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1
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Liu X, Zhang S, Qiu H, Xie ZQ, Tang WF, Chen Y, Wei X. Investigation of high-mobility group box 1 variants with lymph node status and colorectal cancer risk. World J Gastrointest Oncol 2025; 17:102584. [DOI: 10.4251/wjgo.v17.i4.102584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/31/2024] [Accepted: 01/22/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Accumulating studies indicated that maintain nuclei homeostasis was deemed to the protective factors for the occurrence of cancer. Thus, high-mobility group box 1 (HMGB1) might influence the risk and poorer prognoses of colorectal cancer (CRC).
AIM This study was designed to investigate whether HMGB1 polymorphisms influence the risk and lymph node metastasis (LNM) of CRC.
METHODS Firstly, we designed an investigation with 1003 CRC patients and 1303 cancer-free controls to observe whether HMGB1 rs1412125 T > C and rs1045411 C > T SNPs could influence the risk of cancer. Subsequently, we carried out a correlation-analysis to assess whether these SNPs could alter the risk of LNM.
RESULTS The current investigation suggested a relationship of HMGB1 rs1412125 SNP with the increased susceptibility of CRC. In a subgroup analysis, our findings suggested that this SNP could enhance an occurrence of CRC in ≥ 61 years, non-drinker and body mass index < 24 kg/m2 subgroups. However, we found that there was null association between HMGB1 rs1412125 SNP and LNM, even in different CRC region. These observations were confirmed by calculating the power value (more than 0.8). The association of HMGB1 rs1045411 C > T SNP with CRC risk and LNM was not found in any compare.
CONCLUSION This study highlights a possible association between HMGB1 rs1412125 polymorphism and the increased risk of CRC. In the future, more studies should be conducted to explore HMGB1 rs1412125 polymorphism in relation to CRC development.
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Affiliation(s)
- Xin Liu
- Department of General Surgery, Changzhou Third People’s Hospital, Changzhou 213001, Jiangsu Province, China
| | - Sheng Zhang
- Department of General Surgery, Changzhou Third People’s Hospital, Changzhou 213001, Jiangsu Province, China
| | - Hao Qiu
- Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Zhi-Qiang Xie
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Wei-Feng Tang
- Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210000, Jiangsu Province, China
| | - Yu Chen
- Department of Medical Oncology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuqing 350014, Fujian Province, China
| | - Xi Wei
- Department of Pathology, Affiliated People’s Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu Province, China
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2
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Sasaki R, Luo Y, Kishi S, Ogata R, Nishiguchi Y, Sasaki T, Ohmori H, Fujiwara-Tani R, Kuniyasu H. Oxidative High Mobility Group Box-1 Accelerates Mitochondrial Transfer from Mesenchymal Stem Cells to Colorectal Cancer Cells Providing Cancer Cell Stemness. Int J Mol Sci 2025; 26:1192. [PMID: 39940960 PMCID: PMC11818411 DOI: 10.3390/ijms26031192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 01/25/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Mitochondria are important organelles for cell metabolism and tissue survival. Their cell-to-cell transfer is important for the fate of recipient cells. Recently, bone marrow mesenchymal stem cells (BM-MSCs) have been reported to provide mitochondria to cancer cells and rescue mitochondrial dysfunction in cancer cells. However, the details of the mechanism have not yet been fully elucidated. In this study, we investigated the humoral factors inducing mitochondrial transfer (MT) and the mechanisms. BM-MSCs produced MT in colorectal cancer (CRC) cells damaged by 5-fluorouracil (5-FU), but were suppressed by the anti-high mobility group box-1 (HMGB1) antibody. BM-MSCs treated with oxidized HMGB1 had increased expression of MT-associated genes, whereas reduced HMGB1 did not. Inhibition of nuclear factor-κB, a downstream factor of HMGB1 signaling, significantly decreased MT-associated gene expression. CRC cells showed increased stemness and decreased 5-FU sensitivity in correlation with MT levels. In a mouse subcutaneous tumor model of CRC, 5-FU sensitivity decreased and stemness increased by the MT from host mouse BM-MSCs. These results suggest that oxidized HMGB1 induces MTs from MSCs to CRC cells and promotes cancer cell stemness. Targeting of oxidized HMGB1 may attenuate stemness of CRCs.
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Grants
- 19K16564 Ministry of Education, Culture, Sports, Science and Technology
- 23K10481 Ministry of Education, Culture, Sports, Science and Technology
- 22K11396 Ministry of Education, Culture, Sports, Science and Technology
- 22K11396 Ministry of Education, Culture, Sports, Science and Technology
- 21K06926 Ministry of Education, Culture, Sports, Science and Technology
- 23K19900 Ministry of Education, Culture, Sports, Science and Technology
- 20K21659 Ministry of Education, Culture, Sports, Science and Technology
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Affiliation(s)
- Rika Sasaki
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (R.S.); (Y.L.); (S.K.); (R.O.); (Y.N.); (T.S.); (H.O.); (R.F.-T.)
| | - Yi Luo
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (R.S.); (Y.L.); (S.K.); (R.O.); (Y.N.); (T.S.); (H.O.); (R.F.-T.)
| | - Shingo Kishi
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (R.S.); (Y.L.); (S.K.); (R.O.); (Y.N.); (T.S.); (H.O.); (R.F.-T.)
- Pathology Laboratory, Research Institute, Tokushukai Nozaki Hospital, 2-10-50 Tanigawa, Daito 574-0074, Osaka, Japan
| | - Ruiko Ogata
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (R.S.); (Y.L.); (S.K.); (R.O.); (Y.N.); (T.S.); (H.O.); (R.F.-T.)
| | - Yukiko Nishiguchi
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (R.S.); (Y.L.); (S.K.); (R.O.); (Y.N.); (T.S.); (H.O.); (R.F.-T.)
| | - Takamitsu Sasaki
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (R.S.); (Y.L.); (S.K.); (R.O.); (Y.N.); (T.S.); (H.O.); (R.F.-T.)
| | - Hitoshi Ohmori
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (R.S.); (Y.L.); (S.K.); (R.O.); (Y.N.); (T.S.); (H.O.); (R.F.-T.)
| | - Rina Fujiwara-Tani
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (R.S.); (Y.L.); (S.K.); (R.O.); (Y.N.); (T.S.); (H.O.); (R.F.-T.)
| | - Hiroki Kuniyasu
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (R.S.); (Y.L.); (S.K.); (R.O.); (Y.N.); (T.S.); (H.O.); (R.F.-T.)
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3
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Kathirasan DRAL, Normizan SN'IB, Salleh NABM, Poh-Yen K. Recent progress on small molecule TLR4 antagonist against triple-negative breast cancer progression and complications. Bioorg Med Chem 2024; 116:118000. [PMID: 39561584 DOI: 10.1016/j.bmc.2024.118000] [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: 08/05/2024] [Revised: 11/02/2024] [Accepted: 11/08/2024] [Indexed: 11/21/2024]
Abstract
Toll-like receptor 4 (TLR4) plays a vital role in the innate immune response, but its overactivation has been associated with several diseases, such as aggressive progression of triple-negative breast cancer (TNBC). As a result, inhibiting TLR4 has emerged as a potential therapeutic strategy for this challenging breast cancer subtype. This review summarizes recent advancements in the development of small-molecule TLR4 antagonists to suppress TNBC growth, metastasis, and chemotherapy resistance. We also examine their potential in managing cancer-related complications and propose future directions for their application in TNBC therapy.
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Affiliation(s)
- Darsshen Ramana A L Kathirasan
- Faculty Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, 30450 Ipoh, Perak, Malaysia; Pharmacy Department, Hospital Raja Permaisuri Bainun, Jalan Raja Ashman Shah, 30450 Ipoh, Perak, Malaysia
| | - Siti Nor 'Izzah Binti Normizan
- Faculty Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, 30450 Ipoh, Perak, Malaysia
| | | | - Khor Poh-Yen
- Faculty Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, 30450 Ipoh, Perak, Malaysia.
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4
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Liu M, Jiang H, Momeni MR. Epigenetic regulation of autophagy by non-coding RNAs and exosomal non-coding RNAs in colorectal cancer: A narrative review. Int J Biol Macromol 2024; 273:132732. [PMID: 38823748 DOI: 10.1016/j.ijbiomac.2024.132732] [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: 03/18/2024] [Revised: 05/16/2024] [Accepted: 05/19/2024] [Indexed: 06/03/2024]
Abstract
One of the major diseases affecting people globally is colorectal cancer (CRC), which is primarily caused by a lack of effective medical treatment and a limited understanding of its underlying mechanisms. Cellular autophagy functions to break down and eliminate superfluous proteins and substances, thereby facilitating the continual replacement of cellular elements and generating vital energy for cell processes. Non-coding RNAs and exosomal ncRNAs have a crucial impact on regulating gene expression and essential cellular functions such as autophagy, metastasis, and treatment resistance. The latest research has indicated that specific ncRNAs and exosomal ncRNA to influence the process of autophagy in CRC cells, which could have significant consequences for the advancement and treatment of this disease. It has been determined that a variety of ncRNAs have a vital function in regulating the genes essential for the formation and maturation of autophagosomes. Furthermore, it has been confirmed that ncRNAs have a considerable influence on the signaling pathways associated with autophagy, such as those involving AMPK, AKT, and mTOR. Additionally, numerous ncRNAs have the potential to affect specific genes involved in autophagy. This study delves into the control mechanisms of ncRNAs and exosomal ncRNAs and examines how they simultaneously influence autophagy in CRC.
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Affiliation(s)
- Minghua Liu
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110000, Liaoning, China
| | - Hongfang Jiang
- Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang 110000, Liaoning, China.
| | - Mohammad Reza Momeni
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.
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5
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Tsai WE, Liu YT, Kuo FH, Cheng WY, Shen CC, Chiao MT, Huang YF, Liang YJ, Yang YC, Hsieh WY, Chen JP, Liu SY, Chiu CD. Crocetin Enhances Temozolomide Efficacy in Glioblastoma Therapy Through Multiple Pathway Suppression. Curr Neurovasc Res 2024; 21:320-336. [PMID: 39092730 DOI: 10.2174/0115672026332275240731054001] [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: 05/23/2024] [Revised: 06/25/2024] [Accepted: 06/28/2024] [Indexed: 08/04/2024]
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is an aggressive type of brain tumor that is difficult to remove surgically. Research suggests that substances from saffron, namely crocetin and crocin, could be effective natural treatments, showing abilities to kill cancer cells. METHODS Our study focused on evaluating the effects of crocetin on glioma using the U87 cell line. We specifically investigated how crocetin affects the survival, growth, and spread of glioma cells, exploring its impact at concentrations ranging from 75-150 μM. The study also included experiments combining crocetin with the chemotherapy drug Temozolomide (TMZ) to assess potential synergistic effects. RESULTS Crocetin significantly reduced the viability, proliferation, and migration of glioma cells. It achieved these effects by decreasing the levels of Matrix Metallopeptidase 9 (MMP-9) and Ras homolog family member A (RhoA), proteins that are critical for cancer progression. Additionally, crocetin inhibited the formation of cellular structures necessary for tumor growth. It blocked multiple points of the Ak Strain Transforming (AKT) signaling pathway, which is vital for cancer cell survival. This treatment led to increased cell death and disrupted the cell cycle in the glioma cells. When used in combination with TMZ, crocetin not only enhanced the reduction of cancer cell growth but also promoted cell death and reduced cell replication. This combination therapy further decreased levels of high mobility group box 1 (HMGB1) and Receptor for Advanced Glycation End-products (RAGE), proteins linked to inflammation and tumor progression. It selectively inhibited certain pathways involved in the cellular stress response without affecting others. CONCLUSION Our results underscore the potential of crocetin as a treatment for glioma. It targets various mechanisms involved in tumor growth and spread, offering multiple avenues for therapy. Further studies are essential to fully understand and utilize crocetin's benefits in treating glioma.
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Affiliation(s)
- Wei-En Tsai
- Taichung Municipal Taichung First Senior High School, Taichung, Taiwan
| | - Yen-Tsen Liu
- Taichung Municipal Taichung First Senior High School, Taichung, Taiwan
| | - Fu-Hsuan Kuo
- Center for Geriatrics and Gerontology, Taichung Veterans Hospital, Taichung, 40705, Taiwan
| | - Wen-Yu Cheng
- Department of Minimally Invasive Skull Base Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Physical Therapy, Hung Kuang University, Taichung, Taiwan
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Chiung-Chyi Shen
- Department of Minimally Invasive Skull Base Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Physical Therapy, Hung Kuang University, Taichung, Taiwan
- Basic Medical Education, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Ming-Tsang Chiao
- Department of Minimally Invasive Skull Base Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yu-Fen Huang
- Department of Minimally Invasive Skull Base Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yea-Jiuen Liang
- Department of Minimally Invasive Skull Base Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yi-Chin Yang
- Department of Minimally Invasive Skull Base Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Wan-Yu Hsieh
- Department of Minimally Invasive Skull Base Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Jun-Peng Chen
- Biostatistics Task Force, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Szu-Yuan Liu
- Department of Neurosurgery, Oncology Neurosurgery Division, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Life Science, College of Life Science, Graduate Institute of Life Science, National Chung Hsing University, Taichung, Taiwan
| | - Cheng-Di Chiu
- Spine Center, China Medical University Hospital, Taichung, Taiwan
- Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan
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6
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Ghiringhelli F, Rébé C. Using immunogenic cell death to improve anticancer efficacy of immune checkpoint inhibitors: From basic science to clinical application. Immunol Rev 2024; 321:335-349. [PMID: 37593811 DOI: 10.1111/imr.13263] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 07/10/2023] [Accepted: 07/19/2023] [Indexed: 08/19/2023]
Abstract
Even though the discovery of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, a high proportion of patients do not respond. Moreover, some types of cancers are refractory to these treatments. Thus, the need to find predictive biomarkers of efficacy and to evaluate the association with other treatments, such as chemotherapy or radiotherapy, appears to be essential. Because ICIs reactivate or maintain an active status of T cells, one possibility is to combine these treatments with therapies that engage an immune response against tumor cells. Thus, by inducing immunogenic cell death (ICD) of cancer cells, some conventional anticancer treatments induce such immune response and may have an interest to be combined with ICIs. In this review, we explore preclinical studies and clinical trials that evaluate the combination of ICIs with ICD inducers. More than inducing ICD, some of these treatments appear to modulate the tumor microenvironment and more particularly to inhibit immunosuppression, thus improving treatment efficacy.
