Yan
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Yawen Deng
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Xianghua Lin
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Jing Shao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Medical Research Center, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Xiaohong Luo
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Chaohui Duan
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China.
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CCL5 deficiency promotes liver repair by improving inflammation resolution and liver regeneration through M2 macrophage polarization. Cell Mol Immunol 2019; 17:753-764. [PMID: 31481754 DOI: 10.1038/s41423-019-0279-0] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 08/11/2019] [Indexed: 02/06/2023] Open
Abstract
Despite the diverse etiologies of drug-induced liver injury (DILI), innate immunity activation is a common feature involved in DILI progression. However, the involvement of innate immunity regulation in inflammation resolution and liver regeneration in DILI remains obscure. Herein, we identified the chemokine CCL5 as a central mediator of innate immunity regulation in the pathogenesis of DILI. First, we showed that serum and hepatic CCL5 levels are elevated in both DILI patients and an APAP-induced liver injury (AILI) mouse model. Interestingly, both nonparenchymal cells and stressed hepatocytes are cell sources of CCL5 induction in response to liver injury. Functional experiments showed that CCL5 deficiency has no effect on the early phase of AILI but promotes liver repair in the late phase mainly by promoting inflammation resolution and liver regeneration, which are associated with an increased number of hepatic M2 macrophages. Mechanistically, CCL5 can directly activate M1 polarization and impede M2 polarization through the CCR1- and CCR5-mediated activation of the MAPK and NF-κB pathways. We then showed that CCL5 inhibition mediated by either a CCL5-neutralizing antibody or the antagonist Met-CCL5 can greatly alleviate liver injury and improve survival in an AILI mouse model. Our data demonstrate CCL5 induction during DILI, identify CCL5 as a novel innate immunity regulator in macrophage polarization, and suggest that CCL5 blockage is a promising therapeutic strategy for the treatment of DILI.
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Jain A, Barve A, Zhao Z, Fetse JP, Liu H, Li Y, Cheng K. Targeted Delivery of an siRNA/PNA Hybrid Nanocomplex Reverses Carbon Tetrachloride-Induced Liver Fibrosis. ADVANCED THERAPEUTICS 2019; 2. [PMID: 33072857 DOI: 10.1002/adtp.201900046] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Liver fibrosis is a wound healing process with excessive accumulation of extracellular matrix in the liver. We recently discovered a PCBP2 siRNA that reverses fibrogenesis in activated hepatic stellate cells (HSCs), which are the key players in liver fibrogenesis. However, targeted delivery of siRNAs to HSCs still remains a challenge. Herein, we developed a new strategy to fabricate a multicomponent nanocomplex using siRNA/PNA hybrid instead of chemically conjugated siRNA, thus increasing the scalability and feasibility of the siRNA nanocomplex for animal studies. We modified the nanocomplex with an insulin growth factor 2 receptor (IGF2R)-specific peptide, which specifically binds to activated HSCs. The siRNA nanocomplex shows a controllable size and high serum stability. The nanocomplex also demonstrates high cellular uptake in activated HSCs in vitro and in vivo. Anti-fibrotic activity of the siRNA nanocomplex was evaluated in rats with carbon tetrachloride-induced liver fibrosis. Treatment with the PCBP2 siRNA nanocomplex significantly inhibits the mRNA expressions of PCBP2 and type I collagen in fibrotic liver. Histology study revealed that the siRNA nanocomplex efficiently reduces the protein level of type I collagen and reverses liver fibrosis. Our data suggest that the nanocomplex efficiently delivers the siRNA to fibrotic liver and produces a potent anti-fibrotic effect.
