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1
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Li H, Wang S, Yang Z, Meng X, Niu M. Nanomaterials modulate tumor-associated macrophages for the treatment of digestive system tumors. Bioact Mater 2024; 36:376-412. [PMID: 38544737 PMCID: PMC10965438 DOI: 10.1016/j.bioactmat.2024.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/25/2024] [Accepted: 03/03/2024] [Indexed: 11/25/2024] Open
Abstract
The treatment of digestive system tumors presents challenges, particularly in immunotherapy, owing to the advanced immune tolerance of the digestive system. Nanomaterials have emerged as a promising approach for addressing these challenges. They provide targeted drug delivery, enhanced permeability, high bioavailability, and low toxicity. Additionally, nanomaterials target immunosuppressive cells and reshape the tumor immune microenvironment (TIME). Among the various cells in the TIME, tumor-associated macrophages (TAMs) are the most abundant and play a crucial role in tumor progression. Therefore, investigating the modulation of TAMs by nanomaterials for the treatment of digestive system tumors is of great significance. Here, we present a comprehensive review of the utilization of nanomaterials to modulate TAMs for the treatment of gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer. We also investigated the underlying mechanisms by which nanomaterials modulate TAMs to treat tumors in the digestive system. Furthermore, this review summarizes the role of macrophage-derived nanomaterials in the treatment of digestive system tumors. Overall, this research offers valuable insights into the development of nanomaterials tailored for the treatment of digestive system tumors.
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Affiliation(s)
- Hao Li
- Department of Interventional Radiology, First Hospital of China Medical University, Shenyang, China
| | - Shuai Wang
- Department of Interventional Radiology, First Hospital of China Medical University, Shenyang, China
| | - Zhengqiang Yang
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xianwei Meng
- Laboratory of Controllable Preparation and Application of Nanomaterials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Meng Niu
- China Medical University, Shenyang, China
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2
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Yang H, Zhang Z, Zhou X, Binbr Abe Menen N, Rouhi O. Achieving enhanced sensitivity and accuracy in carcinoembryonic antigen (CEA) detection as an indicator of cancer monitoring using thionine/chitosan/graphene oxide nanocomposite-modified electrochemical immunosensor. ENVIRONMENTAL RESEARCH 2023; 238:117163. [PMID: 37722583 DOI: 10.1016/j.envres.2023.117163] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/09/2023] [Accepted: 09/15/2023] [Indexed: 09/20/2023]
Abstract
The current study has focused on electrochemical immunosensing of carcinoembryonic antigen (CEA) employing an immobilized antibody on a thionine, chitosan, or graphene oxide nanocomposite modified glassy carbon electrode (anti-CEA/THi-CS-GO/GCE) as an indicator of cancer monitoring. THi-CS-GO nanocomposites were made using ultrasonication, and analyses of their morphology and crystal structure using SEM, FTIR, and XRD showed that thionine and chitosan molecules were intercalated with stacking interactions with both the top and bottom of GO nanosheets. Electrochemical experiments revealed anti-CEA, THi-CS-GO/GCE to have exceptional sensitivity and selectivity towards CEA compounds. The detection limit value was established to be 0.8 pg/mL when it was discovered that variations in the decrease peak current were directly proportional to the logarithm concentration of CEA over a wide range from 10-3 to 104 ng/mL. Results of testing the immunosensor's application capability for detecting CEA in a sample of human serum show that ELISA and DPV results are very congruent. The produced immunosensor demonstrated adequate immunosensor precision in determining CEA in prepared genuine samples of human serum and clinical applications.
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Affiliation(s)
- Hongli Yang
- Department of Science and Education, General Hospital of Panzhihua Steel Group, Panzhihua, 617000, Sichuan, China
| | - Zaihua Zhang
- General Surgery Department, Panzhihua Group General Hospital, Panzhihua, 617000, Sichuan, China
| | - Xiaohong Zhou
- Oncology hematology Department, Fengdu County People's Hospital of Chongqing, Chongqing, 400000, China.
| | | | - Omid Rouhi
- Department of Chemistry, Qaemshahr Branch, Islamic Azad University, Qaemshahr, Iran.
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3
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Choi EL, Taheri N, Chandra A, Hayashi Y. Cellular Senescence, Inflammation, and Cancer in the Gastrointestinal Tract. Int J Mol Sci 2023; 24:9810. [PMID: 37372958 PMCID: PMC10298598 DOI: 10.3390/ijms24129810] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/05/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Due to modern medical advancements, greater proportions of the population will continue to age with longer life spans. Increased life span, however, does not always correlate with improved health span, and may result in an increase in aging-related diseases and disorders. These diseases are often attributed to cellular senescence, in which cells become disengaged from the cell cycle and inert to cell death. These cells are characterized by a proinflammatory secretome. The proinflammatory senescence-associated secretory phenotype, although part of a natural function intended to prevent further DNA damage, creates a microenvironment suited to tumor progression. This microenvironment is most evident in the gastrointestinal tract (GI), where a combination of bacterial infections, senescent cells, and inflammatory proteins can lead to oncogenesis. Thus, it is important to find potential senescence biomarkers as targets of novel therapies for GI diseases and disorders including cancers. However, finding therapeutic targets in the GI microenvironment to reduce the risk of GI tumor onset may also be of value. This review summarizes the effects of cellular senescence on GI aging, inflammation, and cancers, and aims to improve our understanding of these processes with a goal of enhancing future therapy.
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Affiliation(s)
- Egan L. Choi
- Graduate Research Education Program (Choi), Mayo Clinic, Rochester, MN 55905, USA;
| | - Negar Taheri
- Department of Physiology and Biomedical Engineering (Taheri, Chandra and Hayashi), Mayo Clinic, Rochester, MN 55905, USA; (N.T.); (A.C.)
- Division of Gastroenterology and Hepatology (Taheri and Hayashi), Mayo Clinic, Rochester, MN 55905, USA
| | - Abhishek Chandra
- Department of Physiology and Biomedical Engineering (Taheri, Chandra and Hayashi), Mayo Clinic, Rochester, MN 55905, USA; (N.T.); (A.C.)
- Robert and Arlene Kogod Center on Aging (Chandra), Mayo Clinic, Rochester, MN 55905, USA
| | - Yujiro Hayashi
- Department of Physiology and Biomedical Engineering (Taheri, Chandra and Hayashi), Mayo Clinic, Rochester, MN 55905, USA; (N.T.); (A.C.)