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Affiliation(s)
- François Ghiringhelli
- Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France
- Equipe TIRECs, Labellisée Ligue Contre le Cancer, Centre de Recherche INSERM LNC-UMR1231, Dijon, France
- University of Bourgogne Franche-Comté, Dijon, France
- Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France
- Genetic and Immunology Medical Institute, Dijon, France
| | - Cédric Rébé
- Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France
- Equipe TIRECs, Labellisée Ligue Contre le Cancer, Centre de Recherche INSERM LNC-UMR1231, Dijon, France
- University of Bourgogne Franche-Comté, Dijon, France
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7
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Zhang Y, Doan BT, Gasser G. Metal-Based Photosensitizers as Inducers of Regulated Cell Death Mechanisms. Chem Rev 2023; 123:10135-10155. [PMID: 37534710 DOI: 10.1021/acs.chemrev.3c00161] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2023]
Abstract
Over the last few decades, various forms of regulated cell death (RCD) have been discovered and were found to improve cancer treatment. Although there are several reviews on RCD induced by photodynamic therapy (PDT), a comprehensive summary covering metal-based photosensitizers (PSs) as RCD inducers has not yet been presented. In this review, we systematically summarize the works on metal-based PSs that induce different types of RCD, including ferroptosis, immunogenic cell death (ICD), and pyroptosis. The characteristics and mechanisms of each RCD are explained. At the end of each section, a summary of the reported commonalities between different metal-based PSs inducing the same RCD is emphasized, and future perspectives on metal-based PSs inducing novel forms of RCD are discussed at the end of the review. Considering the essential roles of metal-based PSs and RCD in cancer therapy, we hope that this review will provide the stage for future advances in metal-based PSs as RCD inducers.
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Affiliation(s)
- Yiyi Zhang
- Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemistry, 75005 Paris, France
| | - Bich-Thuy Doan
- Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory of Synthesis, Electrochemistry, Imaging and Analytical Systems for Diagnosis, 75005 Paris, France
| | - Gilles Gasser
- Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemistry, 75005 Paris, France
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8
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Sprooten J, Laureano RS, Vanmeerbeek I, Govaerts J, Naulaerts S, Borras DM, Kinget L, Fucíková J, Špíšek R, Jelínková LP, Kepp O, Kroemer G, Krysko DV, Coosemans A, Vaes RD, De Ruysscher D, De Vleeschouwer S, Wauters E, Smits E, Tejpar S, Beuselinck B, Hatse S, Wildiers H, Clement PM, Vandenabeele P, Zitvogel L, Garg AD. Trial watch: chemotherapy-induced immunogenic cell death in oncology. Oncoimmunology 2023; 12:2219591. [PMID: 37284695 PMCID: PMC10240992 DOI: 10.1080/2162402x.2023.2219591] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 05/25/2023] [Accepted: 05/25/2023] [Indexed: 06/08/2023] Open
Abstract
Immunogenic cell death (ICD) refers to an immunologically distinct process of regulated cell death that activates, rather than suppresses, innate and adaptive immune responses. Such responses culminate into T cell-driven immunity against antigens derived from dying cancer cells. The potency of ICD is dependent on the immunogenicity of dying cells as defined by the antigenicity of these cells and their ability to expose immunostimulatory molecules like damage-associated molecular patterns (DAMPs) and cytokines like type I interferons (IFNs). Moreover, it is crucial that the host's immune system can adequately detect the antigenicity and adjuvanticity of these dying cells. Over the years, several well-known chemotherapies have been validated as potent ICD inducers, including (but not limited to) anthracyclines, paclitaxels, and oxaliplatin. Such ICD-inducing chemotherapeutic drugs can serve as important combinatorial partners for anti-cancer immunotherapies against highly immuno-resistant tumors. In this Trial Watch, we describe current trends in the preclinical and clinical integration of ICD-inducing chemotherapy in the existing immuno-oncological paradigms.
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Affiliation(s)
- Jenny Sprooten
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Raquel S. Laureano
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Isaure Vanmeerbeek
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Jannes Govaerts
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Stefan Naulaerts
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Daniel M. Borras
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Lisa Kinget
- Laboratory of Experimental Oncology, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
| | - Jitka Fucíková
- Department of Immunology, Charles University, 2Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
- Sotio Biotech, Prague, Czech Republic
| | - Radek Špíšek
- Department of Immunology, Charles University, 2Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
- Sotio Biotech, Prague, Czech Republic
| | - Lenka Palová Jelínková
- Department of Immunology, Charles University, 2Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
- Sotio Biotech, Prague, Czech Republic
| | - Oliver Kepp
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe Labellisée Par la Liguecontre le Cancer, Université de Paris, sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
| | - Guido Kroemer
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe Labellisée Par la Liguecontre le Cancer, Université de Paris, sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
- Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Institut du Cancer Paris CARPEM, Paris, France
| | - Dmitri V. Krysko
- Cell Death Investigation and Therapy (CDIT) Laboratory, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Insitute Ghent, Ghent University, Ghent, Belgium
| | - An Coosemans
- Laboratory of Tumor Immunology and Immunotherapy, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
| | - Rianne D.W. Vaes
- Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Dirk De Ruysscher
- Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, The Netherlands
- Department of Radiotherapy, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Steven De Vleeschouwer
- Department Neurosurgery, University Hospitals Leuven, Leuven, Belgium
- Department Neuroscience, Laboratory for Experimental Neurosurgery and Neuroanatomy, KU Leuven, Leuven, Belgium
- Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium
| | - Els Wauters
- Laboratory of Respiratory Diseases and Thoracic Surgery (Breathe), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Evelien Smits
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium
- Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Antwerp, Belgium
| | - Sabine Tejpar
- Molecular Digestive Oncology, Department of Oncology, Katholiek Universiteit Leuven, Leuven, Belgium
- Cell Death and Inflammation Unit, VIB-Ugent Center for Inflammation Research (IRC), Ghent, Belgium
| | - Benoit Beuselinck
- Laboratory of Experimental Oncology, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
| | - Sigrid Hatse
- Laboratory of Experimental Oncology, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
| | - Hans Wildiers
- Laboratory of Experimental Oncology, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
| | - Paul M. Clement
- Laboratory of Experimental Oncology, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
| | - Peter Vandenabeele
- Cell Death and Inflammation Unit, VIB-Ugent Center for Inflammation Research (IRC), Ghent, Belgium
- Molecular Signaling and Cell Death Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Laurence Zitvogel
- Tumour Immunology and Immunotherapy of Cancer, European Academy of Tumor Immunology, Gustave Roussy Cancer Center, Inserm, Villejuif, France
| | - Abhishek D. Garg
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
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9
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Photon- and Proton-Mediated Biological Effects: What Has Been Learned? LIFE (BASEL, SWITZERLAND) 2022; 13:life13010030. [PMID: 36675979 PMCID: PMC9866122 DOI: 10.3390/life13010030] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/14/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022]
Abstract
The current understanding of the effects of radiation is gradually becoming broader. However, it still remains unclear why some patients respond to radiation with a pronounced positive response, while in some cases the disease progresses. This is the motivation for studying the effects of radiation therapy not only on tumor cells, but also on the tumor microenvironment, as well as studying the systemic effects of radiation. In this framework, we review the biological effects of two types of radiotherapy: photon and proton irradiations. Photon therapy is a commonly used type of radiation therapy due to its wide availability and long-term history, with understandable and predictable outcomes. Proton therapy is an emerging technology, already regarded as the method of choice for many cancers in adults and children, both dosimetrically and biologically. This review, written after the analysis of more than 100 relevant literary sources, describes the local effects of photon and proton therapy and shows the mechanisms of tumor cell damage, interaction with tumor microenvironment cells and effects on angiogenesis. After systematic analysis of the literature, we can conclude that proton therapy has potentially favorable toxicological profiles compared to photon irradiation, explained mainly by physical but also biological properties of protons. Despite the fact that radiobiological effects of protons and photons are generally similar, protons inflict reduced damage to healthy tissues surrounding the tumor and hence promote fewer adverse events, not only local, but also systemic.
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Roussot N, Ghiringhelli F, Rébé C. Tumor Immunogenic Cell Death as a Mediator of Intratumor CD8 T-Cell Recruitment. Cells 2022; 11:cells11223672. [PMID: 36429101 PMCID: PMC9688834 DOI: 10.3390/cells11223672] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/15/2022] [Accepted: 11/16/2022] [Indexed: 11/22/2022] Open
Abstract
The success of anticancer treatments relies on a long-term response which can be mediated by the immune system. Thus, the concept of immunogenic cell death (ICD) describes the capacity of dying cancer cells, under chemotherapy or physical stress, to express or release danger-associated molecular patterns (DAMPs). These DAMPs are essential to activate dendritic cells (DCs) and to stimulate an antigen presentation to CD8 cytotoxic cells. Then, activated CD8 T cells exert their antitumor effects through cytotoxic molecules, an effect which is transitory due to the establishment of a feedback loop leading to T-cell exhaustion. This phenomenon can be reversed using immune checkpoint blockers (ICBs), such as anti-PD-1, PD-L1 or CTLA-4 Abs. However, the blockade of these checkpoints is efficient only if the CD8 T cells are recruited within the tumor. The CD8 T-cell chemoattraction is mediated by chemokines. Hence, an important question is whether the ICD can not only influence the DC activation and resulting CD8 T-cell activation but can also favor the chemokine production at the tumor site, thus triggering their recruitment. This is the aim of this review, in which we will decipher the role of some chemokines (and their specific receptors), shown to be released during ICD, on the CD8 T-cell recruitment and antitumor response. We will also analyze the clinical applications of these chemokines as predictive or prognostic markers or as new targets which should be used to improve patients' response.
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Affiliation(s)
- Nicolas Roussot
- Cancer Biology Transfer Platform, Centre Georges-François Leclerc, F-21000 Dijon, France
- Equipe Labellisée Ligue Contre le Cancer, Centre de Recherche INSERM LNC-UMR1231, F-21000 Dijon, France
- UFR Sciences de Santé, University Bourgogne Franche-Comté, F-21000 Dijon, France
- Department of Medical Oncology, Centre Georges-François Leclerc, F-21000 Dijon, France
| | - François Ghiringhelli
- Cancer Biology Transfer Platform, Centre Georges-François Leclerc, F-21000 Dijon, France
- Equipe Labellisée Ligue Contre le Cancer, Centre de Recherche INSERM LNC-UMR1231, F-21000 Dijon, France
- UFR Sciences de Santé, University Bourgogne Franche-Comté, F-21000 Dijon, France
- Department of Medical Oncology, Centre Georges-François Leclerc, F-21000 Dijon, France
- Genetic and Immunology Medical Institute, F-21000 Dijon, France
- Correspondence: (F.G.); (C.R.)
| | - Cédric Rébé
- Cancer Biology Transfer Platform, Centre Georges-François Leclerc, F-21000 Dijon, France
- Equipe Labellisée Ligue Contre le Cancer, Centre de Recherche INSERM LNC-UMR1231, F-21000 Dijon, France
- UFR Sciences de Santé, University Bourgogne Franche-Comté, F-21000 Dijon, France
- Correspondence: (F.G.); (C.R.)
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11
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Patient-Specific Mathematical Model of the Clear Cell Renal Cell Carcinoma Microenvironment. J Pers Med 2022; 12:jpm12101681. [PMID: 36294824 PMCID: PMC9605269 DOI: 10.3390/jpm12101681] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/21/2022] [Accepted: 09/30/2022] [Indexed: 11/04/2022] Open
Abstract
The interactions between cells and molecules in the tumor microenvironment can give insight into the initiation and progression of tumors and their optimal treatment options. In this paper, we developed an ordinary differential equation (ODE) mathematical model of the interaction network of key players in the clear cell renal cell carcinoma (ccRCC) microenvironment. We then performed a global gradient-based sensitivity analysis to investigate the effects of the most sensitive parameters of the model on the number of cancer cells. The results indicate that parameters related to IL-6 have high a impact on cancer cell growth, such that decreasing the level of IL-6 can remarkably slow the tumor's growth.
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Heparin Protects Human Neural Progenitor Cells from Zika Virus-Induced Cell Death While Preserving Their Differentiation into Mature Neuroglial Cells. J Virol 2022; 96:e0112222. [PMID: 36121298 PMCID: PMC9555206 DOI: 10.1128/jvi.01122-22] [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] [Indexed: 11/28/2022] Open
Abstract
Zika virus (ZIKV) is an arbovirus member of the Flaviviridae family that causes severe congenital brain anomalies in infected fetuses. The key target cells of ZIKV infection, human neural progenitor cells (hNPCs), are highly permissive to infection that causes the inhibition of cell proliferation and induces cell death. We have previously shown that pharmaceutical-grade heparin inhibits virus-induced cell death with negligible effects on in vitro virus replication in ZIKV-infected hNPCs at the “high” multiplicity of infection (MOI) of 1. Here, we show that heparin inhibits formation of ZIKV-induced intracellular vacuoles, a signature of paraptosis, and inhibits necrosis and apoptosis of hNPCs grown as neurospheres (NS). To test whether heparin preserved the differentiation of ZIKV-infected hNPCs into neuroglial cells, hNPCs were infected at the MOI of 0.001. In this experimental condition, heparin inhibited ZIKV replication by ca. 2 log10, mostly interfering with virion attachment, while maintaining its protective effect against ZIKV-induced cytopathicity. Heparin preserved differentiation into neuroglial cells of hNPCs that were obtained from either human-induced pluripotent stem cells (hiPSC) or by fetal tissue. Quite surprisingly, multiple additions of heparin to hNPCs enabled prolonged virus replication while preventing virus-induced cytopathicity. Collectively, these results highlight the potential neuroprotective effect of heparin that could serve as a lead compound to develop novel agents for preventing the damage of ZIKV infection on the developing brain. IMPORTANCE ZIKV is a neurotropic virus that invades neural progenitor cells (NPCs), causing inhibition of their proliferation and maturation into neurons and glial cells. We have shown previously that heparin, an anticoagulant also used widely during pregnancy, prevents ZIKV-induced cell death with negligible inhibition of virus replication. Here, we demonstrate that heparin also exerts antiviral activity against ZIKV replication using a much lower infectious inoculum. Moreover, heparin interferes with different modalities of virus-induced cell death. Finally, heparin-induced prevention of virus-induced NPC death allows their differentiation into neuroglial cells despite the intracellular accumulation of virions. These results highlight the potential use of heparin, or pharmacological agents derived from it, in pregnant women to prevent the devastating effects of ZIKV infection on the developing brain of their fetuses.