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Affiliation(s)
- Akshay Jain
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Ashutosh Barve
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Zhen Zhao
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - John Peter Fetse
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Hao Liu
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Yuanke Li
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Kun Cheng
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
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Xu T, Deng R, Li X, Zhang Y, Gao MQ. RNA-seq analysis of different inflammatory reactions induced by lipopolysaccharide and lipoteichoic acid in bovine mammary epithelial cells. Microb Pathog 2019; 130:169-177. [DOI: 10.1016/j.micpath.2019.03.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 01/02/2019] [Accepted: 03/11/2019] [Indexed: 12/11/2022]
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Select sequencing of clonally expanded CD8 + T cells reveals limits to clonal expansion. Proc Natl Acad Sci U S A 2019; 116:8995-9001. [PMID: 30992377 PMCID: PMC6500157 DOI: 10.1073/pnas.1902649116] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
T cells are a central component of our immune system. They express a T cell receptor (TCR) on their surface, which detects pathogens and stimulates the T cell to initiate an immune response. Upon exposure to a specific pathogen, some T cells are activated and clonally expand. These pathogen-specific clonally expanded T cells, however, are generally rare and difficult to isolate. We have developed a technology (SELECT-seq) to isolate this rare population and to analyze their transcriptome and TCR composition. Therefore, our work may be the key to achieving a better understanding of pathogen-specific T cell clonality and function. To permit the recognition of antigens, T cells generate a vast diversity of T cell receptor (TCR) sequences. Upon binding of the TCR to an antigen–MHC complex, T cells clonally expand to establish an immune response. To study antigen-specific T cell clonality, we have developed a method that allows selection of rare cells, based on RNA expression, before in-depth scRNA-seq (named SELECT-seq). We applied SELECT-seq to collect both TCR sequences and then transcriptomes from single cells of peripheral blood lymphocytes activated by a Mycobacterium tuberculosis (Mtb) lysate. TCR sequence analysis allowed us to preferentially select expanded conventional CD8+ T cells as well as invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells. The iNKT and MAIT cells have a highly similar transcriptional pattern, indicating that they carry out similar immunological functions and differ considerably from conventional CD8+ T cells. While there is no relationship between expression profiles and clonal expansion in iNKT or MAIT cells, highly expanded conventional CD8+ T cells down-regulate the interleukin 2 (IL-2) receptor alpha (IL2RA, or CD25) protein and show signs of senescence. This suggests inherent limits to clonal expansion that act to diversify the T cell response repertoire.
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Nishikawa G, Kawada K, Nakagawa J, Toda K, Ogawa R, Inamoto S, Mizuno R, Itatani Y, Sakai Y. Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression via CCR5. Cell Death Dis 2019; 10:264. [PMID: 30890699 PMCID: PMC6424976 DOI: 10.1038/s41419-019-1508-2] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 02/21/2019] [Accepted: 03/05/2019] [Indexed: 12/14/2022]
Abstract
Mesenchymal stem cells (MSCs) are recruited from BM to the stroma of developing tumors, where they serve as critical components of the tumor microenvironment by secreting growth factors, cytokines, and chemokines. The role of MSCs in colorectal cancer (CRC) progression was controversial. In this study, we found that C-C chemokine receptor type 5 (CCR5) ligands (i.e., C-C motif chemokine ligand 3 (CCL3), CCL4, and CCL5) were highly produced from MSCs using a chemokine array screening with conditioned media from the cultured human MSCs. A relatively strong CCR5 expression could be detected within the cytoplasm of several CRC cell lines. Regarding the effect of MSC, we found that the xenografts in which CCR5-overexpressing HCT116 cells were inoculated into immunocompromised mice were highly promoted in vivo by a mixture with MSCs. Notably, the CCR5 inhibitor, maraviroc, significantly abolished the MSC-induced tumor growth in vivo. In human clinical specimens (n = 89), 20 cases (29%) were high for CCR5, whereas 69 cases (71%) were low. Statistical analyses indicated that CCR5 expression in primary CRC was associated with CRC patients’ prognosis. Especially, stage III/IV patients with CCR5-high CRCs exhibited a significantly poorer prognosis than those with CCR5-low CRCs. Furthermore, we investigated the effects of preoperative serum CCR5 ligands on patients’ prognosis (n = 114), and found that CRC patients with high serum levels of CCL3 and CCL4 exhibited a poorer prognosis compared to those with low levels of CCL3 and CCL4, while there was no association between CCL5 and prognosis. These results suggest that the inhibition of MSC–CRC interaction by a CCR5 inhibitor could provide the possibility of a novel therapeutic strategy for CRC, and that serum levels of CCL3 and CCL4 could be predictive biomarkers for the prognosis of CRC patients.