- Division of Gastroenterology and Hepatology (Taheri and Hayashi), Mayo Clinic, Rochester, MN 55905, USA
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4
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Fang Y, Yan C, Zhao Q, Zhao B, Liao Y, Chen Y, Wang D, Tang D. The Association Between Gut Microbiota, Toll-Like Receptors, and Colorectal Cancer. Clin Med Insights Oncol 2022; 16:11795549221130549. [PMID: 36338264 PMCID: PMC9634190 DOI: 10.1177/11795549221130549] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 09/16/2022] [Indexed: 11/05/2022] Open
Abstract
The large number of microbes found in the gut are involved in various critical biological processes in the human body and have dynamic and complex interactions with the immune system. Disruptions in the host's gut microbiota and the metabolites produced during fermentation promote the development of intestinal inflammation and colorectal cancer (CRC). Toll-like receptors (TLRs) recognize specific microbial-associated molecular patterns specific to microorganisms whose signaling is involved in maintaining intestinal homeostasis or, under certain conditions, mediating dysbiosis-associated intestinal inflammation. The signaling pathways of TLRs are described first, followed by a discussion of the interrelationship between gut microbes and TLRs, including the activation of TLRs by gut microbes and the effect of TLRs on the distribution of gut microbiota, particularly the role of microbes in colorectal carcinogenesis via TLRs. Finally, we discuss the potential roles of various TLRs in colorectal cancer.
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Affiliation(s)
- Yongkun Fang
- Department of General Surgery,
Institute of General Surgery, Northern Jiangsu People’s Hospital, Clinical Medical
College, Yangzhou University, Yangzhou, China
| | - Cheng Yan
- Department of Clinical Medical College,
Dalian Medical University, Dalian, China
- The People’s Hospital Of QianNan,
Duyun, China
| | - Qi Zhao
- Department of Clinical Medicine,
Clinical Medical College, Yangzhou University, Yangzhou, China
- Changshu No.2 People’s Hospital,
Suzhou, China
| | - Bin Zhao
- Department of Clinical Medical College,
Dalian Medical University, Dalian, China
| | - Yiqun Liao
- Department of Clinical Medical College,
Dalian Medical University, Dalian, China
| | - Yuji Chen
- Department of Clinical Medicine,
Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Daorong Wang
- Department of General Surgery,
Institute of General Surgery, Northern Jiangsu People’s Hospital, Clinical Medical
College, Yangzhou University, Yangzhou, China
| | - Dong Tang
- Department of General Surgery,
Institute of General Surgery, Northern Jiangsu People’s Hospital, Clinical Medical
College, Yangzhou University, Yangzhou, China
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5
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Khare VM, Saxena VK, Pasternak MA, Nyinawabera A, Singh KB, Ashby CR, Tiwari AK, Tang Y. The expression profiles of chemokines, innate immune and apoptotic genes in tumors caused by Rous Sarcoma Virus (RSV-A) in chickens. Genes Immun 2021; 23:12-22. [PMID: 34934184 DOI: 10.1038/s41435-021-00158-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/18/2021] [Accepted: 12/07/2021] [Indexed: 11/09/2022]
Abstract
Innate immune genes play an important role in the immune responses to Rous sarcoma virus (RSV)-induced tumor formation and metastasis. Here, we determined in vivo expression of chemokines, innate immune and apoptotic genes in Synthetic Broiler Dam Line (SDL) chickens following RSV-A infection. The mRNA expression of genes was determined at the primary site of infection and in different organs of progressor, regressor and non-responder chicks, using RT-qPCR. Our results indicated a significant upregulation of: (1) chemokines, such as MIP1β and RANTES, (2) the innate immune gene TLR4, and (3) p53, a tumor-suppressor gene, at the site of primary infection in progressor chickens. In contrast, inducible nitric oxide synthase (iNOS) gene expression was significantly downregulated in progressor chicks compared to uninfected, control chicks. All of the innate immune genes were significantly upregulated in the lungs and liver of the progressor and regressor chicks compared to control chicks. In the spleen of progressor chicks, RANTES, iNOS and p53 gene expression were significantly increased, whereas MIP1β and TLR4 gene expression was significantly downregulated, compared to control chicks. The lungs and livers of non-responder chicks expressed a low level of iNOS and MIP1β, whereas RANTES, TLR4, and p53 gene expression were significantly upregulated compared to uninfected control chicks. In addition, there was a significant downregulation of RANTES, MIP1β, and TLR4 gene expression in non-responder chicks. These results suggest the different response to infection of chicks with RSV-A is due to differential changes in the expression of innate immune genes in different organs.
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Affiliation(s)
- Vishwa M Khare
- Eurofins Lancaster Laboratories, Philadelphia, PA, 19104, USA. .,Disease Genetics and Biotechnology Lab, CARI, Izatnagar, UP, 243 122, India.
| | - Vishesh K Saxena
- Disease Genetics and Biotechnology Lab, CARI, Izatnagar, UP, 243 122, India
| | - Mariah A Pasternak
- Department of Pharmacology and Experimental Therapeutics, The University of Toledo, Toledo, OH, 43614, USA
| | - Angelique Nyinawabera
- Department of Pharmacology and Experimental Therapeutics, The University of Toledo, Toledo, OH, 43614, USA
| | - Kunwar B Singh
- Animal Science Department, Rohilkhand University, Bareilly, UP, India
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, St. John's University, Queens, USA
| | - Amit K Tiwari
- Department of Pharmacology and Experimental Therapeutics, The University of Toledo, Toledo, OH, 43614, USA.
| | - Yuan Tang
- Department of Bioengineering, The University of Toledo, Toledo, OH, 43614, USA.