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Hypoxia-induced HMGB1 promotes glioma stem cells self-renewal and tumorigenicity via RAGE. iScience 2022; 25:104872. [PMID: 36034219 PMCID: PMC9399482 DOI: 10.1016/j.isci.2022.104872] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 06/10/2022] [Accepted: 07/29/2022] [Indexed: 11/23/2022] Open
Abstract
Glioma stem cells (GSCs) in the hypoxic niches contribute to tumor initiation, progression, and recurrence in glioblastoma (GBM). Hypoxia induces release of high-mobility group box 1 (HMGB1) from tumor cells, promoting the development of tumor. Here, we report that HMGB1 is overexpressed in human GBM specimens. Hypoxia promotes the expression and secretion of HMGB1 in GSCs. Furthermore, silencing HMGB1 results in the loss of stem cell markers and a reduction in self-renewal ability of GSCs. Additionally, HMGB1 knockdown inhibits the activation of RAGE-dependent ERK1/2 signaling pathway and arrests the cell cycle in GSCs. Consistently, FPS-ZM1, an inhibitor of RAGE, downregulates HMGB1 expression and the phosphorylation of ERK1/2, leading to a reduction in the proliferation of GSCs. In xenograft mice of GBM, HMGB1 knockdown inhibits tumor growth and promotes mouse survival. Collectively, these findings uncover a vital function for HMGB1 in regulating GSC self-renewal potential and tumorigenicity.
Glioma stem cells overexpress HMGB1 in human glioblastoma Hypoxia induces the upregulation and release of HMGB1 in glioma stem cells HMGB1 promotes the self-renewal of glioma stem cells via RAGE Targeting HMGB1 inhibits the tumorigenesis of glioma stem cells
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Syukri A, Budu, Hatta M, Amir M, Rohman MS, Mappangara I, Kaelan C, Wahyuni S, Bukhari A, Junita AR, Primaguna MR, Dwiyanti R, Febrianti A. Doxorubicin induced immune abnormalities and inflammatory responses via HMGB1, HIF1-α and VEGF pathway in progressive of cardiovascular damage. Ann Med Surg (Lond) 2022; 76:103501. [PMID: 35340325 PMCID: PMC8943401 DOI: 10.1016/j.amsu.2022.103501] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 03/08/2022] [Accepted: 03/08/2022] [Indexed: 02/06/2023] Open
Abstract
Background Doxorubicin (DOX) is a commonly used treatment for cancer and the mechanism of DOX-induced cardiomyocyte damage in cardiovascular disease is not fully understood. High-mobility group box 1 (HMGB1), strong induce proinflammatory cytokines via damage associated molecular pattern (DAMP) which its interaction with the receptor of advanced glycation end products (RAGE), that affect cytokine release, and angiogenesis via the role of HMBG1, HIF-1α and VEGF as an important regulator in these cardiac failure processes. Hypoxia-inducible factor-1α (HIF-1α) is plays an important role in the cellular response to systemic oxygen levels of cells and VEGF is an angiogenic factor and can stimulate cellular responses on the surface of endothelial cells will be described Objective The aim of this article is to comprehensively review the role of HMGB1, HIF-1α, and VEGF in DOX-induced Cardiovascular Disease and its molecular mechanisms. Methods The data in this study were collect by search the keyword combinations of medical subject headings (MeSH) of “HMGB1”, “HIF-1 α”, “VEGF”, “DOX” and “Cardiovascular disease” and relevant reference lists were manually searched in PubMed, EMBASE and Scopus database. All relevant articles in data base above were included and narratively discussed in this review article. Results Several articles were revealed that molecular mechanisms of the DOX in cardiomyocyte damage and related to HMGB1, HIF-1α and VEGF and may potential treatment and prevention to cardiovascular disease in DOX intervention. Conclusion HMGB1, HIF-1α and VEGF has a pivotal regulator in DOX-induce cardiomyocyte damage and predominantly acts through different pathways. The role of HMGB1 in DOX-induced myocardial damage suggests that HMGB1 is a mediator of DOX-induced damage. In addition, DOX can inhibit HIF-1α activity where DOX can decrease HIF-1α expression and HIF-1α is also responsible for upregulation of several angiogenic factors, including VEGF. VEGF plays an important role in angiogenesis and anti-angiogenesis both in vitro and in vivo and reduces the side effects of DOX markedly. In addition, the administration of anti-angiogenesis will show an inhibitory effect on angiogenesis mediated by the VEGF signaling pathway and triggered by DOX in cells.
The effect of Doxorubicin (DOX) induced cardiovascular damage via several pathways. Cardiovascular damage can involve HMGB1, HIF-1α, and VEGF. HMGB1, HIF-1α, and VEGF as a pivotal regulator in DOX-induce cardiomyocyte damage. HMGB1, HIF-1α, and VEGF in cardiovascular diseases will be predominantly acting through different pathways.
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Sen S, Won M, Levine MS, Noh Y, Sedgwick AC, Kim JS, Sessler JL, Arambula JF. Metal-based anticancer agents as immunogenic cell death inducers: the past, present, and future. Chem Soc Rev 2022; 51:1212-1233. [PMID: 35099487 PMCID: PMC9398513 DOI: 10.1039/d1cs00417d] [Citation(s) in RCA: 107] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cancer is the deadliest disease in the world behind heart disease. Sadly, this remains true even as we suffer the ravages of the Covid-19 pandemic. Whilst current chemo- and radiotherapeutic treatment strategies have significantly improved the patient survival rate, disease reoccurrence continues to pose a deadly risk for all too many patients. Incomplete removal of tumour cells from the body increases the chances of metastasis and developing resistance against current treatments. Immunotherapy represents a therapeutic modality that has helped to overcome these limitations in recent decades. However, further progress is needed. So-called immunogenic cell death (ICD) is a recently discovered and unique mode of cell death that could trigger this necessary further progress. ICD involves stimulation of a tumour-specific immune response as a downstream effect. Facilitated by certain treatment modalities, cells undergoing ICD can trigger the IFN-γ mediated immune response involving cytotoxic T cells (CTLs) and γδ T cells that eradicate residual tumour cells. In recent years, there has been a significant increase in the number of small-molecules being tested as potential ICD inducers. A large number of these ICD inducers are metal-based complexes. In fact, anticancer metal drugs based on Pt, Ru, Ir, Cu, and Au are now known to give rise to an immune response against tumour cells as the result of ICD. Advances have also been made in terms of exploiting combinatorial and delivery strategies. In favourable cases, these approaches have been shown to increase the efficacy of otherwise ICD "silent" metal complexes. Taken in concert, rationally designed novel anticancer metal complexes that can act as ICD inducers show promise as potential new immunotherapies for neoplastic disease. This Tutorial Review will allow the readers to assess the progress in this fast-evolving field thus setting the stage for future advances.
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Affiliation(s)
- Sajal Sen
- Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712-1224, USA.
| | - Miae Won
- Department of Chemistry, Korea University, Seoul 02841, Korea.
| | - Matthew S Levine
- Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712-1224, USA.
| | - Yuvin Noh
- Department of Chemistry, Korea University, Seoul 02841, Korea.
| | - Adam C Sedgwick
- Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712-1224, USA.
| | - Jong Seung Kim
- Department of Chemistry, Korea University, Seoul 02841, Korea.
| | - Jonathan L Sessler
- Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712-1224, USA.
| | - Jonathan F Arambula
- Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712-1224, USA.
- OncoTEX, Inc. 3800 North Lamar Blvd., Austin, Texas 78756, USA
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Mast Cell–Tumor Interactions: Molecular Mechanisms of Recruitment, Intratumoral Communication and Potential Therapeutic Targets for Tumor Growth. Cells 2022; 11:cells11030349. [PMID: 35159157 PMCID: PMC8834237 DOI: 10.3390/cells11030349] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 01/08/2022] [Accepted: 01/13/2022] [Indexed: 12/13/2022] Open
Abstract
Mast cells (MCs) are tissue-resident immune cells that are important players in diseases associated with chronic inflammation such as cancer. Since MCs can infiltrate solid tumors and promote or limit tumor growth, a possible polarization of MCs to pro-tumoral or anti-tumoral phenotypes has been proposed and remains as a challenging research field. Here, we review the recent evidence regarding the complex relationship between MCs and tumor cells. In particular, we consider: (1) the multifaceted role of MCs on tumor growth suggested by histological analysis of tumor biopsies and studies performed in MC-deficient animal models; (2) the signaling pathways triggered by tumor-derived chemotactic mediators and bioactive lipids that promote MC migration and modulate their function inside tumors; (3) the possible phenotypic changes on MCs triggered by prevalent conditions in the tumor microenvironment (TME) such as hypoxia; (4) the signaling pathways that specifically lead to the production of angiogenic factors, mainly VEGF; and (5) the possible role of MCs on tumor fibrosis and metastasis. Finally, we discuss the novel literature on the molecular mechanisms potentially related to phenotypic changes that MCs undergo into the TME and some therapeutic strategies targeting MC activation to limit tumor growth.
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Pathak C, Vaidya FU, Waghela BN, Chhipa AS, Tiwari BS, Ranjan K. Advanced Glycation End Products-Mediated Oxidative Stress and Regulated Cell Death Signaling in Cancer. HANDBOOK OF OXIDATIVE STRESS IN CANCER: MECHANISTIC ASPECTS 2022:535-550. [DOI: 10.1007/978-981-15-9411-3_44] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Troitskaya OS, Novak DD, Richter VA, Koval OA. Immunogenic Cell Death in Cancer Therapy. Acta Naturae 2022; 14:40-53. [PMID: 35441043 PMCID: PMC9013441 DOI: 10.32607/actanaturae.11523] [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: 07/16/2021] [Accepted: 12/20/2021] [Indexed: 12/20/2022] Open
Abstract
Apoptosis plays a crucial role in chemotherapy-induced cell death. The conventional theory holding that apoptosis needs to be immunologically silent has recently been revised, and the concept of immunogenic cell death (ICD) has been proposed. This review describes the main features of ICD induction. These ICD markers are important for the effectiveness of anticancer therapy, as well as for basic research into cell death regulation. The mechanism of the "vaccination effect" of dying cancer cells undergoing ICD has been fully described, including the activation of specific antitumor response after re-challenge by the same living tumor cells. This review also discusses the whole set of molecular events attributing cell death to immunogenic type: the exposure of calreticulin and the heat shock protein HSP70 to the outer surface of the cell membrane and the release of the nuclear protein HMGB1 and ATP into the extracellular space. ICD inducers of various nature (chemotherapy drugs, cytotoxic proteins, and oncolytic viruses), as well as physical methods, are classified in the current review.
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Affiliation(s)
- O. S. Troitskaya
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090 Russia
| | - D. D. Novak
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090 Russia
- Novosibirsk State University, Novosibirsk, 630090 Russia
| | - V. A. Richter
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090 Russia
| | - O. A. Koval
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090 Russia
- Novosibirsk State University, Novosibirsk, 630090 Russia
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Li L, Liu H, Tao W, Wen S, Fu X, Yu S. Pharmacological Inhibition of HMGB1 Prevents Muscle Wasting. Front Pharmacol 2021; 12:731386. [PMID: 34867338 PMCID: PMC8637759 DOI: 10.3389/fphar.2021.731386] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 10/18/2021] [Indexed: 12/19/2022] Open
Abstract
Background: Cachexia is a multifactorial disorder characterized by weight loss and muscle wasting, making up for about 20% of cancer-related death. However, there are no effective drugs to combat cachexia at present. Methods: In this study, the effect of CT26 exosomes on C2C12 myotubes was observed. We compared serum HMGB1 level in cachexia and non-cachexia colon cancer patients. We further explored HMGB1 expression level in CT26 exosome. We added recombinant HMGB1 to C2C12 myotubes to observe the effects of HMGB1 on C2C12 myotubes and detected the expression level of the muscle atrophy-related proteins. Then, we used the HMGB1 inhibitor glycyrrhizin to reverse the effects of HMGB1 on C2C12 myotubes. Finally, HMGB1 inhibitor glycyrrhizin was utilized to relieve cachexia in CT26 cachexia mouse model. Results: Exosomes containing HMGB1 led to muscle atrophy with significantly decreased myotube diameter and increased expression of muscle atrophy-related proteins Atrogin1 and MuRF1. Further, we detected that HMGB1 induced the muscle atrophy mainly via TLR4/NF-κB pathway. Administration of the HMGB1 inhibitor glycyrrhizin could relieve muscle wasting in vitro and attenuate the progression of cachexia in vivo. Conclusion: These findings demonstrate the cachectic role of HMGB1, whether it is soluble form of HMGB1 or secreted from tumor cells as part of exosomes. HMGB1 inhibitor glycyrrhizin might be a promising drug in colon cancer cachexia.
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Affiliation(s)
- Lu Li
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiquan Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Weili Tao
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Su Wen
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaofen Fu
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiying Yu
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Tajbakhsh A, Gheibi Hayat SM, Movahedpour A, Savardashtaki A, Loveless R, Barreto GE, Teng Y, Sahebkar A. The complex roles of efferocytosis in cancer development, metastasis, and treatment. Biomed Pharmacother 2021; 140:111776. [PMID: 34062411 DOI: 10.1016/j.biopha.2021.111776] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 05/22/2021] [Accepted: 05/24/2021] [Indexed: 12/12/2022] Open
Abstract
When tumor cells are killed by targeted therapy, radiotherapy, or chemotherapy, they trigger their primary tumor by releasing pro-inflammatory cytokines. Microenvironmental interactions can also promote tumor heterogeneity and development. In this line, several immune cells within the tumor microenvironment, including macrophages, dendritic cells, regulatory T-cells, and CD8+ and CD4+ T cells, are involved in the clearance of apoptotic tumor cells through a process called efferocytosis. Although the efficiency of apoptotic tumor cell efferocytosis is positive under physiological conditions, there are controversies regarding its usefulness in treatment-induced apoptotic tumor cells (ATCs). Efferocytosis can show the limitation of cytotoxic treatments, such as chemotherapy and radiotherapy. Since cytotoxic treatments lead to extensive cell mortality, efferocytosis, and macrophage polarization toward an M2 phenotype, the immune response may get involved in tumor recurrence and metastasis. Tumor cells can use the anti-inflammatory effect of apoptotic tumor cell efferocytosis to induce an immunosuppressive condition that is tumor-tolerant. Since M2 polarization and efferocytosis are tumor-promoting processes, the receptors on macrophages act as potential targets for cancer therapy. Moreover, researchers have shown that efferocytosis-related molecules/pathways are potential targets for cancer therapy. These include phosphatidylserine and calreticulin, Tyro3, Axl, and Mer tyrosine kinase (MerTK), receptors of tyrosine kinase, indoleamine-2,3-dioxygenase 1, annexin V, CD47, TGF-β, IL-10, and macrophage phenotype switch are combined with conventional therapy, which can be more effective in cancer treatment. Thus, we set out to investigate the advantages and disadvantages of efferocytosis in treatment-induced apoptotic tumor cells.