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Affiliation(s)
- Gen Nishikawa
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kenji Kawada
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| | - Jun Nakagawa
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kosuke Toda
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ryotaro Ogawa
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Susumu Inamoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Rei Mizuno
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshiro Itatani
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshiharu Sakai
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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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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44
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Chen W, Zhang J, Fan HN, Zhu JS. Function and therapeutic advances of chemokine and its receptor in nonalcoholic fatty liver disease. Therap Adv Gastroenterol 2018; 11:1756284818815184. [PMID: 30574191 PMCID: PMC6295708 DOI: 10.1177/1756284818815184] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 10/24/2018] [Indexed: 02/04/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of hepatic pathology, ranging from simple accumulation of fat in its most benign form, steatohepatitis, to cirrhosis in its most advanced form. The prevalence of NAFLD is 20-30% in adults, and 10-20% of patients with NAFLD progress to nonalcoholic steatohepatitis (NASH) which is predicted to be the leading cause of liver transplantation over the next 10 years. Therefore, it is essential to explore effective diagnostic and treatment strategies for NAFLD patients. Chemokines are a family of small and highly conserved proteins (molecular weight ranging from 8 to 12 kDa) involved in regulating the migration and activities of hepatocytes, Kupffer cells (KCs), hepatic stellate cells (HSCs), endothelial cells and circulating immune cells. Accumulating data show that chemokine and its receptor act vital roles in the pathogenesis of NAFLD. Herein, we summarize the involvement of the chemokine and its receptor in the pathogenesis of NAFLD and explore the novel pharmacotherapeutic avenues for patients with NAFLD.
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Affiliation(s)
- Wei Chen
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Jing Zhang
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Hui-Ning Fan
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
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Zheng W, Yang J, Dong Z, Wang L, Fang M, Wu W, Yao D, Yao M. High mobility group box 3 as an emerging biomarker in diagnosis and prognosis of hepatocellular carcinoma. Cancer Manag Res 2018; 10:5979-5989. [PMID: 30538547 PMCID: PMC6255278 DOI: 10.2147/cmar.s181742] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Purpose High mobility group box 3 (HMGB3) is associated with hepatocytes malignant transformation by our previous work. We continued to investigate the diagnostic and prognostic values of HMGB3 for hepatocellular carcinoma (HCC). Patients and methods Circulating HMGB3 levels were quantitatively detected in a cohort of 225 patients with chronic liver diseases by ELISA and compared with alpha-fetoprotein by the receiver operating characteristic curve. HMGB3 expression in tissues of 170 HCC was detected by tissue microarray and immunohistochemistry. Relationship between HMGB3 level and HCC prognosis was evaluated by the Kaplan-Meier curves and Cox regression model. Results The incidence of serum HMGB3 >2.0 ng/mL was 75.6% in HCC (96/127), 20.8% in liver cirrhosis (10/48), 16.0% in chronic hepatitis (8/50), and none in healthy controls (0/49). Significant difference (P<0.001) of circulating HMGB3 level was found between HCC and benign liver diseases. Total diagnostic sensitivity of serum HMGB3 plus alpha-fetoprotein was up to 89.0% for HCC. Higher HMGB3 expression was confirmed to be 73.5% in HCC tissues (125/170) >30.6% in their paracancerous tissues (52/170). HMGB3 expression was closely related to tumor size, TNM stage, poor survival, and high recurrence, suggesting an independent prognosis factor for HCC. Conclusion HMGB3 with aberrant expression could be a novel diagnostic and prognostic marker for HCC.