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6
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Beilmann-Lehtonen I, Hagström J, Mustonen H, Koskensalo S, Haglund C, Böckelman C. High Tissue TLR5 Expression Predicts Better Outcomes in Colorectal Cancer Patients. Oncology 2021; 99:589-600. [PMID: 34139707 DOI: 10.1159/000516543] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 04/13/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Colorectal cancer (CRC), the third most common cancer globally, caused 881,000 cancer deaths in 2018. Toll-like receptors (TLRs), the primary sensors of pathogen-associated molecular patterns and damage-associated molecular patterns, activate innate and adaptive immune systems and participate in the development of an inflammatory tumor microenvironment. We aimed to explore the prognostic value of TLR3, TLR5, TLR7, and TLR9 tissue expressions in CRC patients. METHODS Using immunohistochemistry, we analyzed tissue microarray samples from 825 CRC patients who underwent surgery between 1982 and 2002 at the Department of Surgery, Helsinki University Hospital, Finland. After analyzing a pilot series of 205 tissue samples, we included only TLR5 and TLR7 in the remainder of the patient series. We evaluated the associations between TLR5 and TLR7 tissue expressions, clinicopathologic variables, and survival. Using the Kaplan-Meier method, we generated survival curves, determining significance using the log-rank test. Univariate and multivariate survival analyses relied on the Cox proportional hazards model. RESULTS The 5-year disease-specific survival was 55.9% among TLR5-negative (95% confidence interval [CI] 50.6-61.2%) and 61.9% (95% CI 56.6-67.2%; p = 0.011, log-rank test) among TLR5-positive patients. In the Cox multivariate survival analysis adjusted for age, sex, stage, location, and grade, positive TLR5 immunoexpression (hazard ratio [HR] 0.74; 95% CI 0.59-0.92; p = 0.007) served as an independent positive prognostic factor. TLR7 immunoexpression exhibited no prognostic value in the survival analysis across the entire cohort (HR 0.97; 95% CI 0.78-1.20; p = 0.754) nor in subgroup analyses. CONCLUSIONS We show for the first time that a high TLR5 tumor tissue expression associates with a better prognosis in CRC patients.
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Affiliation(s)
- Ines Beilmann-Lehtonen
- Department of Transplantation and Liver Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jaana Hagström
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Department of Oral Pathology and Radiology, University of Turku, Turku, Finland
| | - Harri Mustonen
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Selja Koskensalo
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Caj Haglund
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Camilla Böckelman
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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7
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Manz SM, Losa M, Fritsch R, Scharl M. Efficacy and side effects of immune checkpoint inhibitors in the treatment of colorectal cancer. Therap Adv Gastroenterol 2021; 14:17562848211002018. [PMID: 33948110 PMCID: PMC8053828 DOI: 10.1177/17562848211002018] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 02/17/2021] [Indexed: 02/04/2023] Open
Abstract
Colorectal cancers (CRCs) remain one of the most common and challenging neoplasia in the Western world. The response rate of immunotherapeutic treatment approaches in a subset of advanced CRCs is remarkable and has sustainably changed treatment regimens. Unfortunately, currently available immunotherapeutics only displayed significant antitumoral activity - in terms of progression free survival (PFS) and objective response rate (ORR) - in microsatellite instability-high (MSI-H)/DNA mismatch repair deficient (dMMR) CRCs. Subsequently, these remarkable results had led to the US Food and Drug Administration's approval of both immune checkpoint inhibitors (ICIs) pembrolizumab and nivolumab in the treatment of advanced MSI-H/dMMR CRCs. However, in microsatellite stable (MSS)/DNA mismatch repair proficient (pMMR) CRCs, ICIs have clearly failed to meet their expectations and are therefore not considered effective. As the vast majority of CRCs display a molecular MSS/pMMR profile, current treatment approaches endeavor to improve tumor immunogenicity that consecutively leads to increased proinflammatory cytokine levels as well as tumor infiltrating T-cells, which in turn may be targeted by various immunotherapeutic agents. Therefore, ongoing studies are investigating novel synergistic therapy modalities and approaches to overcome a "cold" to "hot" tumor conversion in MSS/pMMR CRCs. In this review, we summarize the efficacy and possible immune-related adverse events as well as novel therapeutic approaches of ICIs in the treatment of MSI-H/dMMR and MSS/pMMR CRCs.
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Affiliation(s)
- Salomon M. Manz
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Marco Losa
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Ralph Fritsch
- Center for Medical Oncology and Hematology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland
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8
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Almquist DR, Ahn DH, Bekaii-Saab TS. The Role of Immune Checkpoint Inhibitors in Colorectal Adenocarcinoma. BioDrugs 2021; 34:349-362. [PMID: 32246441 DOI: 10.1007/s40259-020-00420-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Over the past decade, immune checkpoint inhibitors (ICI) have proven to be promising agents in a number of solid tumor malignancies. Pembrolizumab and nivolumab are ICIs that target programmed cell death protein 1 and both have been approved by the US Food and Drug Administration for the treatment of microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) colorectal cancer (CRC). In MSI-H/dMMR CRC, these agents were found to have considerable antitumor activity and are now used in the treatment of this disease. However, MSI-H/dMMR tumors account for only 5% of metastatic CRC and the remaining patients are identified as being microsatellite stable/DNA mismatch repair proficient (MSS/pMMR). In MSS/pMMR CRC, ICIs were found to have no antitumor activity and they are not currently used in the treatment of the disease. However, ongoing research is expanding our knowledge of how the human immune system interacts with cancer cells. Identifying mechanisms to improve our immune response to MSS/pMMR CRC is of utmost importance. In this review, we discuss available clinical data and the emerging role of immune-based strategies to overcome the resistance to ICI therapy in the treatment of MSS/pMMR CRC.
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Affiliation(s)
- Daniel R Almquist
- Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Mayo Clinic Hospital, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA
| | - Daniel H Ahn
- Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Mayo Clinic Hospital, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA
| | - Tanios S Bekaii-Saab
- Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Mayo Clinic Hospital, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA.
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9
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Rezasoltani S, Ghanbari R, Looha MA, Mojarad EN, Yadegar A, Stewart D, Aghdaei HA, Zali MR. Expression of Main Toll-Like Receptors in Patients with Different Types of Colorectal Polyps and Their Relationship with Gut Microbiota. Int J Mol Sci 2020; 21:8968. [PMID: 33255933 PMCID: PMC7729598 DOI: 10.3390/ijms21238968] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 11/23/2020] [Accepted: 11/23/2020] [Indexed: 12/14/2022] Open
Abstract
Abnormal activation of Toll-like receptor (TLRs) signaling can result in colon cancer development. The aim of this study was to investigate the expression of important TLRs in different histological types of colorectal polyps and evaluate their relationship with intestinal microbiota. The expression levels of TLR2, 3, 4, and 5 were analyzed in intestinal biopsy specimens of 21 hyperplastic polyp (HP), 16 sessile serrated adenoma (SSA), 29 tubular adenoma (TA), 21 villous/tubulovillous (VP/TVP) cases, and 31 normal controls. In addition, selected gut bacteria including Streptococcus bovis, Enterococcus faecalis, Enterotoxigenic Bacteroides fragilis (ETBF), Fusobacterium nucleatum, Porphyromonas spp., Lactobacillus spp., Roseburia spp., and Bifidobacterium spp. were quantified in fecal samples using absolute qRT PCR, and, finally, the association between TLRs and these gut microbiota- was evaluated by Spearman's correlation coefficient. Higher expression of TLR2 and TLR4 in VP/TVP and TA, and lower expression levels of TLR3 and TLR5 in all type of polyps were observed. The differences in TLR expression patterns was not only dependent on the histology, location, size, and dysplasia grade of polyps but also related to the intestinal microbiota patterns. TLR2 and TLR4 expression was directly associated with the F. nucleatum, E. faecalis, S. bovis, Porphyromonas, and inversely to Bifidobacterium, Lactobacillus, and Roseburia quantity. Furthermore, TLR3 and TLR5 expression was directly associated with Bifidobacterium, Roseburia, and Lactobacillus quantity. Our results suggest a possible critical role of TLRs during colorectal polyp progression. An abnormal regulation of TLRs in relation to gut microbial quantity may contribute to carcinogenesis.