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Affiliation(s)
- Amir Tajbakhsh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Mohammad Gheibi Hayat
- Department of Medical Biotechnology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Ahmad Movahedpour
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Savardashtaki
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Reid Loveless
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - George E Barreto
- Department of Biological Sciences, University of Limerick, Limerick, Ireland; Health Research Institute, University of Limerick, Limerick, Ireland
| | - Yong Teng
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA; Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Medical Laboratory, Imaging and Radiologic Sciences, College of Allied Health, Augusta University, Augusta, GA 30912, USA
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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21
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Gorgulho CM, Krishnamurthy A, Lanzi A, Galon J, Housseau F, Kaneno R, Lotze MT. Gutting it Out: Developing Effective Immunotherapies for Patients With Colorectal Cancer. J Immunother 2021; 44:49-62. [PMID: 33416261 PMCID: PMC8092416 DOI: 10.1097/cji.0000000000000357] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 11/27/2020] [Indexed: 12/20/2022]
Abstract
Risk factors for colorectal cancer (CRC) include proinflammatory diets, sedentary habits, and obesity, in addition to genetic syndromes that predispose individuals to this disease. Current treatment relies on surgical excision and cytotoxic chemotherapies. There has been a renewed interest in immunotherapy as a treatment option for CRC given the success in melanoma and microsatellite instable (MSI) CRC. Immunotherapy with checkpoint inhibitors only plays a role in the 4%-6% of patients with MSIhigh tumors and even within this subpopulation, response rates can vary from 30% to 50%. Most patients with CRC do not respond to this modality of treatment, even though colorectal tumors are frequently infiltrated with T cells. Tumor cells limit apoptosis and survive following intensive chemotherapy leading to drug resistance and induction of autophagy. Pharmacological or molecular inhibition of autophagy improves the efficacy of cytotoxic chemotherapy in murine models. The microbiome clearly plays an etiologic role, in some or most colon tumors, realized by elegant findings in murine models and now investigated in human clinical trials. Recent results have suggested that cancer vaccines may be beneficial, perhaps best as preventive strategies. The search for therapies that can be combined with current approaches to increase their efficacy, and new knowledge of the biology of CRC are pivotal to improve the care of patients suffering from this disease. Here, we review the basic immunobiology of CRC, current "state-of-the-art" immunotherapies and define those areas with greatest therapeutic promise for the future.
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Affiliation(s)
- Carolina Mendonça Gorgulho
- Department of Microbiology and Immunology, Institute of Biosciences of Botucatu, São Paulo State University, UNESP, Botucatu, SP, Brazil
- Department of Pathology, School of Medicine of Botucatu, São Paulo State University, UNESP, Botucatu, SP, Brazil
- DAMP Laboratory, Department of Surgery, University of Pittsburgh, Pittsburgh - PA, USA
| | | | - Anastasia Lanzi
- INSERM, Laboratory of Integrative Cancer Immunology, Equipe Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Sorbonne Université, Sorbonne Paris Cité, Université de Paris, Paris, France
| | - Jérôme Galon
- INSERM, Laboratory of Integrative Cancer Immunology, Equipe Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Sorbonne Université, Sorbonne Paris Cité, Université de Paris, Paris, France
| | - Franck Housseau
- Sidney Kimmel Comprehensive Cancer Centre, Johns Hopkins School of Medicine, CRB-I Room 4M59, 1650 Orleans Street, Baltimore, MD, USA
| | - Ramon Kaneno
- Department of Microbiology and Immunology, Institute of Biosciences of Botucatu, São Paulo State University, UNESP, Botucatu, SP, Brazil
- Department of Pathology, School of Medicine of Botucatu, São Paulo State University, UNESP, Botucatu, SP, Brazil
| | - Michael T. Lotze
- DAMP Laboratory, Department of Surgery, University of Pittsburgh, Pittsburgh - PA, USA
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22
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Interactions between tumor-derived proteins and Toll-like receptors. Exp Mol Med 2020; 52:1926-1935. [PMID: 33299138 PMCID: PMC8080774 DOI: 10.1038/s12276-020-00540-4] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/20/2020] [Accepted: 11/02/2020] [Indexed: 12/23/2022] Open
Abstract
Damage-associated molecular patterns (DAMPs) are danger signals (or alarmins) alerting immune cells through pattern recognition receptors (PRRs) to begin defense activity. Moreover, DAMPs are host biomolecules that can initiate a noninflammatory response to infection, and pathogen-associated molecular pattern (PAMPs) perpetuate the inflammatory response to infection. Many DAMPs are proteins that have defined intracellular functions and are released from dying cells after tissue injury or chemo-/radiotherapy. In the tumor microenvironment, DAMPs can be ligands for Toll-like receptors (TLRs) expressed on immune cells and induce cytokine production and T-cell activation. Moreover, DAMPs released from tumor cells can directly activate tumor-expressed TLRs that induce chemoresistance, migration, invasion, and metastasis. Furthermore, DAMP-induced chronic inflammation in the tumor microenvironment causes an increase in immunosuppressive populations, such as M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). Therefore, regulation of DAMP proteins can reduce excessive inflammation to create an immunogenic tumor microenvironment. Here, we review tumor-derived DAMP proteins as ligands of TLRs and discuss their association with immune cells, tumors, and the composition of the tumor microenvironment. Tumor cells killed by radiotherapy or chemotherapy release signaling molecules that stimulate both immune response and tumor aggressiveness; regulating these molecules could improve treatment efficacy. Tae Heung Kang, Yeong-Min Park, and co-workers at Konkuk University, Seoul, South Korea, have reviewed the role of damage-associated molecular patterns (DAMPs) in immunity and cancer. These signaling molecules act as danger signals, activating immune cells by binding to specific receptors. However, tumor cells have the same receptors, and DAMPs binding triggers chemoresistance and increases invasiveness. The researchers report that although DAMPs can trigger a helpful immune response, they can also cause chronic inflammation, which in turn promotes an immune suppression response, allowing tumors to escape immune detection. Improving our understanding of the functions of different DAMPs could improve our ability to boost the immune response and decrease tumor aggressiveness.
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23
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Armstrong VS, Fitzgerald LW, Bathe OF. Cancer-Associated Muscle Wasting-Candidate Mechanisms and Molecular Pathways. Int J Mol Sci 2020; 21:ijms21239268. [PMID: 33291708 PMCID: PMC7729509 DOI: 10.3390/ijms21239268] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/27/2020] [Accepted: 11/30/2020] [Indexed: 12/11/2022] Open
Abstract
Excessive muscle loss is commonly observed in cancer patients and its association with poor prognosis has been well-established. Cancer-associated sarcopenia differs from age-related wasting in that it is not responsive to nutritional intervention and exercise. This is related to its unique pathogenesis, a result of diverse and interconnected mechanisms including inflammation, disordered metabolism, proteolysis and autophagy. There is a growing body of evidence that suggests that the tumor is the driver of muscle wasting by its elaboration of mediators that influence each of these pro-sarcopenic pathways. In this review, evidence for these tumor-derived factors and putative mechanisms for inducing muscle wasting will be reviewed. Potential targets for future research and therapeutic interventions will also be reviewed.
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Affiliation(s)
- Victoria S. Armstrong
- Arnie Charbonneau Cancer Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada; (V.S.A.); (L.W.F.)
- Department of Medical Sciences, University of Calgary, Calgary, AB T2N 4Z6, Canada
| | - Liam W. Fitzgerald
- Arnie Charbonneau Cancer Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada; (V.S.A.); (L.W.F.)
- Department of Medical Sciences, University of Calgary, Calgary, AB T2N 4Z6, Canada
| | - Oliver F. Bathe
- Arnie Charbonneau Cancer Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada; (V.S.A.); (L.W.F.)
- Department of Medical Sciences, University of Calgary, Calgary, AB T2N 4Z6, Canada
- Departments of Surgery and Oncology, University of Calgary, Calgary, AB T2N 4Z6, Canada
- Correspondence: ; Tel.: +1-403-521-3275
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24
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Azizian-Farsani F, Abedpoor N, Hasan Sheikhha M, Gure AO, Nasr-Esfahani MH, Ghaedi K. Receptor for Advanced Glycation End Products Acts as a Fuel to Colorectal Cancer Development. Front Oncol 2020; 10:552283. [PMID: 33117687 PMCID: PMC7551201 DOI: 10.3389/fonc.2020.552283] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022] Open
Abstract
Receptor for advanced glycation end-products (RAGE) is a multiligand binding and single-pass transmembrane protein taken in diverse chronic inflammatory conditions. RAGE behaves as a pattern recognition receptor, which binds and is engaged in the cellular response to a variety of damage-associated molecular pattern molecules, as well as HMGB1, S100 proteins, and AGEs (advanced glycation end-products). The RAGE activation turns out to a formation of numerous intracellular signaling mechanisms, resulting in the progression and prolongation of colorectal carcinoma (CRC). The RAGE expression correlates well with the survival of colon cancer cells. RAGE is involved in the tumorigenesis, which increases and develops well in the stressed tumor microenvironment. In this review, we summarized downstream signaling cascade activated by the multiligand activation of RAGE, as well as RAGE ligands and their sources, clinical studies, and tumor markers related to RAGE particularly in the inflammatory tumor microenvironment in CRC. Furthermore, the role of RAGE signaling pathway in CRC patients with diabetic mellitus is investigated. RAGE has been reported to drive assorted signaling pathways, including activator protein 1, nuclear factor-κB, signal transducer and activator of transcription 3, SMAD family member 4 (Smad4), mitogen-activated protein kinases, mammalian target of rapamycin, phosphoinositide 3-kinases, reticular activating system, Wnt/β-catenin pathway, and Glycogen synthase kinase 3β, and even microRNAs.
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Affiliation(s)
| | - Navid Abedpoor
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, Academic Center for Education, Culture and Reasearch (ACECR), Isfahan, Iran
| | | | - Ali Osmay Gure
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey
| | - Mohammad Hossein Nasr-Esfahani
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, Academic Center for Education, Culture and Reasearch (ACECR), Isfahan, Iran
| | - Kamran Ghaedi
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, Academic Center for Education, Culture and Reasearch (ACECR), Isfahan, Iran.,Division of Cellular and Molecular Biology, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
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25
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Xu M, Meng SS, Liang H, Gu ZY. A metal–organic framework with tunable exposed facets as a high-affinity artificial receptor for enzyme inhibition. Inorg Chem Front 2020. [DOI: 10.1039/d0qi00827c] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Copper-based metal-organic framework HKUST-1 was utilized as artificial receptor to recognize positive-charged α-chymotrypsin with high affinity. The affinity between them could be tuned through comprehensive synthetic design of exposed facets.
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Affiliation(s)
- Ming Xu
- Jiangsu Key Laboratory of Biofunctional Materials
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials
- College of Chemistry and Materials Science
- Nanjing Normal University
- Nanjing
| | - Sha-Sha Meng
- Jiangsu Key Laboratory of Biofunctional Materials
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials
- College of Chemistry and Materials Science
- Nanjing Normal University
- Nanjing
| | - Hong Liang
- Jiangsu Key Laboratory of Biofunctional Materials
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials
- College of Chemistry and Materials Science
- Nanjing Normal University
- Nanjing
| | - Zhi-Yuan Gu
- Jiangsu Key Laboratory of Biofunctional Materials
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials
- College of Chemistry and Materials Science
- Nanjing Normal University
- Nanjing
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26
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Role of Metastasis-Related Genes in Cisplatin Chemoresistance in Gastric Cancer. Int J Mol Sci 2019; 21:ijms21010254. [PMID: 31905926 PMCID: PMC6981396 DOI: 10.3390/ijms21010254] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 12/23/2019] [Accepted: 12/26/2019] [Indexed: 02/06/2023] Open
Abstract
The role of metastasis-related genes in cisplatin (CDDP) chemoresistance in gastric cancer is poorly understood. Here, we examined the expression of four metastasis-related genes (namely, c-met, HMGB1, RegIV, PCDHB9) in 39 cases of gastric cancer treated with neoadjuvant therapy with CDDP or CDDP+5-fluorouracil and evaluated its association with CDDP responsiveness. Comparison of CDDP-sensitive cases with CDDP-resistant cases, the expression of c-met, HMGB1, and PCDHB9 was correlated with CDDP resistance. Among them, the expression of HMGB1 showed the most significant correlation with CDDP resistance in multivariate analysis. Treatment of TMK-1 and MKN74 human gastric cancer cell lines with ethyl pyruvate (EP) or tanshinone IIA (TAN), which are reported to inhibit HMGB1 signaling, showed a 4–5-fold increase in inhibition by CDDP. Treatment with EP or TAN also suppressed the expression of TLR4 and MyD88 in the HMGB1 signal transduction pathway and suppressed the activity of NFκB in both cell lines. These results suggest that the expression of these cancer metastasis-related genes is also related to anticancer drug resistance and that suppression of HMGB1 may be particularly useful for CDDP sensitization.
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27
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Rébé C, Demontoux L, Pilot T, Ghiringhelli F. Platinum Derivatives Effects on Anticancer Immune Response. Biomolecules 2019; 10:E13. [PMID: 31861811 PMCID: PMC7022223 DOI: 10.3390/biom10010013] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 12/16/2019] [Accepted: 12/16/2019] [Indexed: 12/12/2022] Open
Abstract
Along with surgery and radiotherapy, chemotherapeutic agents belong to the therapeutic arsenal in cancer treatment. In addition to their direct cytotoxic effects, these agents also impact the host immune system, which might enhance or counteract their antitumor activity. The platinum derivative compounds family, mainly composed of carboplatin, cisplatin and oxaliplatin, belongs to the chemotherapeutical arsenal used in numerous cancer types. Here, we will focus on the effects of these molecules on antitumor immune response. These compounds can induce or not immunogenic cell death (ICD), and some strategies have been found to induce or further enhance it. They also regulate immune cells' fate. Platinum derivatives can lead to their activation. Additionally, they can also dampen immune cells by selective killing or inhibiting their activity, particularly by modulating immune checkpoints' expression.