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Affiliation(s)
- Wenjie Zheng
- Medical School of Nantong University, Nantong 226001, Jiangsu, China, , .,Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China,
| | - Junling Yang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China,
| | - Zhizhen Dong
- Department of Diagnostics, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Li Wang
- Medical School of Nantong University, Nantong 226001, Jiangsu, China, ,
| | - Miao Fang
- Medical School of Nantong University, Nantong 226001, Jiangsu, China, ,
| | - Wei Wu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China,
| | - Dengfu Yao
- Medical School of Nantong University, Nantong 226001, Jiangsu, China, , .,Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China,
| | - Min Yao
- Medical School of Nantong University, Nantong 226001, Jiangsu, China, ,
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46
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Li L, Liu YD, Zhan YT, Zhu YH, Li Y, Xie D, Guan XY. High levels of CCL2 or CCL4 in the tumor microenvironment predict unfavorable survival in lung adenocarcinoma. Thorac Cancer 2018; 9:775-784. [PMID: 29722145 PMCID: PMC6026602 DOI: 10.1111/1759-7714.12643] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 03/22/2018] [Accepted: 03/22/2018] [Indexed: 12/11/2022] Open
Abstract
Background Tumor‐associated immune factors are heterogeneous and play an important role in determining outcome in cancer patients. In this study, the expression levels of immune factors in tumor tissue‐conditioned media from lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) were analyzed. Methods LUAD and LUSC tissue specimens were collected immediately after surgery for antibody array analysis and real‐time quantitative PCR. Results Higher levels of chemokines MCP1/CCL2 (21.11‐fold increase) and MIP‐1β/CCL4 (19.33‐fold increase) were identified in LUAD than in LUSC. Western blot and quantitative real‐time PCR analyses showed higher co‐expression of CCL2 and CCL4 in LUAD tissues compared to LUSC (P < 0.0001). Immunofluorescent co‐staining showed a high percentage of CCL2+/CD68+ and CCL4+/CD68+ tumor‐associated macrophages in LUAD compared to LUSC tissues, which might be responsible for the higher expression of CCL2 and CCL4 in LUAD samples. Kaplan–Meier curves showed that CCL2 overexpression in patients with LUSC was associated with beneficial overall survival (OS; P = 0.048) and progression‐free survival (PFS; P = 0.012); however, LUAD patients with higher CCL2 expression had unfavorable OS (P = 6.7e−08) and PFS (P = 0.00098). Similarly, CCL4 overexpression predicted favorable PFS (P = 0.021) in patients with LUSC, but patients with high CCL4 levels in LUAD had shorter OS (P = 0.013). Conclusion Our study revealed that CCL2 and CCL4 expression levels could serve as potential prognostic biomarkers and therapeutic targets for NSCLC patients.
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Affiliation(s)
- Lei Li
- State Key Laboratory of Oncology, South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yong-Dong Liu
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yu-Ting Zhan
- State Key Laboratory of Oncology, South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ying-Hui Zhu
- State Key Laboratory of Oncology, South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yan Li
- State Key Laboratory of Oncology, South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Dan Xie
- State Key Laboratory of Oncology, South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xin-Yuan Guan
- State Key Laboratory of Oncology, South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
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47
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Fan W, Ye G. Microarray analysis for the identification of specific proteins and functional modules involved in the process of hepatocellular carcinoma originating from cirrhotic liver. Mol Med Rep 2018; 17:5619-5626. [PMID: 29436633 PMCID: PMC5866002 DOI: 10.3892/mmr.2018.8555] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 06/30/2017] [Indexed: 02/06/2023] Open
Abstract
In order to identify the potential pathogenesis of hepatocellular carcinoma (HCC) developing from cirrhosis, a microarray‑based transcriptome profile was analyzed. The GSE63898 expression profile was downloaded from the Gene Expression Omnibus database, which included data from 228 HCC tissue samples and 168 cirrhotic tissue samples. The Robust Multi‑array Average in the Affy package of R was used for raw data processing and Student's t‑test was used to screen differentially expressed genes (DEGs). An enrichment analysis was then conducted using the Database for Annotation, Visualization and Integrated Discovery online tool, and the protein‑protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes and Cytoscape. Furthermore, the MCODE plug‑in of Cytoscape was used to conduct a sub‑module analysis. A total of 634 DEGs were identified between HCC and cirrhosis, of which 165 were upregulated and 469 were downregulated. According to the cut‑off criteria, the PPI network was constructed and Jun proto‑oncogene, AP‑1 transcription factor subunit (degree, 39), Fos proto‑oncogene, AP‑1 transcription factor subunit (degree, 34) and v‑myc avian myelocytomatosis viral oncogene homolog (degree, 32) were identified as the hub nodes of the PPI network. Based on the sub‑module analysis, four specific modules were identified. In particular, module 1 was significantly enriched in the chemokine signaling pathway, and C‑X‑C motif chemokine ligand 12, C‑C motif chemokine receptor 7 (CCR7) and C‑C motif chemokine ligand 5 (CCL5) were three important proteins in this module. Module 4 was significantly enriched in chemical carcinogenesis, and cytochrome P450 family 2 subfamily E member 1, cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and cytochrome P450 family 2 subfamily A member 6 (CYP2A6) were three important proteins in this module. In conclusion, the present study revealed that CCR7, CCL5, CYP2C9 and CYP2A6 are novel genes identified in the development of HCC; however, the actual functions of these genes require verification.