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Affiliation(s)
- Sama Rezasoltani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717411, Iran; (S.R.); (M.A.L.)
| | - Reza Ghanbari
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran 1411713135, Iran;
| | - Mehdi Azizmohammad Looha
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717411, Iran; (S.R.); (M.A.L.)
| | - Ehsan Nazemalhosseini Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717411, Iran; (E.N.M.); (M.R.Z.)
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717411, Iran;
| | - Delisha Stewart
- Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USA
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717411, Iran; (S.R.); (M.A.L.)
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717411, Iran; (E.N.M.); (M.R.Z.)
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10
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Yoshida T, Miura T, Matsumiya T, Yoshida H, Morohashi H, Sakamoto Y, Kurose A, Imaizumi T, Hakamada K. Toll-Like Receptor 3 as a Recurrence Risk Factor and a Potential Molecular Therapeutic Target in Colorectal Cancer. Clin Exp Gastroenterol 2020; 13:427-438. [PMID: 33061521 PMCID: PMC7537813 DOI: 10.2147/ceg.s252157] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 09/02/2020] [Indexed: 12/21/2022] Open
Abstract
Purpose Colorectal cancer (CRC) often recurs after curative resection. Identification of major risk factors for CRC recurrence is important for effective prevention and treatment. In this study, we examined the potential relationship between CRC and TLR3 as this remains unclear. Patients and Methods Correlations between TLR3 immunostaining and clinicopathological factors and prognosis were examined in 50 samples that were randomly extracted from 264 patients with CRC from January 2010 to December 2011. Chemokines induced by TLR3 agonist stimulation were also examined using TLR3-positive human CRC cell lines. Furthermore, the association between TLR3 and chemokine expression was assessed by analyzing the immunohistochemistry of surgical specimens. Results Of the 50 patients, 14 (28%) were TLR3-negative. In the comparison of clinicopathological factors between the TLR3-negative and -positive groups, there were more lymph node metastasis-positive cases in the TLR3-negative group, and this difference was significant. Furthermore, there was no difference in overall survival rates between the two groups, but the 5-year recurrence-free survival (RFS) was significantly lower in the TLR3-negative group (46.2%) than in the TLR3-positive group (78.1%). Analysis of 5-year RFS using factors thought to be related to recurrence identified a high tumor budding and a TLR3-negative status as independent risk factors for recurrence. TLR3 activation of CRC cell lines induced expression of C-C motif chemokine ligand 2 (CCL2), C-C motif chemokine ligand 5 (CCL5), and interleukin-8. The expressions of CCL2, CCL5, and IL-8 were observed in the TLR3-positive tumor cells of surgical specimens. Conclusion Non-expression of TLR3 in CRC cells was associated with lymph node metastasis and was an independent risk factor for recurrence. These results suggest that TLR3 may not only be used as a prognostic factor and a risk factor for recurrence, but further studies on the involvement of TLR3 with tumor growth may provide new therapeutic strategies.
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Affiliation(s)
- Tatsuya Yoshida
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Takuya Miura
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Tomoh Matsumiya
- Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Hidemi Yoshida
- Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Hajime Morohashi
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Yoshiyuki Sakamoto
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Akira Kurose
- Department of Anatomic Pathology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Tadaatsu Imaizumi
- Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Kenichi Hakamada
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
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11
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Luo Q, Zeng L, Tang C, Zhang Z, Chen Y, Zeng C. TLR9 induces colitis-associated colorectal carcinogenesis by regulating NF-κB expression levels. Oncol Lett 2020; 20:110. [PMID: 32863923 PMCID: PMC7448563 DOI: 10.3892/ol.2020.11971] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 07/08/2020] [Indexed: 12/19/2022] Open
Abstract
Chronic colorectal inflammation has been associated with colorectal cancer (CRC); however, its exact molecular mechanisms remain unclear. The present study aimed to investigate the effect of Toll-like receptor 9 (TLR9) on the development of colitis-associated CRC (CAC) through its regulation of the NF-κB signaling pathway. By using a CAC mouse model and immunohistochemistry, the present study discovered that the protein expression levels of TLR9 were gradually upregulated during the development of CRC. In addition, the expression levels of TLR9 were revealed to be positively correlated with NF-κB and Ki67 expression levels. In vitro, inhibiting TLR9 expression levels using chloroquine decreased the cell viability, proliferation and migration of the CRC cell line HT29, and further experiments indicated that this may occur through downregulating the expression levels of NF-κB, proliferating cell nuclear antigen and Bcl-xl. In conclusion, the findings of the present study suggested that TLR9 may serve an important role in the development of CAC by regulating NF-κB signaling.