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Affiliation(s)
- Cédric Rébé
- Platform of Transfer in Cancer Biology, Centre Georges-François Leclerc, F-21000 Dijon, France
- University of Bourgogne-Franche-Comté, F-21000 Dijon, France; (L.D.); (T.P.); (F.G.)
- INSERM LNC-UMR1231, F-21000 Dijon, France
| | - Lucie Demontoux
- University of Bourgogne-Franche-Comté, F-21000 Dijon, France; (L.D.); (T.P.); (F.G.)
- INSERM LNC-UMR1231, F-21000 Dijon, France
| | - Thomas Pilot
- Platform of Transfer in Cancer Biology, Centre Georges-François Leclerc, F-21000 Dijon, France
- University of Bourgogne-Franche-Comté, F-21000 Dijon, France; (L.D.); (T.P.); (F.G.)
- INSERM LNC-UMR1231, F-21000 Dijon, France
| | - François Ghiringhelli
- Platform of Transfer in Cancer Biology, Centre Georges-François Leclerc, F-21000 Dijon, France
- University of Bourgogne-Franche-Comté, F-21000 Dijon, France; (L.D.); (T.P.); (F.G.)
- INSERM LNC-UMR1231, F-21000 Dijon, France
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28
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Targeting AXL and RAGE to prevent geminin overexpression-induced triple-negative breast cancer metastasis. Sci Rep 2019; 9:19150. [PMID: 31844158 PMCID: PMC6915698 DOI: 10.1038/s41598-019-55702-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 11/28/2019] [Indexed: 02/07/2023] Open
Abstract
Dissemination of metastatic precursors from primaries is the primary reason for patient death. Dissemination encompasses tumor cells invasion of stroma, followed by intravasation through the endothelium barrier into the bloodstream. Here, we describe how geminin-overexpressing tumor cells acquire dissemination ability. Acetylated HMGB1 (Ac-HMGB1) secreted by geminin-overexpressing cells activates RAGE and CXCR4 expression on mesenchymal stem cells (MSCs) located in tumor stroma. Through secreting CXCL12, geminin-overexpressing cells recruit these CXCR4+-MSCs into the tumor. Within the tumor, MSCs differentiate into S100A4-secreting cancer-associated fibroblasts (CAFs). S100A4, in a reciprocal manner, activates geminin-overexpressing cells to secrete CCL2 that recruits M0-macrophages from the stroma into the tumor. Within the tumor, CCL2 polarizes M0-macrophages into Gas6-secreting M2-tumor-associated macrophages (M2-TAMs). In concert, geminin-overexpression, S100A4/RAGE and Gas6/AXL signaling promote the invasive and intravasation abilities in geminin-overexpressing cells through exacerbating their stemness and epithelial-to-mesenchymal phenotypes and enhancing expression and functional interaction of CD151 and α3β1-integrin in geminin-overexpressing cells. Tumors formed following injection of geminin-overexpressing cells admixed with MSCs/CAFs grew faster, metastasized earlier, especially to lungs, and were extremely sensitive to anti-c-Abl, anti-RAGE, and anti-AXL drugs. These data support an intrinsic ability in geminin-overexpressing tumor cells to promote their metastatic potential through recruitment and bi-directional interactions with MSCs/CAFs and M2-TAMs.
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29
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Kawahara I, Goto K, Kodama K, Luo Y, Fujiwara-Tani R, Mori T, Miyagawa Y, Tanaka H, Kodama H, Hosoito N, Taniguchi Y, Kuniyasu H. Magnetic Hyperthermia Using Self-Controlled Heating Elements Consisting of Fe-Al Milling Alloy Induces Cancer Cell Apoptosis while Preserving Skeletal Muscle. Pathobiology 2019; 86:254-262. [PMID: 31722347 DOI: 10.1159/000501524] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 03/04/2019] [Indexed: 01/17/2023] Open
Abstract
Necrosis-inducing anticancer drugs enhance high-mobility group box 1 (HMGB1) release during cell necrosis, and HMGB1-induced autophagy in skeletal muscle induces muscle atrophy. We evaluated the efficacy of magnetic hyperthermia therapy (MHT) using a low-energy magnetic field and self-controlled heating elements in tumor treatment. MHT-induced apoptosis by heating mouse subcutaneous tumors at 43°C using a heat-controlling iron-aluminum (Fe-Al) milling alloy. In contrast, MHT using Fe line-induced necrosis by heating to approximately 100°C. Furthermore, MHT with Fe-Al milling alloy reduced stemness. In hyperthermia using age line or Fe-Al milling alloy, both of them provided histological degeneration in skeletal muscle; however, qualitative differences were observed. MHT using Fe-line induced pronounced autophagy, decrease of myosin heavy chain content, and increase in serum HMGB1. In contrast, MHT using Fe-Al milling alloy induced heat shock protein 90 but no autophagy and decreased serum HMGB1. Therefore, MHT using Fe-Al milling alloy might be a good method for local treatment of tumors to reduce skeletal muscle atrophy.
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Affiliation(s)
- Isao Kawahara
- Department of Molecular Pathology, Nara Medical University, Kashihara, Japan.,Division of Rehabilitation, Hanna Central Hospital, Ikoma, Japan
| | - Kei Goto
- Department of Molecular Pathology, Nara Medical University, Kashihara, Japan
| | - Kenji Kodama
- Graduate School of Materials Science, Nara Institute of Science and Technology, Nara, Japan
| | - Yi Luo
- Department of Molecular Pathology, Nara Medical University, Kashihara, Japan
| | - Rina Fujiwara-Tani
- Department of Molecular Pathology, Nara Medical University, Kashihara, Japan
| | - Takuya Mori
- Department of Molecular Pathology, Nara Medical University, Kashihara, Japan.,Division of Rehabilitation, Hanna Central Hospital, Ikoma, Japan
| | - Yoshihiro Miyagawa
- Department of Molecular Pathology, Nara Medical University, Kashihara, Japan
| | | | | | - Nobuyoshi Hosoito
- Department of Mechanical Engineering, Nara National College of Technology, Ikoma, Japan
| | - Yukinori Taniguchi
- Graduate School of Materials Science, Nara Institute of Science and Technology, Nara, Japan
| | - Hiroki Kuniyasu
- Department of Molecular Pathology, Nara Medical University, Kashihara, Japan,
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30
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Cheng KJ, Alshawsh MA, Mejia Mohamed EH, Thavagnanam S, Sinniah A, Ibrahim ZA. HMGB1: an overview of its versatile roles in the pathogenesis of colorectal cancer. Cell Oncol (Dordr) 2019; 43:177-193. [PMID: 31677065 DOI: 10.1007/s13402-019-00477-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In recent years, the high mobility group box-1 (HMGB1) protein, a damage-associated molecular pattern (DAMP) molecule, has been found to play multifunctional roles in the pathogenesis of colorectal cancer. Although much attention has been given to the diagnostic and prognostic values of HMGB1 in colorectal cancer, the exact functional roles of the protein as well as the mechanistic pathways involved have remained poorly defined. This systematic review aims to discuss what is currently known about the roles of HMGB1 in colorectal cancer development, growth and progression, and to highlight critical areas for future investigations. To achieve this, the bibliographic databases Pubmed, Scopus, Web of Science and ScienceDirect were systematically screened for articles from inception till June 2018, which address associations of HMGB1 with colorectal cancer. CONCLUSIONS HMGB1 plays multiple roles in promoting the pathogenesis of colorectal cancer, despite a few contradicting studies. HMGB1 may differentially regulate disease-related processes, depending on the redox status of the protein in colorectal cancer. Binding of HMGB1 to various protein partners may alter the impact of HMGB1 on disease progression. As HMGB1 is heavily implicated in the pathogenesis of colorectal cancer, it is crucial to further improve our understanding of the functional roles of HMGB1 not only in colorectal cancer, but ultimately in all types of cancers.
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Affiliation(s)
- Kim Jun Cheng
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | | | | | - Surendran Thavagnanam
- Paediatric Department, Royal London Hospital, Whitechapel Road, Whitechapel, London, E1 1BB, UK
| | - Ajantha Sinniah
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Zaridatul Aini Ibrahim
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
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31
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Zhang L, Shi H, Chen H, Gong A, Liu Y, Song L, Xu X, You T, Fan X, Wang D, Cheng F, Zhu H. Dedifferentiation process driven by radiotherapy-induced HMGB1/TLR2/YAP/HIF-1α signaling enhances pancreatic cancer stemness. Cell Death Dis 2019; 10:724. [PMID: 31558702 PMCID: PMC6763460 DOI: 10.1038/s41419-019-1956-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 08/16/2019] [Accepted: 09/04/2019] [Indexed: 12/17/2022]
Abstract
Differentiated cancer cells reacquiring stem cell traits following radiotherapy may enrich cancer stem cells and accelerate tumor recurrence and metastasis. We are interested in the mechanistic role of dying cells-derived HMGB1 in CD133- pancreatic cancer cells dedifferentiation following radiotherapy. We firstly confirmed that X-ray irradiation induced differentiation of CD133- pancreatic cancer cells, from either sorted from patient samples or established cell lines, into cancer stem-like cells (iCSCs). Using an in vitro coculture model, X-ray irradiation induced dying cells to release HMGB1, which further promoted CD133- pancreatic cancer cells regaining stem cell traits, such as higher sphere forming ability and expressed higher level of stemness-related genes and proteins. Inhibiting the expression and activity of HMGB1 attenuated the dedifferentiation stimulating effect of irradiated, dying cells on C133- pancreatic cancer cells in vitro and in PDX models. Mechanistically, HMGB1 binding with TLR2 receptor functions in a paracrine manner to affect CD133- pancreatic cancer cells dedifferentiation via activating Hippo-YAP pathway and HIF-1α expression in oxygen independent manner in vitro and in vivo. We conclude that X-ray irradiation induces CD133- pancreatic cancer cell dedifferentiation into a CSC phenotype, and inhibiting HMGB1 may be a strategy to prevent CSC enrichment and further pancreatic carcinoma relapse.
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MESH Headings
- AC133 Antigen/metabolism
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism
- Animals
- Cell Death/radiation effects
- Cell Dedifferentiation/radiation effects
- Cell Line, Tumor
- Chromatin Immunoprecipitation
- Epithelial-Mesenchymal Transition/genetics
- Epithelial-Mesenchymal Transition/radiation effects
- Female
- HMGB1 Protein/genetics
- HMGB1 Protein/metabolism
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Mice
- Mice, Inbred BALB C
- Mice, Inbred NOD
- Mice, Nude
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/radiotherapy
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/radiation effects
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/radiotherapy
- Signal Transduction/genetics
- Signal Transduction/radiation effects
- Toll-Like Receptor 2/genetics
- Toll-Like Receptor 2/metabolism
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Transplantation, Heterologous
- YAP-Signaling Proteins
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Affiliation(s)
- Lirong Zhang
- The Affiliated Hospital of Jiangsu University, 212001, Zhenjiang, China
| | - Hui Shi
- The Affiliated Hospital of Jiangsu University, 212001, Zhenjiang, China
| | - Hongbo Chen
- School of Pharmaceutical Sciences (Shenzhen), SYSU, 518107, Shenzhen, China
| | - Aihua Gong
- School of Medicine, Jiangsu University, 212013, Zhenjiang, China
| | - Yanfang Liu
- The First People's Hospital of Zhenjiang, 212001, Zhenjiang, China
| | - Lian Song
- The Affiliated Hospital of Jiangsu University, 212001, Zhenjiang, China
| | - Xuewen Xu
- The Affiliated Hospital of Jiangsu University, 212001, Zhenjiang, China
| | - Tao You
- The Affiliated Hospital of Jiangsu University, 212001, Zhenjiang, China
| | - Xin Fan
- The Affiliated Hospital of Jiangsu University, 212001, Zhenjiang, China
| | - Dongqing Wang
- The Affiliated Hospital of Jiangsu University, 212001, Zhenjiang, China.
| | - Fang Cheng
- The Affiliated Hospital of Jiangsu University, 212001, Zhenjiang, China.
- School of Pharmaceutical Sciences (Shenzhen), SYSU, 518107, Shenzhen, China.
- Faculty of Science and Engineering, ÅboAkademi University and Turku Centre for Biotechnology, FI-20520, Turku, Finland.
| | - Haitao Zhu
- The Affiliated Hospital of Jiangsu University, 212001, Zhenjiang, China.
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32
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Di X, He G, Chen H, Zhu C, Qin Q, Yan J, Zhang X, Sun X. High-mobility group box 1 protein modulated proliferation and radioresistance in esophageal squamous cell carcinoma. J Gastroenterol Hepatol 2019; 34:728-735. [PMID: 29968320 DOI: 10.1111/jgh.14371] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 06/14/2018] [Accepted: 06/23/2018] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND AIM The high-mobility group box 1 (HMGB1) protein plays an important role in a lot of biological behaviors, including DNA damage repair, gene transcription, cell replication, and cell death, and its expression is higher in many solid tumors tissues than in their adjacent normal tissues, and it is always involved in tumor proliferation, metastasis, therapeutic tolerance, and poor prognosis. However, HMGB1 in proliferation and radioresistance of esophageal squamous cell carcinoma (ESCC) remains poorly understood. In this study, the effect of HMGB1 on proliferation, cell death, DNA damage repair and radioresistance, and its underlying mechanism was investigated in human ESCC. METHODS The immunohistochemistry scores of tumor and adjacent normal tissues in ESCC tissue microarray were analyzed. Stable HMGB1 knockdown cell lines were constructed using Kyse150 and Kyse450 cells. Cell viability, radioresistance, apoptosis, autophagy, and DNA damage were determined using CCK-8, 5-ethynyl-2'-deoxyuridine, clonogenic survival assay, immunofluorescence, flow cytometry, and western blot assays. RESULTS Differential analyses showed that the expression of HMGB1 in esophageal cancer tissue was significantly higher than that in adjacent normal tissues. The downregulation of HMGB1 could effectively inhibit proliferation, increase radiosensitivity, impair DNA damage repair abilities, reduce autophagy, and increase apoptosis rates in ESCC cells after irradiation. CONCLUSIONS HMGB1 is expected to be a potential target for ESCC therapy and radiosensitization.