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Affiliation(s)
- Wufeng Fan
- Section of Medical Affairs, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei 441000, P.R. China
| | - Guangming Ye
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
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48
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Lien MY, Lin CW, Tsai HC, Chen YT, Tsai MH, Hua CH, Yang SF, Tang CH. Impact of CCL4 gene polymorphisms and environmental factors on oral cancer development and clinical characteristics. Oncotarget 2018; 8:31424-31434. [PMID: 28404909 PMCID: PMC5458219 DOI: 10.18632/oncotarget.15615] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 01/22/2017] [Indexed: 12/20/2022] Open
Abstract
In Taiwan, oral cancer has causally been associated with environmental carcinogens. CCL4 (C-C chemokine ligand 4), a macrophage inflammatory protein with a key role in inflammation and immune-regulation, was implicated in carcinogenesis by facilitating instability in the tumor environment. The purpose of this study was to identify gene polymorphisms of CCL4 specific to patients with oral squamous cell carcinoma (OSCC) susceptibility and clinicopathological characteristics. A total of 2,053 participants, including 1192 healthy people and 861 patients with oral cancer, were recruited for this study. Three single-nucleotide polymorphisms (SNPs) of the CCL4 gene were analyzed by a real-time PCR. We found that the T/T homozygotes of CCL4 rs1634507 G/T polymorphism and the GG haplotype of 2 CCL4 SNPs (rs1634507 and rs10491121) combined were associated with oral-cancer susceptibility. In addition, TA haplotype significantly decreased the risks for oral cancer by 0.118 fold. Among 1420 smokers, CCL4 polymorphisms carriers with the betel-nut chewing habit had a 15.476–20.247-fold greater risk of having oral cancer compared to CCL4 wild-type (WT) carriers without the betel-nut chewing habit. Finally, patients with oral cancer who had A/G heterozygotes of CCL4 rs10491121 A/G polymorphism showed a lower risk for an advanced tumor size (> T2) (p=0.046), compared to those patients with AA homozygotes. Our results suggest that the CCL4 rs1634507 SNP have potential predictive significance in oral carcinogenesis. Gene-environment interactions of CCL4 polymorphisms might influence oral-cancer susceptibility. CCL4 rs10491121 may be a factor to predict the tumor size in OSCC patients.
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Affiliation(s)
- Ming-Yu Lien
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.,Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chiao-Wen Lin
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan.,Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Hsiao-Chi Tsai
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
| | - Yng-Tay Chen
- Department of Pediatrics, Medical Research and Medical Genetics, China Medical College Hospital, Taichung, Taiwan
| | - Ming-Hsui Tsai
- Department of Otolaryngology, China Medical University Hospital, Taichung, Taiwan
| | - Chun-Hung Hua
- Department of Otorhinolaryngology, China Medical University Hospital, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chih-Hsin Tang
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.,Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
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Li YF, Yuan YY, Zhang YM, Zhao N, Zhang Q, Meng FX, Gao RP, Yu BF, Zhang YH, Guo R, Wang HL, Xie J, Xu J, Qin Q, Dong XS. HSVtk/GCV system on hepatoma carcinoma cells: Construction of the plasmid pcDNA3.1‑pAFP-TK and targeted killing effect. Mol Med Rep 2017; 16:764-772. [PMID: 28560395 PMCID: PMC5482189 DOI: 10.3892/mmr.2017.6657] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 03/17/2017] [Indexed: 12/17/2022] Open
Abstract
Previous studies demonstrated that herpes simplex virus thymidine kinase (HSVtk) could phosphorylate non-toxic gancyclovir (GCV) efficiently to produce phosphorylated products that result in cell apoptosis, to kill tumor cells. The present study aimed to construct a plasmid vector, pcDNA3.1-pAFP-TK, carrying the suicide gene driven by the alpha-fetoprotein (AFP) promoter, to investigate the cytotoxicity of HSVtk/GCV suicide gene system on hepatoma carcinoma cells. Reverse transcription-polymerase chain reaction and western blotting results demonstrated that the HSVtk gene was effectively expressed in HepG2 hepatoma carcinoma cells transfected with pcDNA3.1-pAFP-TK plasmid, whereas HSVtk gene expression was not detected in normal HL-7702 liver cells. In addition, MTT assays indicated that cell viability of HepG2 cells with the plasmid pcDNA3.1-pAFP-TK decreased in a dose-dependent manner following treatment with GCV for 48 h. Flow cytometry also revealed that the cell apoptosis rate and mitochondrial membrane potential reduction rate in the HepG2 cells treated with HSVtk/GCV suicide gene system were significantly higher than in the control group. Apoptosis rates in the control group and the pcDNA3.1-pAFP-TK group were (1.00±0.62%) and (38.70±6.03%), respectively. Mitochondrial membrane potential reduction rates in the control group and the pcDNA3.1-pAFP-TK group were (0.57±0.11%) and (22.84±5.79%), respectively. Caspase-3 staining demonstrated that activated caspase-3 increased significantly in the HepG2 cells treated with HSVtk/GCV suicide gene system, whereas in the control group activated caspase-3 increase was not observed. The results of the present study, therefore, indicated that HSVtk suicide gene was obviously expressed in the HepG2 cells and that the HSVtk/GCV system was effective at killing HepG2 hepatoma carcinoma cells.