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Affiliation(s)
- Qingtian Luo
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.,Department of Gastroenterology, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, Jiangxi 341000, P.R. China
| | - Ling Zeng
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Chaotao Tang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhendong Zhang
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Youxiang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Chunyan Zeng
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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12
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Jiang N, Xie F, Chen L, Chen F, Sui L. The effect of TLR4 on the growth and local inflammatory microenvironment of HPV-related cervical cancer in vivo. Infect Agent Cancer 2020; 15:12. [PMID: 32095158 PMCID: PMC7027303 DOI: 10.1186/s13027-020-0279-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 02/04/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Cervical cancer is the most common malignancy of the female lower genital tract. In our previous study, we found that TLR4 promotes cervical cancer cell growth in vitro. The aim of this study was to further explore the role of TLR4 in HPV-related cervical cancer in vivo by using a nude mouse xenograft model. METHODS Cervical cancer-derived HeLa and CaSki cells (5 × 107/mL) were either stimulated with an optimal concentration of LPS for the appropriate time (HeLa cells were treated with 1 μg/mL LPS for 1 h, and CaSki cells were treated with 2 μg/mL LPS for 1.5 h) or transfected with TLR4 shRNA and then injected subcutaneously into the dorsal right posterior side of nude mice. The shortest width and longest diameter of the transplanted tumors in the nude mice were measured every 3 days.TLR4, IL-6,iNOS, IL-8,COX-2, MIP-3α, TGF-β1 and VEGF expression levels in the transplanted tumor tissue were detected by immunohistochemistry. RESULTS The tumor formation rate was 100% in both HeLa and CaSki nude mouse groups. The tumors grew faster, and the cachexia symptoms were more serious in the LPS groups than in the control group. In contrast, the tumors grew slower, and the cachexia symptoms were milder in the TLR4-silenced groups. TLR4, iNOS, IL-6, MIP-3α and VEGF were highly expressed in the transplanted tumor tissues from the LPS groups, and their expression levels were decreased in the TLR4-silenced groups. CONCLUSION TLR4 expression is closely associated with the tumorigenesis and growth of HPV-positive cervical cancer; TLR4 promotes HPV-positive cervical tumor growth and facilitates the formation of a local immunosuppressive microenvironment. Eventually, these conditions may lead to cervical cancer development.
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Affiliation(s)
- Ninghong Jiang
- Medical center for diagnosis and treatment of cervical disease, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011 China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011 China
| | - Feng Xie
- Medical center for diagnosis and treatment of cervical disease, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011 China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011 China
| | - Limei Chen
- Medical center for diagnosis and treatment of cervical disease, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011 China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011 China
| | - Fang Chen
- Medical center for diagnosis and treatment of cervical disease, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011 China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011 China
| | - Long Sui
- Medical center for diagnosis and treatment of cervical disease, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011 China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011 China
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13
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Pandey NO, Chauhan AV, Raithatha NS, Patel PK, Khandelwal R, Desai AN, Choxi Y, Kapadia RS, Jain ND. Association of TLR4 and TLR9 polymorphisms and haplotypes with cervical cancer susceptibility. Sci Rep 2019; 9:9729. [PMID: 31278284 PMCID: PMC6611874 DOI: 10.1038/s41598-019-46077-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 06/21/2019] [Indexed: 12/13/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) in TLR genes may serve as a crucial marker for early susceptibility of various cancers including cervical cancer. The present study was therefore designed to ascertain the role of TLR4 and TLR9 SNPs and haplotypes to hrHPV infection and cervical cancer susceptibility. The study included 110 cervical cancer biopsies and 141 cervical smears from age-matched healthy controls of Gujarati ethnicity of Western India. hrHPV 16 and 18 were detected using Real-time PCR. Eight SNPs, four each in TLR4 and TLR9 were analyzed using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism and Allele-Specific PCR. HPV 16 and 18 were detected in 68% cervical cancer cases. TLR4 rs4986790, rs1927911 and TLR9 rs187084 showed association with HPV 16/18 infection. CC and CT genotypes of TLR4 rs11536889 and rs1927911 respectively, and TC, CC genotypes of TLR9 rs187084, as well as minor alleles of TLR4 rs4986790 and TLR9 rs187084, were associated with the increased risk of cervical cancer. Stage-wise analysis revealed TLR9 rs187084 and rs352140 to be associated with early-stage cancer. TLR4 haplotype GTAC and TLR9 haplotype GATC were associated with the increased risk of cervical cancer while TLR4 haplotype GCAG was associated with the decreased risk. TLR4 haplotype GCAG and TLR9 haplotype GATC showed association with increased susceptibility to hrHPV infection. In conclusion, the present study revealed association of TLR4 and TLR9 polymorphisms and haplotypes with hrHPV infection and cervical cancer risk. Further evaluation of a larger sample size covering diverse ethnic populations globally is warranted.
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Affiliation(s)
- Nilesh O Pandey
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology (CHARUSAT), Changa, Anand, India
| | - Alex V Chauhan
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology (CHARUSAT), Changa, Anand, India
| | - Nitin S Raithatha
- Department of Obstetrics and Gynaecology, Pramukh Swami Medical College, Shree Krishna Hospital, Karamsad, Anand, India
| | - Purvi K Patel
- Department of Obstetrics and Gynaecology, Sir Sayajirao General Hospital and Medical College, Vadodara, India
| | - Ronak Khandelwal
- Department of Obstetrics and Gynaecology, Sir Sayajirao General Hospital and Medical College, Vadodara, India
| | - Ajesh N Desai
- Department of Obstetrics & Gynaecology, GMERS Medical College and Hospital, Ahmedabad, India
| | - Yesha Choxi
- Department of Obstetrics & Gynaecology, GMERS Medical College and Hospital, Ahmedabad, India
| | - Rutul S Kapadia
- Department of Obstetrics & Gynaecology, GMERS Medical College and Hospital, Ahmedabad, India
| | - Neeraj D Jain
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology (CHARUSAT), Changa, Anand, India.
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14
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Gao C, Qiao T, Zhang B, Yuan S, Zhuang X, Luo Y. TLR9 signaling activation at different stages in colorectal cancer and NF-kappaB expression. Onco Targets Ther 2018; 11:5963-5971. [PMID: 30271180 PMCID: PMC6151094 DOI: 10.2147/ott.s174274] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background The relationship of inflammation and tumor is becoming more and more important in the study on the pathogenesis of colorectal cancer. The role of TLR9-mediated immune inflammation reaction in the process is not currently clear. The purpose of the study was to discuss the correlation of TLR9 signal activation with tumor progression by detecting the expression of TLR9 and its downstream molecule NF-kappaB in colorectal cancer tissues at different stages. Methods TLR9 expression in colorectal cancer tissues was detected by immunohistochemical streptavidin-perosidase method and Western blot. Results The result showed that the high expression of TLR9 was correlated with tumor poorly differentiation, invasion and liver metastasis, the abnomal increasing levels of CEA in blood. With the signal activation, the levels of TLR9 protein raised more in advanced colorectal cancer than in early colorectal cancer. Afterward, we found that the activation of specific expression of TLR9 signal was related to histologic origin. TLR9-C expression displayed in both advanced cancer and para-carcinoma tissues, and TLR9-R protein was predominat in partial sigmoid and rectal cancer tissues. With the differential expression of TLR9, the levels of its downstream molecule NF-kappaB protein increased in colon cancer tissues and decreased in rectal cancer tissues. Conclusion The results confirmed that TLR9 signaling activation participated in the clinical process of colorectal cancer and influenced NF-kappaB expression.