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Affiliation(s)
- Xiaoke Di
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guofeng He
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hui Chen
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Caiqiang Zhu
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qin Qin
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jingjing Yan
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaowen Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinchen Sun
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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van Dijk DP, Krill M, Farshidfar F, Li T, Rensen SS, Olde Damink SW, Dixon E, Sutherland FR, Ball CG, Mazurak VC, Baracos VE, Bathe OF. Host phenotype is associated with reduced survival independent of tumour biology in patients with colorectal liver metastases. J Cachexia Sarcopenia Muscle 2019; 10:123-130. [PMID: 30378742 PMCID: PMC6438330 DOI: 10.1002/jcsm.12358] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 08/24/2018] [Accepted: 09/13/2018] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Most prognostic scoring systems for colorectal liver metastases (CRLMs) account for factors related to tumour biology. Little is known about the effects of the host phenotype to the tumour. Our objective was to delineate the relationship of systemic inflammation and body composition features [i.e. low skeletal muscle mass (sarcopenia) and low visceral adipose tissue (VAT)], two well-described host phenotypes in cancer. METHODS Clinical data and pre-operative blood samples were collected from 99 patients who underwent resection of CRLM. Pre-operative computed tomography scans were available for 97 patients; body composition was analysed at the L3 level, stratified for sex and age. Clinicopathological variables, serum C-reactive protein (CRP), and various body composition variables were evaluated. Overall survival was evaluated as a function of these same variables in multivariate Cox regression analysis. RESULTS Skeletal muscle was significantly correlated with VAT (r = 0.46, P < 0.001). Of patients with sarcopenia, 35 (65%) also had low VAT. C-reactive protein was elevated (≥5 mg/mL) in 42 patients (43.3%). Elevated CRP was more common in patients with sarcopenia (73.8% vs. 51.1%, P = 0.029). The most significant prognostic factors were the coincidence of elevated CRP and adverse body composition features (sarcopenia and/or low VAT; hazard ratio 4.3, 95% confidence interval 1.5-13.0, P = 0.008), as well as Fong clinical prognostic score (hazard ratio 2.9, 95% confidence interval 1.5-5.5, P = 0.002). CONCLUSIONS Body composition in patients with CRLM is not directly linked to the presence of systemic inflammation. However, when systemic inflammation coincides with sarcopenia and/or low VAT, prognosis is adversely affected, independent of the Fong clinical prognostic score.
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Affiliation(s)
- David P.J. van Dijk
- Department of SurgeryMaastricht University Medical CentreMaastrichtThe Netherlands
- NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtThe Netherlands
| | - Matthew Krill
- Department of Surgery and Oncology, Tom Baker Cancer CentreUniversity of CalgaryCalgaryCanada
| | | | - Ting Li
- Department of Surgery and Oncology, Tom Baker Cancer CentreUniversity of CalgaryCalgaryCanada
| | - Sander S. Rensen
- Department of SurgeryMaastricht University Medical CentreMaastrichtThe Netherlands
- NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtThe Netherlands
| | - Steven W.M. Olde Damink
- Department of SurgeryMaastricht University Medical CentreMaastrichtThe Netherlands
- NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtThe Netherlands
- Department of General, Visceral and Transplantation SurgeryRWTH University Hospital AachenAachenGermany
- Institute for Liver and Digestive HealthUniversity College LondonLondonUK
| | - Elijah Dixon
- Department of Surgery and Oncology, Tom Baker Cancer CentreUniversity of CalgaryCalgaryCanada
| | - Francis R. Sutherland
- Department of Surgery and Oncology, Tom Baker Cancer CentreUniversity of CalgaryCalgaryCanada
| | - Chad G. Ball
- Department of Surgery and Oncology, Tom Baker Cancer CentreUniversity of CalgaryCalgaryCanada
| | - Vera C. Mazurak
- Division of Human Nutrition, Department of Agricultural, Food and Nutritional ScienceUniversity of AlbertaEdmontonCanada
| | | | - Oliver F. Bathe
- Department of Surgery and Oncology, Tom Baker Cancer CentreUniversity of CalgaryCalgaryCanada
- Arnie Charbonneau Cancer InstituteCalgaryCanada
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Qian F, Xiao J, Gai L, Zhu J. HMGB1-RAGE signaling facilitates Ras-dependent Yap1 expression to drive colorectal cancer stemness and development. Mol Carcinog 2018; 58:500-510. [PMID: 30456802 DOI: 10.1002/mc.22944] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 10/14/2018] [Accepted: 11/12/2018] [Indexed: 12/13/2022]
Abstract
HMGB1-RAGE signaling plays an integral role in inflammation-driven carcinogenesis. In the present study, we showed that RAGE has direct association with K-Ras following HMGB1 exposure in colorectal cancer (CRC) cells. Immunofluorescence analysis revealed a significant co-localization between RAGE and K-Ras in HMGB1-exposed CRC cells. Moreover, we uncovered that HMGB1-mediated RAGE activation led to Yap1 accumulation in a Ras-dependent mechanism in CRC cells. HMGB1 activated the expression of Yap1 downstream stemness marker proteins CD44 and Sox2 in RAGE- and Ras-dependent manners. Furthermore, HMGB1 exposure led to the proliferation of CRC cells and the expansion of CRC stem cells. RAGE, Yap1 and CD44 were overexpressed in CRC specimens. Linear regression analysis revealed that the expression of RAGE was positively correlated with Yap1 in clinical CRC specimens. Both of RAGE and Yap1 expression were correlated with advanced histological grades, lymph node metastasis and TNM stages. Finally, we revealed that both of RAGE and Yap1 expression could predicted unfavorable prognosis in CRC patients. These findings implicated that HMGB1-RAGE signaling may promote Yap1 activation and CRC progression, shedding new light on the mechanisms underlying inflammation-driven CRC development.
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Affiliation(s)
- Fei Qian
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Jianjia Xiao
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, China.,Department of Hepatobiliary surgery, Taizhou Hospital of Traditional Chinese Medicine, Taizhou, China
| | - Ling Gai
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, China
| | - Jianwei Zhu
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, China
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Englinger B, Pirker C, Heffeter P, Terenzi A, Kowol CR, Keppler BK, Berger W. Metal Drugs and the Anticancer Immune Response. Chem Rev 2018; 119:1519-1624. [DOI: 10.1021/acs.chemrev.8b00396] [Citation(s) in RCA: 174] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Bernhard Englinger
- Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
| | - Christine Pirker
- Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
| | - Petra Heffeter
- Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
- Research Cluster “Translational Cancer Therapy Research”, University of Vienna and Medical University of Vienna, Vienna, Austria
| | - Alessio Terenzi
- Research Cluster “Translational Cancer Therapy Research”, University of Vienna and Medical University of Vienna, Vienna, Austria
- Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria
| | - Christian R. Kowol
- Research Cluster “Translational Cancer Therapy Research”, University of Vienna and Medical University of Vienna, Vienna, Austria
- Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria
| | - Bernhard K. Keppler
- Research Cluster “Translational Cancer Therapy Research”, University of Vienna and Medical University of Vienna, Vienna, Austria
- Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria
| | - Walter Berger
- Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
- Research Cluster “Translational Cancer Therapy Research”, University of Vienna and Medical University of Vienna, Vienna, Austria
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HMGB1 promotes ERK-mediated mitochondrial Drp1 phosphorylation for chemoresistance through RAGE in colorectal cancer. Cell Death Dis 2018; 9:1004. [PMID: 30258050 PMCID: PMC6158296 DOI: 10.1038/s41419-018-1019-6] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 07/09/2018] [Accepted: 08/27/2018] [Indexed: 12/12/2022]
Abstract
Dysfunctional mitochondria have been shown to enhance cancer cell proliferation, reduce apoptosis, and increase chemoresistance. Chemoresistance develops in nearly all patients with colorectal cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. However, the effect of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission on chemoresistance in colorectal cancer is unclear. Here, we found that the release of high-mobility group box 1 protein (HMGB1) in conditioned medium from dying cells by chemotherapeutic drugs and resistant cells, which triggered Drp1 phosphorylation via its receptor for advanced glycation end product (RAGE). RAGE signals ERK1/2 activation to phosphorylate Drp1 at residue S616 triggerring autophagy for chemoresistance and regrowth in the surviving cancer cells. Abolishment of Drp1 phosphorylation by HMGB1 inhibitor and RAGE blocker significantly enhance sensitivity to the chemotherapeutic treatment by suppressing autophagy. Furthermore, patients with high phospho-Drp1Ser616 are associated with high risk on developing tumor relapse, poor 5-year disease-free survival (DFS) and 5-year overall survival (OS) after neoadjuvant chemoradiotherapy (neoCRT) treatment in locally advanced rectal cancer (LARC). Moreover, patients with RAGE-G82S polymorphism (rs2070600) are associated with high phospho-Drp1Ser616 within tumor microenvironment. These findings suggest that the release of HMGB1 from dying cancer cells enhances chemoresistance and regrowth via RAGE-mediated ERK/Drp1 phosphorylation.
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van Vloten JP, Workenhe ST, Wootton SK, Mossman KL, Bridle BW. Critical Interactions between Immunogenic Cancer Cell Death, Oncolytic Viruses, and the Immune System Define the Rational Design of Combination Immunotherapies. THE JOURNAL OF IMMUNOLOGY 2018; 200:450-458. [PMID: 29311387 DOI: 10.4049/jimmunol.1701021] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 08/23/2017] [Indexed: 12/13/2022]
Abstract
Oncolytic viruses (OVs) are multimodal cancer therapeutics, with one of their dominant mechanisms being in situ vaccination. There is a growing consensus that optimal cancer therapies should generate robust tumor-specific immune responses. Immunogenic cell death (ICD) is a paradigm of cellular demise culminating in the spatiotemporal release of danger-associated molecular patterns that induce potent anticancer immunity. Alongside traditional ICD inducers like anthracycline chemotherapeutics and radiation, OVs have emerged as novel members of this class of therapeutics. OVs replicate in cancers and release tumor Ags, which are perceived as dangerous because of simultaneous expression of pathogen-associated molecular patterns that activate APCs. Therefore, OVs provide the target Ags and danger signals required to induce adaptive immune responses. This review discusses why OVs are attractive candidates for generating ICD, biological barriers limiting their success in the clinic, and groundbreaking strategies to potentiate ICD and antitumor immunity with rationally designed OV-based combination therapies.
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Affiliation(s)
- Jacob P van Vloten
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada
| | - Samuel T Workenhe
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada.,McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario L8S 4L8, Canada; and.,Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4L8, Canada
| | - Sarah K Wootton
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada
| | - Karen L Mossman
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada.,McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario L8S 4L8, Canada; and.,Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4L8, Canada
| | - Byram W Bridle
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada;
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Huang M, Geng Y, Deng Q, Li R, Shao X, Zhang Z, Xu W, Wu Y, Ma Q. Translationally controlled tumor protein affects colorectal cancer metastasis through the high mobility group box 1-dependent pathway. Int J Oncol 2018; 53:1481-1492. [PMID: 30066846 PMCID: PMC6086624 DOI: 10.3892/ijo.2018.4502] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 06/06/2018] [Indexed: 12/14/2022] Open
Abstract
Recently, accumulating evidence from clinical and experimental researches have suggested that translationally controlled tumor protein (TCTP) and high mobility group box 1 (HMGB1) are implicated in colorectal cancer (CRC) metastasis. However, whether there is an interconnection between these two tumor-promoting proteins and how they affect CRC metastasis remain to be fully elucidated. In the present study, the expression level of TCTP in CRC tissues was assessed by immunohistochemical staining and immunoblotting, and the serum concentration of HMGB1 in patients with CRC was detected by enzyme-linked immunosorbent assay. In vitro, following the modulation of TCTP expression in colon cancer LoVo cells, the translocation behavior of HMGB1 was observed by immunofluorescence assay. Furthermore, the activity of nuclear factor-κB (NF-κB) in LoVo cells was evaluated by immunoblotting and luciferase assay, and the invasion ability of LoVo cells after different treatments was determined using cell invasion assay. In vivo, xenograft tumor model was established and the correlation of TCTP and HMGB1 expression in xenografted tumors was studied by immunohistochemical examination. The results revealed that the expression level of TCTP in CRC tissue and the serum concentration of HMGB1 in patients with CRC were significantly increased, and there was a strong positive correlation between them. In vitro experiments showed that the overexpression of TCTP on LoVo cells resulted in the release of HMGB1 from the nucleus to the cytoplasm and into the extracellular space. In addition, the overexpression of TCTP led to the activation of NF-κB in LoVo cells, and this effect was reversed by treatment with antibodies targeting HMGB1 or to its receptors Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products advanced glycation end products (RAGE). Furthermore, inhibition of the HMGB1-TLR4/RAGE-NF-κB pathway significantly inhibited the TCTP-stimulated invasion of LoVo cells. In vivo experiments demonstrated that the over-expression of TCTP in nude mice promoted the development and spread of xenografted tumors, and concurrently enhanced the expression of HMGB1 in tumor tissues. Collectively, these findings suggested that TCTP promotes CRC metastasis through regulating the behaviors of HMGB1 and the downstream activation of the NF-κB signaling pathway.