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Affiliation(s)
- Yong-Fang Li
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Yang-Yang Yuan
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Ying-Min Zhang
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Na Zhao
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Qi Zhang
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Fan-Xiu Meng
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Ran-Peng Gao
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Bao-Feng Yu
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Yue-Hong Zhang
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Rui Guo
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Hai-Long Wang
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Jun Xie
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Jun Xu
- Department of General Surgery, Affiliated Tumor Hospital of Shanxi Medical University, Taiyuan, Shanxi 030013, P.R. China
| | - Qin Qin
- Central Laboratory, Shanxi Provincial People's Hospital, Shanxi Medical University, Taiyuan, Shanxi 030012, P.R. China
| | - Xiu-Shan Dong
- Department of General Surgery, Shanxi Dayi Hospital, Taiyuan, Shanxi 030032, P.R. China
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50
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Peng J, Wu Y, Tian X, Pang J, Kuai L, Cao F, Qin X, Zhong J, Li X, Li Y, Sun X, Chen L, Jiang Y. High-Throughput Sequencing and Co-Expression Network Analysis of lncRNAs and mRNAs in Early Brain Injury Following Experimental Subarachnoid Haemorrhage. Sci Rep 2017; 7:46577. [PMID: 28417961 PMCID: PMC5394545 DOI: 10.1038/srep46577] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 03/17/2017] [Indexed: 12/22/2022] Open
Abstract
Subarachnoid haemorrhage (SAH) is a fatal neurovascular disease following cerebral aneurysm rupture with high morbidity and mortality rates. Long non-coding RNAs (lncRNAs) are a type of mammalian genome transcript, are abundantly expressed in the brain and are involved in many nervous system diseases. However, little is currently known regarding the influence of lncRNAs in early brain injury (EBI) after SAH. This study analysed the expression profiles of lncRNAs and mRNAs in SAH brain tissues of mice using high-throughput sequencing. The results showed a remarkable difference in lncRNA and mRNA transcripts between SAH and control brains. Approximately 617 lncRNA transcripts and 441 mRNA transcripts were aberrantly expressed at 24 hours after SAH. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that the differentially expressed mRNAs were mostly involved in inflammation. Based on the lncRNA/mRNA co-expression network, knockdown of fantom3_F730004F19 reduced the mRNA and protein levels of CD14 and toll-like receptor 4 (TLR4) and attenuated inflammation in BV-2 microglia cells. These results indicate that lncRNA fantom3_F730004F19 may be associated with microglia induced inflammation via the TLR signaling pathway in EBI following SAH. LncRNA represent a potential therapeutic target for the prognosis, diagnosis, and treatment of SAH.
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Affiliation(s)
- Jianhua Peng
- Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yue Wu
- Department of Neurosurgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaocui Tian
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, College of Pharmacy, Chongqing, China
| | - Jinwei Pang
- Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Li Kuai
- Department of Ophthalmology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Fang Cao
- Department of Neurovascular Disease, the Affiliated Hospital of Zunyi Medical College, Zunyi, China
| | - Xinghu Qin
- Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Neurosurgery, People’s Hospital of Deyang City, Deyang, China
| | - Jianjun Zhong
- Department of Neurosurgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xinshen Li
- Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yong Li
- Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiaochuan Sun
- Department of Neurosurgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ligang Chen
- Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yong Jiang
- Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, China
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