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Affiliation(s)
- Caixia Gao
- Department of Oncology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China,
| | - Tiankui Qiao
- Department of Oncology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China,
| | - Bin Zhang
- Department of Oncology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China,
| | - Sujuan Yuan
- Department of Oncology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China,
| | - Xibing Zhuang
- Department of Oncology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China,
| | - Youjun Luo
- Department of Oncology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China,
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15
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Zhang X, Wu F, Men K, Huang R, Zhou B, Zhang R, Zou R, Yang L. Modified Fe 3O 4 Magnetic Nanoparticle Delivery of CpG Inhibits Tumor Growth and Spontaneous Pulmonary Metastases to Enhance Immunotherapy. NANOSCALE RESEARCH LETTERS 2018; 13:240. [PMID: 30120629 PMCID: PMC6097979 DOI: 10.1186/s11671-018-2661-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 08/06/2018] [Indexed: 02/07/2023]
Abstract
As a novel toll-like receptor 9 (TLR9) agonist, synthetic unmethylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotides can stimulate a Th1 immune response and potentially be used as therapeutic agents or vaccine adjuvants for the treatment of cancer. However, some drawbacks of CpG limit their applications, such as rapid elimination by nuclease-mediated degradation and poor cellular uptake. Therefore, repeat high-dose drug administration is required for treatment. In this work, a CpG delivery system based on 3-aminopropyltriethoxysilane (APTES)-modified Fe3O4 nanoparticles (FeNPs) was designed and studied for the first time to achieve better bioactivity of CpG. In our results, we designed FeNP-delivered CpG particles (FeNP/CpG) with a small average size of approximately 50 nm by loading CpG into FeNPs. The FeNP/CpG particle delivery system, with enhanced cell uptake of CpG in bone marrow-derived dendritic cells (BMDCs) in vitro and through intratumoral injection, showed significant antitumor ability by stimulating better humoral and cellular immune responses in C26 colon cancer and 4T1 breast cancer xenograft models in vivo over those of free CpG. Moreover, mice treated by FeNP/CpG particles had delayed tumor growth with an inhibitory rate as high as 94.4%. In addition, approximately 50% of the tumors in the C26 model appeared to regress completely. Similarly, there were lower pulmonary metastases and a 69% tumor inhibitory rate in the 4T1 breast cancer tumor model than those in the untreated controls. In addition to their effectiveness, the easy preparation, safety, and high stability of FeNP/CpG particles also make them an attractive antitumor immunotherapy.
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Affiliation(s)
- Xueyan Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fengbo Wu
- Department of Pharmacy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Ke Men
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Rong Huang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bailin Zhou
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Rui Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Rui Zou
- China West Normal University, No.1 Shi Da Road, Nanchong, 637002, China
| | - Li Yang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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16
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Moradi-Marjaneh R, Hassanian SM, Fiuji H, Soleimanpour S, Ferns GA, Avan A, Khazaei M. Toll like receptor signaling pathway as a potential therapeutic target in colorectal cancer. J Cell Physiol 2018; 233:5613-5622. [PMID: 29150944 DOI: 10.1002/jcp.26273] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Accepted: 11/06/2017] [Indexed: 12/14/2022]
Abstract
Toll like receptor (TLR) signaling is involved in activating innate and adaptive immune responses and plays a critical role in inflammation-induced diseases such as colorectal cancer (CRC). Dysregulation of this signaling pathway can result in disturbance of epithelial layer hemostasis, chronic inflammatory, excessive repair responses, and development of CRC. There is now substantial evidence for the benefit of targeting of this pathway in cancer treatment, and several agents have been approved, such as BCG (Bacillus Calmette Guérin), MPL (monophosphoryl lipid A) and imiquimod. This review summarizes the current knowledge about the different functions of TLRs on tumor cells and their application in cancer therapy with particular emphasis on recent preclinical and clinical research in treatment of CRC.
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Affiliation(s)
- Reyhaneh Moradi-Marjaneh
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Microanatomy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Fiuji
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saman Soleimanpour
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, United Kingdom
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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17
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Abstract
Over the past few years, the role of immunotherapy in colorectal cancer (CRC) has expanded, specifically in subsets of CRC with microsatellite instability (MSI) for which newer agents, such as programmed death-1 (PD-1) inhibitors, are efficacious. While other immunotherapeutic agents are more immature in development, they have the potential to enhance the efficacy of PD-1 inhibitors and play a role in the treatment algorithm for all subsets of CRC patients. In this review, we will discuss immunotherapeutic agents in development in patients with CRC. We will review the later phase studies that elucidate the role of immunotherapy in CRC and provide hope for changing the treatment paradigm for CRC in the future.
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Affiliation(s)
- Sukeshi Patel Arora
- University of Texas Health Science Center San Antonio, 7979 Wurzbach Rd, MC8026, San Antonio, TX 78229, USA
| | - Devalingam Mahalingam
- University of Texas Health Science Center San Antonio, 7979 Wurzbach Rd, MC8026, San Antonio, TX 78229, USA
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18
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The role of TLRs in cervical cancer with HPV infection: a review. Signal Transduct Target Ther 2017; 2:17055. [PMID: 29263932 PMCID: PMC5668671 DOI: 10.1038/sigtrans.2017.55] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 06/20/2017] [Accepted: 07/17/2017] [Indexed: 01/01/2023] Open
Abstract
The main cause of cervical cancer is persistent infection with high-risk human papilloma virus (HR-HPV), but not all human papilloma virus (HPV) infections lead to cervical cancer. The key factors that determine the outcome of HPV infection remain poorly understood, and how the host immune system protects against HPV infection is unclear. Toll-like receptors (TLRs) are a group of pattern recognition receptors present in the cytoplasm and cell membrane, and can specifically recognize pathogen-associated molecular patterns. As the key molecules of innate and acquired immunity, TLRs not only play important roles in the immune defense against infectious diseases, but also are involved in the occurrence and development of a variety of malignant tumors. In cervical cancer caused by HR-HPV infection, TLRs have been found to regulate the local immune microenvironment. The role of TLRs in HR-HPV infection and HPV-induced cervical cancer and its relationship with HPV vaccine are reviewed in this article.