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Affiliation(s)
- Maoliang Huang
- Fuzhou Dingxiang Clinic, Fuzhou, Fujian 350028, P.R. China
| | - Yan Geng
- Department of Intensive Care Unit, 303 Hospital of Chinese People's Liberation Army, Nanning, Guanxi 530021, P.R. China
| | - Qiaoting Deng
- Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Ru Li
- Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Xiangyang Shao
- Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Zhigao Zhang
- Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Weiwen Xu
- Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yingsong Wu
- Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Qiang Ma
- Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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Razmi M, Rabbani-Chadegani A, Hashemi-Niasari F, Ghadam P. Lithium chloride attenuates mitomycin C induced necrotic cell death in MDA-MB-231 breast cancer cells via HMGB1 and Bax signaling. J Trace Elem Med Biol 2018; 48:87-96. [PMID: 29773200 DOI: 10.1016/j.jtemb.2018.03.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 02/19/2018] [Accepted: 03/12/2018] [Indexed: 12/14/2022]
Abstract
The clinical use of potent anticancer drug mitomycin C (MMC) has limited due to side effects and resistance of cancer cells. The aim of this study was to investigate whether lithium chloride (LiCl), as a mood stabilizer, can affect the sensitivity of MDA-MB-231 breast cancer cells to mitomycin C. The cells were exposed to various concentrations of mitomycin C alone and combined with LiCl and the viability determined by trypan blue and MTT assays. Proteins were analyzed by western blot and mRNA expression of HMGB1 MMP9 and Bcl-2 were analyzed by RT-PCR. Flow cytometry was used to determine the cell cycle arrest and percent of apoptotic and necrotic cells. Concentration of Bax assessed by ELISA. Exposure of the cells to mitomycin C revealed IC50 value of 20 μM, whereas pretreatment of the cells with LiCl induced synergistic cytotoxicity and IC50 value declined to 5 μM. LiCl combined with mitomycin C significantly down-regulated HMGB1, MMP9 and Bcl-2 gene expression but significantly increased the level of Bax protein. In addition, the content of HMGB1 in the nuclei decreased and pretreatment with LiCl reduced the content of HMGB1 release induced by MMC. LiCl increased mitomycin C-induced cell shrinkage and PARP fragmentation suggesting induction of apoptosis in these cells. LiCl prevented mitomycin C-induced necrosis and changed the cell death arrest at G2/M-phase. Taking all together, it is suggested that LiCl efficiently enhances mitomycin C-induced apoptosis and HMGB1, Bax and Bcl-2 expression may play a major role in this process, the findings that provide a new therapeutic strategy for LiCl in combination with mitomycin C.
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Affiliation(s)
- Mahdieh Razmi
- Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Azra Rabbani-Chadegani
- Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
| | - Fatemeh Hashemi-Niasari
- Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Parinaz Ghadam
- Department of Biotechnology, Faculty of Biological Science, University of Alzahra, Tehran, Iran
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Wang F, Li X, Huang L, Xu K. High-Mobility Group Protein Box 1 is Upregulated in Children with Henoch-Schonlein Purpura. PEDIATRIC ALLERGY, IMMUNOLOGY, AND PULMONOLOGY 2018. [DOI: 10.1089/ped.2018.0872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Fengying Wang
- Department of Nephrology and Rheumatology, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xiaozhong Li
- Department of Nephrology and Rheumatology, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Lusheng Huang
- Department of Pediatrics, Affiliated Taixing Hospital of Yangzhou University, Taixing, Jiangsu, China
| | - Kang Xu
- Department of Pediatrics, Affiliated Taixing Hospital of Yangzhou University, Taixing, Jiangsu, China
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Chen X, Zhang L, Jiang Y, Song L, Liu Y, Cheng F, Fan X, Cao X, Gong A, Wang D, Zhu H. Radiotherapy-induced cell death activates paracrine HMGB1-TLR2 signaling and accelerates pancreatic carcinoma metastasis. J Exp Clin Cancer Res 2018; 37:77. [PMID: 29615080 PMCID: PMC5883315 DOI: 10.1186/s13046-018-0726-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 03/06/2018] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Dying cells after irradiation could promote the repopulation of surviving cancer cells leading to tumor recurrence. We aim to define the role of dying cells in promoting pancreatic cancer cells metastasis following radiotherapy. METHODS Using the transwell system as the in vitro co-culture model, a small number of untreated pancreatic cancer cells were seeded in the upper chamber, while a larger number of lethally treated pancreatic cancer cells were seeded in the lower chamber. A series of experiments were conducted to investigate the role of dying-cell-derived HMGB1 on the invasion of pancreatic cancer in vitro and cancer metastasis in vivo. We then designed shRNA knockdown and Western blot assays to detect signaling activity. RESULTS We found that dying pancreatic cancer cells significantly promote the invasion of pancreatic cancer cells in vitro and cancer metastasis in vivo. HMGB1 gene knockdown attenuated the migration-stimulating effect of irradiated, dying cells on living pancreatic cancer cells. Finally, we showed that dying-cell-derived HMGB1 functions in a paracrine manner to affect cancer-cell migration dependent on acquiring an epithelial-mesenchymal transition (EMT) phenotype and PI3K/pAkt activation. This process is mediated by the receptor for TLR2. CONCLUSION Our study indicates that, during radiotherapy, dying pancreatic cancer cells activate paracrine signaling events that promote the mobility of surviving tumor cells. We suggest a strategy to inhibit HMGB1 for preventing pancreatic carcinoma relapse and metastasis.
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Affiliation(s)
- Xuelian Chen
- The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Lirong Zhang
- The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Yujie Jiang
- The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Lian Song
- The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Yanfang Liu
- The First People's Hospital of Zhenjiang, Zhenjiang, 212001, China
| | - Fang Cheng
- Faculty of Science and Engineering, Åbo Akademi University and Turku Centre for Biotechnology, -20520, Turku, FI, Finland
| | - Xin Fan
- The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Xiongfeng Cao
- The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Aihua Gong
- School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Dongqing Wang
- The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China.
- Department of Radiology, The Affiliated Hospital of Jiangsu University, Jiangsu University, 438 Jiefang Road, Zhenjiang, Jiangsu Province, 212013, China.
| | - Haitao Zhu
- The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China.
- Department of Radiology, The Affiliated Hospital of Jiangsu University, Jiangsu University, 438 Jiefang Road, Zhenjiang, Jiangsu Province, 212013, China.
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Chai Y, Xiao J, Zhang S, Du Y, Luo Z, Zhou X, Huang K. High-mobility group protein B1 silencing promotes susceptibility of retinoblastoma cells to chemotherapeutic drugs through downregulating nuclear factor-κB. Int J Mol Med 2018; 41:1651-1658. [PMID: 29328447 DOI: 10.3892/ijmm.2018.3379] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 12/13/2017] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to investigate the effects of high-mobility group protein B1 (HMGB1) silencing on the susceptibility of retinoblastoma (RB) cells to chemotherapeutic drugs and the underlying molecular mechanisms. Western blot analysis revealed that vincristine (VCR), etoposide (ETO) and carboplatin (CBP) significantly increased the expression of HMGB1 in Weri‑Rb-1 and Y79 cells compared with the untreated control (P<0.01). siRNA HMGB1 and siRNA negative control (NC) were transfected to Y79 cells by Lipofectamine™ 2000 and, following VCR treatment, the expression of HMGB1 and nuclear factor-κB (NF-κB) was analyzed. siRNA HMGB1 transfection silenced HMGB1 expression. The cytotoxicity of VCR to cells with and without siRNA HMGB1 was investigated by methyl thiazolyl tetrazolium (MTT) assay. siRNA HMGB1 markedly reduced the IC50 value of VCR to RB cells through downregulating the expression of NF-κB, similar to pyrrolidinedithiocarbamate (PDTC). Moreover, following siRNA HMGB1, siRNA NC and ammonium PDTC treatment, the apoptosis of RB cells with VCR incubation was evaluated by Hoechst staining, and the expression of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase (PARP), Beclin 1 and p62 were determined with western blot analysis. The LC3 puncta were determined with immunofluorescence assay. The results demonstrated that VCR treatment significantly downregulated the expression of cleaved caspase-3, cleaved PARP and p62, and upregulated the expression of Beclin 1 in RB cells (P<0.01). Similar to the NF-κB inhibitor PDTC, siRNA HMGB1 significantly promoted apoptosis and suppressed autophagy of VCR‑treated RB cells through reversing the effects of VCR on these signaling molecules (P<0.01). Therefore, HMGB1 silencing promoted the susceptibility of RB cells to chemotherapeutic drugs through downregulating NF-κB.
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Affiliation(s)
- Yong Chai
- Department of Ophthalmology, Jiangxi Children's Hospital, Nanchang, Jiangxi 330006, P.R. China
| | - Juhua Xiao
- Department of Ultrasound, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, P.R. China
| | - Shouhua Zhang
- Department of Ophthalmology, Jiangxi Children's Hospital, Nanchang, Jiangxi 330006, P.R. China
| | - Yunyan Du
- Department of Otolaryngology, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi 330006, P.R. China
| | - Zhipeng Luo
- Department of Gastrointestinal Surgery, Jiangxi Provincial Cancer Hospital, Nanchang, Jiangxi 330029, P.R. China
| | - Xin Zhou
- Department of Ultrasound, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, P.R. China
| | - Kai Huang
- Department of Gastrointestinal Surgery, Jiangxi Provincial Cancer Hospital, Nanchang, Jiangxi 330029, P.R. China
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Klee NS, McCarthy CG, Martinez-Quinones P, Webb RC. Out of the frying pan and into the fire: damage-associated molecular patterns and cardiovascular toxicity following cancer therapy. Ther Adv Cardiovasc Dis 2017; 11:297-317. [PMID: 28911261 PMCID: PMC5933669 DOI: 10.1177/1753944717729141] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 08/09/2017] [Indexed: 12/18/2022] Open
Abstract
Cardio-oncology is a new and rapidly expanding field that merges cancer and cardiovascular disease. Cardiovascular disease is an omnipresent side effect of cancer therapy; in fact, it is the second leading cause of death in cancer survivors after recurrent cancer. It has been well documented that many cancer chemotherapeutic agents cause cardiovascular toxicity. Nonetheless, the underlying cause of cancer therapy-induced cardiovascular toxicity is largely unknown. In this review, we discuss the potential role of damage-associated molecular patterns (DAMPs) as an underlying contributor to cancer therapy-induced cardiovascular toxicity. With an increasing number of cancer patients, as well as extended life expectancy, understanding the mechanisms underlying cancer therapy-induced cardiovascular disease is of the utmost importance to ensure that cancer is the only disease burden that cancer survivors have to endure.
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Affiliation(s)
- Nicole S. Klee
- Department of Physiology, Medical College of Georgia at Augusta University, 1120 15 Street, Augusta, GA 30912, USA
| | - Cameron G. McCarthy
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Patricia Martinez-Quinones
- Departments of Physiology and Surgery, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - R. Clinton Webb
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA, USA
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Koval O, Kochneva G, Tkachenko A, Troitskaya O, Sivolobova G, Grazhdantseva A, Nushtaeva A, Kuligina E, Richter V. Recombinant Vaccinia Viruses Coding Transgenes of Apoptosis-Inducing Proteins Enhance Apoptosis But Not Immunogenicity of Infected Tumor Cells. BIOMED RESEARCH INTERNATIONAL 2017; 2017:3620510. [PMID: 28951871 PMCID: PMC5603130 DOI: 10.1155/2017/3620510] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 07/17/2017] [Accepted: 07/26/2017] [Indexed: 12/16/2022]
Abstract
Genetic modifications of the oncolytic vaccinia virus (VV) improve selective tumor cell infection and death, as well as activation of antitumor immunity. We have engineered a double recombinant VV, coding human GM-CSF, and apoptosis-inducing protein apoptin (VV-GMCSF-Apo) for comparing with the earlier constructed double recombinant VV-GMCSF-Lact, coding another apoptosis-inducing protein, lactaptin, which activated different cell death pathways than apoptin. We showed that both these recombinant VVs more considerably activated a set of critical apoptosis markers in infected cells than the recombinant VV coding GM-CSF alone (VV-GMCSF-dGF): these were phosphatidylserine externalization, caspase-3 and caspase-7 activation, DNA fragmentation, and upregulation of proapoptotic protein BAX. However, only VV-GMCSF-Lact efficiently decreased the mitochondrial membrane potential of infected cancer cells. Investigating immunogenic cell death markers in cancer cells infected with recombinant VVs, we demonstrated that all tested recombinant VVs were efficient in calreticulin and HSP70 externalization, decrease of cellular HMGB1, and ATP secretion. The comparison of antitumor activity against advanced MDA-MB-231 tumor revealed that both recombinants VV-GMCSF-Lact and VV-GMCSF-Apo efficiently delay tumor growth. Our results demonstrate that the composition of GM-CSF and apoptosis-inducing proteins in the VV genome is very efficient tool for specific killing of cancer cells and for activation of antitumor immunity.
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Affiliation(s)
- Olga Koval
- Department of Biotechnology, Institute of Chemical Biology and Fundamental Medicine, SB RAS, Novosibirsk, Russia
- Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia
| | - Galina Kochneva
- Department of Viral Hepatitis, State Research Center of Virology and Biotechnology “Vector”, Rospotrebnadzor, Koltsovo, Russia
| | - Anastasiya Tkachenko
- Department of Biotechnology, Institute of Chemical Biology and Fundamental Medicine, SB RAS, Novosibirsk, Russia
| | - Olga Troitskaya
- Department of Biotechnology, Institute of Chemical Biology and Fundamental Medicine, SB RAS, Novosibirsk, Russia
- Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia
| | - Galina Sivolobova
- Department of Viral Hepatitis, State Research Center of Virology and Biotechnology “Vector”, Rospotrebnadzor, Koltsovo, Russia
| | - Antonina Grazhdantseva
- Department of Viral Hepatitis, State Research Center of Virology and Biotechnology “Vector”, Rospotrebnadzor, Koltsovo, Russia
| | - Anna Nushtaeva
- Department of Biotechnology, Institute of Chemical Biology and Fundamental Medicine, SB RAS, Novosibirsk, Russia
| | - Elena Kuligina
- Department of Biotechnology, Institute of Chemical Biology and Fundamental Medicine, SB RAS, Novosibirsk, Russia
| | - Vladimir Richter
- Department of Biotechnology, Institute of Chemical Biology and Fundamental Medicine, SB RAS, Novosibirsk, Russia
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Tanabe E, Kitayoshi M, Fujii K, Ohmori H, Luo Y, Kadochi Y, Mori S, Fujiwara R, Nishiguchi Y, Sasaki T, Kuniyasu H. Fatty acids inhibit anticancer effects of 5-fluorouracil in mouse cancer cell lines. Oncol Lett 2017; 14:681-686. [PMID: 28693221 PMCID: PMC5494753 DOI: 10.3892/ol.2017.6190] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 03/14/2017] [Indexed: 12/26/2022] Open
Abstract
The present study investigated the effects of two major dietary fatty acid components, linoleic acid (LA) and elaidic acid (EA), on the antitumor effects of 5-fluorouracil (5-FU) in the LL2, CT26 and CMT93 mouse cancer cell lines. Concurrent treatment with LA and 5-FU elicited a decreased cell viability compared with treatment with 5-FU alone. In addition, increased inhibition of growth was observed following concurrent treatment with EA and 5-FU. Sequential treatment of LA followed by 5-FU abrogated the anticancer effects of 5-FU, and treatment with EA followed by 5-FU increased cancer cell growth in addition to abrogating the anticancer effects of 5-FU. The expression of the stem cell markers CD133 and nucleostemin (NS) increased in all three cell lines treated concurrently with 5-FU and either LA or EA when compared with cells treated with 5-FU alone. Aldehyde dehydrogenase activity in the cancer stem cells (CSCs), in response to concurrent treatment with 5-FU and either LA or EA, was increased compared with 5-FU treatment alone. 5-FU inhibited the growth of CT26 tumors, but co-treatment with either LA or EA abrogated this effect. NS-positive CSCs were more abundant in CT26 tumors treated with 5-FU and either LA or EA compared with those treated with 5-FU alone. The results of the present study suggested that, rather than altering the sensitivity of cancer cells to 5-FU, LA and EA may promote the survival of CSCs. The results indicated that dietary composition during chemotherapy is an important issue.