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19
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Eiró N, González LO, Cid S, Andicoechea A, Vizoso FJ. Matrix metalloproteases expression in different histological types of colorectal polyps. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2017; 109:414-420. [PMID: 28376625 DOI: 10.17235/reed.2017.4551/2016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
INTRODUCTION Colorectal carcinoma (CC) may begin as benign polyps, which may be classified in different histological types with a different risk to develop cancer. Matrix metalloproteases (MMPs) are able to degrade all components in the extracellular matrix and are important tissue-remodeling enzymes and key elements in tumor invasion and metastasis. The aim of this study was to investigate the expression and clinical relevance of MMPs in different histological types of colorectal polyps. METHODS The expression levels of MMP-1, 2, 7, 9, 11, 13 and 14 were analyzed by real-time PCR, Western-blot and immunohistochemistry in 50 patients with different histological types of colorectal polyps, 28 of which developed CC. RESULTS The results indicate that hyperplastic polyps had the lowest levels of MMP-1 and MMP-7, tubular polyps showed higher levels of both MMP-7 and MMP-14, and tubulovillous adenoma showed higher levels of MMP-1, MMP-7 and MMP-14. CONCLUSION MMP expression was decreased in hyperplastic, tubular and tubulovillous adenoma polyps from patients who developed CC. Our findings suggest that MMP expression may be a pathological marker of colorectal polyps and for cancer susceptibility, which may improve strategies for CC prevention based on screening colonoscopy.
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Affiliation(s)
- Noemi Eiró
- Unidad de Investigación, Fundación Hospital de Jove
| | - Luis O González
- Unidad de Investigación y Servicio de Anatomía Pat, Fundación Hospital de Jove
| | - Sandra Cid
- Unidad de Investigación, Fundación Hospital de Jove
| | | | - Francisco J Vizoso
- Unidad de Investigación y Servicio de Cirugía Gene, Fundación Hospital de Jove, España
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20
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Kotredes KP, Thomas B, Gamero AM. The Protective Role of Type I Interferons in the Gastrointestinal Tract. Front Immunol 2017; 8:410. [PMID: 28428788 PMCID: PMC5382159 DOI: 10.3389/fimmu.2017.00410] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 03/22/2017] [Indexed: 12/18/2022] Open
Abstract
The immune system of the gastrointestinal (GI) tract manages the significant task of recognizing and eliminating pathogens while maintaining tolerance of commensal bacteria. Dysregulation of this delicate balance can be detrimental, resulting in severe inflammation, intestinal injury, and cancer. Therefore, mechanisms to relay important signals regulating cell growth and immune reactivity must be in place to support GI homeostasis. Type I interferons (IFN-I) are a family of pleiotropic cytokines, which exert a wide range of biological effects including promotion of both pro- and anti-inflammatory activities. Using animal models of colitis, investigations into the regulation of intestinal epithelium inflammation highlight the role of IFN-I signaling during fine modulation of the immune system. The intestinal epithelium of the gut guides the immune system to differentiate between commensal and pathogenic microbiota, which relies on intimate links with the IFN-I signal-transduction pathway. The current paradigm depicts an IFN-I-induced antiproliferative state in the intestinal epithelium enabling cell differentiation, cell maturation, and proper intestinal barrier function, strongly supporting its role in maintaining baseline immune activity and clearance of damaged epithelia or pathogens. In this review, we will highlight the importance of IFN-I in intestinal homeostasis by discussing its function in inflammation, immunity, and cancer.
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Affiliation(s)
- Kevin P Kotredes
- Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, PA, USA
| | - Brianna Thomas
- Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, PA, USA
| | - Ana M Gamero
- Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, PA, USA
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21
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Lynch D, Murphy A. The emerging role of immunotherapy in colorectal cancer. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:305. [PMID: 27668225 DOI: 10.21037/atm.2016.08.29] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Modulation of the interaction between the immune system and the tumor microenvironment has long been a target of cancer research, including colorectal cancer (CRC). Approaches explored to date include vaccines (autologous, peptide, dendritic cell, viral and bacterial), cytokine therapy, toll-like receptors (TLRs), autologous cell therapy and checkpoint inhibition. Until recently these approaches have been shown to have only modest efficacy in reducing tumor burden. However, significant breakthroughs have been made, with the use of checkpoint inhibitors targeting programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4). Immunotherapy now represents a possible avenue of curative treatment for those with chemo-otherwise refractory tumors. Success with this approach to immunotherapy has largely been confined to tumors with high mutational burdens such as melanoma, renal cell carcinoma (RCC) and non-small cell lung cancer. This observation led to the exploration and successful use of checkpoint inhibitors in those with mismatch repair colorectal cancer which have a relatively high mutational burden. Ongoing trials are focused on further exploring the use of checkpoint inhibitors in addition to investigating the various combinations of immunotherapeutic drugs.
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Affiliation(s)
- David Lynch
- Department of Internal Medicine, University of North Carolina Hospitals, Chapel Hill, North Carolina, USA
| | - Adrian Murphy
- Department Medical Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
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22
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Pierzchalska M, Grabacka M. The potential role of some phytochemicals in recognition of mitochondrial damage-associated molecular patterns. Mitochondrion 2016; 30:24-34. [PMID: 27288721 DOI: 10.1016/j.mito.2016.06.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 06/05/2016] [Accepted: 06/07/2016] [Indexed: 02/07/2023]
Abstract
Mitochondria are the source of damage-associated molecular patterns (DAMPs). DAMPs modulate responses to stress and trauma in animals, influencing the onset of many diseases. Dietary phytochemicals, which target various cellular molecules, are potential modulators of immunological status. In this review the existence of the possible impact of some plant-derived compounds with proven anti-cancer and anti-inflammatory properties (isothiocyanates and curcumin) on DAMPs recognition is highlighted. Special consideration is given to the mtDNA recognizing Toll-like receptor 9 and formyl peptide receptors. In the context of the phytochemicals action, the role of these receptors in epithelial homeostasis is also discussed.