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Affiliation(s)
- Eriko Tanabe
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Misaho Kitayoshi
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Kiyomu Fujii
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Hitoshi Ohmori
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Yi Luo
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Yui Kadochi
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Shiori Mori
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Rina Fujiwara
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Yukiko Nishiguchi
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Takamitsu Sasaki
- Department of Gastroenterological Surgery, Fukuoka University School of Medicine, Fukuoka 814-0133, Japan
| | - Hiroki Kuniyasu
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
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Amornsupak K, Jamjuntra P, Warnnissorn M, O-Charoenrat P, Sa-Nguanraksa D, Thuwajit P, Eccles SA, Thuwajit C. High ASMA + Fibroblasts and Low Cytoplasmic HMGB1 + Breast Cancer Cells Predict Poor Prognosis. Clin Breast Cancer 2017; 17:441-452.e2. [PMID: 28533055 DOI: 10.1016/j.clbc.2017.04.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 04/04/2017] [Accepted: 04/06/2017] [Indexed: 10/19/2022]
Abstract
INTRODUCTION The influence of cancer-associated fibroblasts (CAFs) and high mobility group box 1 (HMGB1) has been recognized in several cancers, although their roles in breast cancer are unclear. The present study aimed to determine the levels and prognostic significance of α-smooth muscle actin-positive (ASMA+) CAFs, plus HMGB1 and receptor for advanced glycation end products (RAGE) in cancer cells. MATERIALS AND METHODS A total of 127 breast samples, including 96 malignant and 31 benign, were examined for ASMA, HMGB1, and RAGE by immunohistochemistry. The χ2 test and Fisher's exact test were used to test the association of each protein with clinicopathologic parameters. The Kaplan-Meier method or log-rank test and Cox regression were used for survival analysis. RESULTS ASMA+ fibroblast infiltration was significantly increased in the tumor stroma compared with that in benign breast tissue. The levels of cytoplasmic HMGB1 and RAGE were significantly greater in the breast cancer tissue than in the benign breast tissues. High ASMA expression correlated significantly with large tumor size, clinical stage III-IV, and angiolymphatic and perinodal invasion. In contrast, increased cytoplasmic HMGB1 correlated significantly with small tumor size, pT stage, early clinical stage, luminal subtype (but not triple-negative subtype), and estrogen receptor and progesterone receptor expression. The levels of ASMA (hazard ratio, 14.162; P = .010) and tumor cytoplasmic HMGB1 (hazard ratio, 0.221; P = .005) could serve as independent prognostic markers for metastatic relapse in breast cancer patients. The ASMA-high/HMGB1-low profile provided the most reliable prediction of metastatic relapse. CONCLUSION We present for the first time, to the best of our knowledge, the potential clinical implications of the combined assessment of ASMA+ fibroblasts and cytoplasmic HMGB1 in breast cancer.
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Affiliation(s)
- Kamolporn Amornsupak
- Department of Immunology, Graduate Program in Immunology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pranisa Jamjuntra
- Department of Immunology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Malee Warnnissorn
- Department of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pornchai O-Charoenrat
- Division of Head, Neck and Breast Surgery, Department of Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Doonyapat Sa-Nguanraksa
- Division of Head, Neck and Breast Surgery, Department of Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Peti Thuwajit
- Department of Immunology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Suzanne A Eccles
- Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Sutton, United Kingdom
| | - Chanitra Thuwajit
- Department of Immunology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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Mokarram P, Albokashy M, Zarghooni M, Moosavi MA, Sepehri Z, Chen QM, Hudecki A, Sargazi A, Alizadeh J, Moghadam AR, Hashemi M, Movassagh H, Klonisch T, Owji AA, Łos MJ, Ghavami S. New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets. Autophagy 2017; 13:781-819. [PMID: 28358273 PMCID: PMC5446063 DOI: 10.1080/15548627.2017.1290751] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC), despite numerous therapeutic and screening attempts, still remains a major life-threatening malignancy. CRC etiology entails both genetic and environmental factors. Macroautophagy/autophagy and the unfolded protein response (UPR) are fundamental mechanisms involved in the regulation of cellular responses to environmental and genetic stresses. Both pathways are interconnected and regulate cellular responses to apoptotic stimuli. In this review, we address the epidemiology and risk factors of CRC, including genetic mutations leading to the occurrence of the disease. Next, we discuss mutations of genes related to autophagy and the UPR in CRC. Then, we discuss how autophagy and the UPR are involved in the regulation of CRC and how they associate with obesity and inflammatory responses in CRC. Finally, we provide perspectives for the modulation of autophagy and the UPR as new therapeutic options for CRC treatment.
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Affiliation(s)
- Pooneh Mokarram
- a Colorectal Research Center and Department of Biochemistry , School of Medicine, Shiraz University of Medical Sciences , Shiraz , Iran
| | - Mohammed Albokashy
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | - Maryam Zarghooni
- c Zabol University of Medical Sciences , Zabol , Iran.,d University of Toronto Alumni , Toronto , ON , Canada
| | - Mohammad Amin Moosavi
- e Department of Molecular Medicine , Institute of Medical Biotechnology, National Institute for Genetic Engineering and Biotechnology , Tehran , Iran
| | - Zahra Sepehri
- c Zabol University of Medical Sciences , Zabol , Iran
| | - Qi Min Chen
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | | | | | - Javad Alizadeh
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | - Adel Rezaei Moghadam
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | - Mohammad Hashemi
- g Department of Clinical Biochemistry , School of Medicine, Zahedan University of Medical Sciences , Zahedan , Iran
| | - Hesam Movassagh
- h Department of Immunology , Rady Faculty of Health Sciences, College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | - Thomas Klonisch
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | - Ali Akbar Owji
- i Department of Clinical Biochemistry , School of Medicine, Shiraz Medical University , Shiraz , Iran
| | - Marek J Łos
- j Małopolska Centre of Biotechnology , Jagiellonian University , Krakow , Poland ; LinkoCare Life Sciences AB , Sweden
| | - Saeid Ghavami
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada.,k Health Policy Research Center , Shiraz University of Medical Sciences , Shiraz , Iran
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Ugrinova I, Pasheva E. HMGB1 Protein: A Therapeutic Target Inside and Outside the Cell. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2016; 107:37-76. [PMID: 28215228 DOI: 10.1016/bs.apcsb.2016.10.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
High-mobility group box 1 protein (HMGB1) is a nonhistone chromosomal protein discovered more than 30 years ago. It is an abundant nuclear protein that has a dual function-in the nucleus, it binds DNA and participates in practically all DNA-dependent processes serving as an architectural factor. Outside the cell, HMGB1 plays a different role-it acts as an alarmine that activates a large number of HMGB1-"competent" cells and mediates a broad range of physiological and pathological responses. This universality makes it an attractive target for innovative therapeutic strategies in the treatment of various diseases. Here we present an overview of the major nuclear and extracellular properties of HMGB1 and describe its interaction with different molecular partners as specific receptors or inhibitors, which are important for its role as a target in multiple diseases. We highlight its pivotal role as a target for cancer treatment at two aspects: first in terms of its substantial impact on the repair capacity of cancer cells, thus affecting the effectiveness of chemotherapy with the antitumor drug cis-platinum and, second, the possibility to be targeted by microRNAs influencing different pathways of human diseases, thus making it a promising candidate for a new strategy for therapeutic interventions against various pathological conditions but mainly cancer.
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Affiliation(s)
- I Ugrinova
- "Roumen Tsanev" Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
| | - E Pasheva
- "Roumen Tsanev" Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, Bulgaria
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Zhang QB, Jia QA, Wang H, Hu CX, Sun D, Jiang RD, Zhang ZL. High-mobility group protein box1 expression correlates with peritumoral macrophage infiltration and unfavorable prognosis in patients with hepatocellular carcinoma and cirrhosis. BMC Cancer 2016; 16:880. [PMID: 27836008 PMCID: PMC5106788 DOI: 10.1186/s12885-016-2883-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Accepted: 10/25/2016] [Indexed: 12/12/2022] Open
Abstract
Background High-mobility group protein box1 (HMGB1) is a pivotal factor in the development and progression of many types of tumor. Its role in hepatocellular carcinoma (HCC), and especially its correlation with intratumoral and peritumoral macrophage infiltration, remains obscure. We analyzed the potential roles and prognostic value of HMGB1 and explored the correlation between HMGB1 and macrophage infiltration in HCC using clinical samples. Methods We reviewed clinicopathological and follow-up data on a cohort of 149 patients with HCC complicated with Hepatitis B-related cirrhosis. We measured the expression of HMGB1 and CD68 in tumoral and peritumoral liver tissues after curative resection and assessed the impacts of the tumor-associated macrophage (TAM) count and HMGB1 expression on clinicopathologic characteristics, overall survival (OS), and recurrence-free survival (RFS). Results Ninety-four of the patients had elevated tumoral HMGB1 expression and 59 of the patients had elevated peritumoral HMGB1 expression, compared to only 4 patients with elevated peritumoral HMGB1 expression in 36 pateints with Hepatitis B virus (HBV)-negative HCC without liver cirrhosis (p < 0.001). The peritumoral HMGB1 expression levels were correlated with tumor invasiveness, BCLC stage, and recurrence. The degree of TAM infiltration was higher in peritumoral tissues with high HMGB1 expression than in peritumoral tissues with low HMGB1 expression (p < 0.001). There was no significant difference in TAM infiltration between tumoral tissues with high and low HMGB1 expression. Kaplan-Meier analysis showed that intratumoral HMGB1 overexpression was associated with poor OS, but not with RFS. High peritumoral HMGB1expression and TAM count, which correlated positively with tumor size and BCLC stage, were independent prognostic factors for OS (p < 0.001 and p = 0.017, respectively) and RFS (p = 0.002 and p = 0.024, respectively). Multivariate analyses indicated peritumoral HMGB1 expression (p = 0.014) and TAM count (p = 0.037), as well as tumor differentiation (p = 0.026), to be independent significant prognostic factors for RFS. Conclusions High HMGB1 expression in peritumoral liver tissues correlated with peritumoral macrophage infiltration and had prognostic value in HCC, suggesting that peritumoral HMGB1 might show promise as a new biomarker to predict HCC progression. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2883-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Qiang-Bo Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan, 250012, China
| | - Qing-An Jia
- Cancer Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Hong Wang
- Department of Anesthesiology, Yidu Central Hospital, Weifang Medical University, Qingzhou, 262500, China
| | - Chun-Xiao Hu
- Department of General Surgery, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan, 250012, China
| | - Dong Sun
- Department of General Surgery, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan, 250012, China
| | - Run-De Jiang
- Department of General Surgery, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan, 250012, China.
| | - Zong-Li Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan, 250012, China.
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Zhang Y, Gao J, Wang X, Deng S, Ye H, Guan W, Wu M, Zhu S, Yu Y, Han W. CXCL4 mediates tumor regrowth after chemotherapy by suppression of antitumor immunity. Cancer Biol Ther 2016; 16:1775-83. [PMID: 26479470 DOI: 10.1080/15384047.2015.1095404] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
The recurrence of colorectal cancer after chemotherapy is the leading cause of its high mortality. We propose that elucidating the mechanisms of tumor regrowth after chemotherapy in tumor-bearing mice may provide new insights into tumor relapse in cancer patients. We firstly report the identification of a chemokine, CXCL4, that plays an important role in the molecular mechanism of cancer regrowth after chemotherapy. A syngenic transplantation tumor model was established with murine colon cancer CT26 cells and treated with 5-FU. Genome-wide gene expression analysis determined that CXCL4 was transiently upregulated in the tumor model. Systemic overexpression of CXCL4 accelerated cancer growth in vivo, but not in vitro. Conversely, the anti-CXCL4 monoclonal antibody (CXCL4-mab) retarded tumor-regrowth after 5-FU treatment in immune-competent mice, but not nude mice. The CXCL4-mab treatment increased the local expression levels of IFN-γ and Gran-b genes in the tumor-bed, and elevated the function of CTLs against CT26 cells. Thus, the colon cancer cells in responding to the cytotoxic stress of 5-FU produce a high level of CXCL4, which suppresses antitumor immunity to confer the residual cancer cells an advantage for regrowth after chemotherapy. Our findings provide a novel target for developing therapeutics aiming to increase antitumor immunity after chemotherapy.
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Affiliation(s)
- Yang Zhang
- a Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University ; Shanghai , PR China
| | - Jing Gao
- a Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University ; Shanghai , PR China
| | - Xia Wang
- a Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University ; Shanghai , PR China
| | - Shaorong Deng
- a Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University ; Shanghai , PR China
| | - Hao Ye
- a Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University ; Shanghai , PR China
| | - Wen Guan
- b Shanghai Municipality Key Laboratory of Veterinary Biotechnology; School of Agriculture and Biology; Shanghai Jiao Tong University ; Shanghai , PR China
| | - Mingyuan Wu
- a Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University ; Shanghai , PR China
| | - Shunying Zhu
- b Shanghai Municipality Key Laboratory of Veterinary Biotechnology; School of Agriculture and Biology; Shanghai Jiao Tong University ; Shanghai , PR China
| | - Yan Yu
- b Shanghai Municipality Key Laboratory of Veterinary Biotechnology; School of Agriculture and Biology; Shanghai Jiao Tong University ; Shanghai , PR China
| | - Wei Han
- a Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University ; Shanghai , PR China
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