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Affiliation(s)
- Malgorzata Pierzchalska
- Department of Food Biotechnology, Faculty of Food Technology, The University of Agriculture in Kraków, Poland.
| | - Maja Grabacka
- Department of Food Biotechnology, Faculty of Food Technology, The University of Agriculture in Kraków, Poland
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23
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Jiang J, Dong L, Qin B, Shi H, Guo X, Wang Y. Decreased expression of TLR7 in gastric cancer tissues and the effects of TLR7 activation on gastric cancer cells. Oncol Lett 2016; 12:631-636. [PMID: 27347192 DOI: 10.3892/ol.2016.4617] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Accepted: 01/26/2016] [Indexed: 12/30/2022] Open
Abstract
The present study aimed to determine the expression of Toll-like receptor 7 (TLR7) in gastric cancer tissues and investigate the effects of its activation on gastric cancer cells. Patients with gastric cancer (n=30) and patients without gastric cancer (control; n=14) who underwent gastroscopy were enrolled in the study. Gastric cancer and cancer-adjacent tissues were obtained from the patients with gastric cancer, and normal gastric epithelial tissues were obtained from the control patients. The TLR7 mRNA and protein expressions in different tissues were investigated by reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemistry. The present study also determined the effects of TLR7 activation by the agonist imiquimod on TLR7 protein expression, proinflammatory cytokine secretion and viability in SGC-7901 gastric cancer cells. The mRNA and protein expression levels of TLR7 were significantly downregulated in gastric cancer tissues compared with cancer-adjacent and normal gastric epithelial tissues (P<0.01). Imiquimod significantly increased TLR7 protein expression levels, and promoted the secretion of proinflammatory cytokines tumor necrosis factor-α and interleukin-6 in SGC-7901 cells. Furthermore, imiquimod inhibited the proliferation of SGC-7901 cells in a dose- and time-dependent manner. Thus, the present study identified that the expression of TLR7 was decreased in gastric cancer tissues, and TLR7 activation enhanced TLR7 expression, promoted the production of proinflammatory cytokines and inhibited the growth of gastric cancer cells.
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Affiliation(s)
- Jiong Jiang
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi 710003, P.R. China
| | - Lei Dong
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi 710003, P.R. China
| | - Bin Qin
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi 710003, P.R. China
| | - Haitao Shi
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi 710003, P.R. China
| | - Xiaoyan Guo
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi 710003, P.R. China
| | - Yan Wang
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi 710003, P.R. China
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Santhanam S, Alvarado DM, Ciorba MA. Therapeutic targeting of inflammation and tryptophan metabolism in colon and gastrointestinal cancer. Transl Res 2016; 167:67-79. [PMID: 26297050 PMCID: PMC4684437 DOI: 10.1016/j.trsl.2015.07.003] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 07/14/2015] [Accepted: 07/23/2015] [Indexed: 12/19/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer death in the United States. Cytotoxic therapies cause significant adverse effects for most patients and do not offer cure in many advanced cases of CRC. Immunotherapy is a promising new approach to harness the body's own immune system and inflammatory response to attack and clear the cancer. Tryptophan metabolism along the kynurenine pathway (KP) is a particularly promising target for immunotherapy. Indoleamine 2,3-dioxygenase 1 (IDO1) is the most well studied of the enzymes that initiate this pathway and it is commonly overexpressed in CRC. Herein, we provide an in-depth review of how tryptophan metabolism and KP metabolites shape factors important to CRC pathogenesis including the host mucosal immune system, pivotal transcriptional pathways of neoplastic growth, and luminal microbiota. This pathway's role in other gastrointestinal (GI) malignancies such as gastric, pancreatic, esophageal, and GI stromal tumors is also discussed. Finally, we highlight how currently available small molecule inhibitors and emerging methods for therapeutic targeting of IDO1 might be applied to colon, rectal, and colitis-associated cancer.
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Affiliation(s)
- Srikanth Santhanam
- Division of Gastroenterology, Washington University School of Medicine, Saint Louis, Mo
| | - David M Alvarado
- Division of Gastroenterology, Washington University School of Medicine, Saint Louis, Mo
| | - Matthew A Ciorba
- Division of Gastroenterology, Washington University School of Medicine, Saint Louis, Mo.
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Li TT, Ogino S, Qian ZR. Toll-like receptor signaling in colorectal cancer: Carcinogenesis to cancer therapy. World J Gastroenterol 2014; 20:17699-17708. [PMID: 25548469 PMCID: PMC4273121 DOI: 10.3748/wjg.v20.i47.17699] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 08/27/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins, and signal expression of major histocompatibility complex proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These protein receptors are characterized by their ability to respond to invading pathogens promptly by recognizing particular TLR ligands, including flagellin and lipopolysaccharide of bacteria, nucleic acids derived from viruses, and zymosan of fungi. There are 2 major TLR pathways; one is mediated by myeloid differentiation factor 88 (MYD88) adaptor proteins, and the other is independent of MYD88. The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1) and all the TLRs, except TLR3, have been shown to activate this pathway. TLR3 and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling. TLRs play a vital role in activating immune responses. TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis, and are highly likely to be involved in the activation of a number of pathways following cancer therapy. Colorectal cancer (CRC) is one of the most common cancers, and accounts for almost half a million deaths annually worldwide. Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum. The key molecules involved in inflammation-driven carcinogenesis include TLRs. As sensors of cell death and tissue remodeling, TLRs may have a universal role in cancer; stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years. TLRs 3/4/7/8/9 are all validated targets for cancer therapy, and a number of companies are developing agonists and vaccine adjuvants. On the other hand, antagonists may favor inhibition of signaling responsible for autoimmune responses. In this paper, we review TLR signaling in CRC from carcinogenesis to cancer therapy.
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MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: from bench to bedside. Crit Rev Oncol Hematol 2014; 94:31-44. [PMID: 25577571 DOI: 10.1016/j.critrevonc.2014.12.002] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 11/06/2014] [Accepted: 12/09/2014] [Indexed: 02/06/2023] Open
Abstract
The adaptive immune system has been the main focus of immunological strategies in oncology with only more recent approaches targeting innate immunity. Endosomal toll-like receptors (TLR-7, TLR-9) activate innate immune responses by signaling damage-associated molecular patterns (DAMP) from decaying tumor cells. This has led to the development of DNA-based TLR-9 agonists, which induce antitumor activity through innate and subsequent adaptive immune responses. Early clinical trials with CpG-ODN as TLR-9 agonists were associated with unfavorable tolerability and narrow clinical efficacy, leading to failure in pivotal trials. dSLIM, the active ingredient of MGN1703, is a DNA-based, radically different molecular alternative to CpG-ODN, which results in genuine antitumor immunomodulation. Preclinical and clinical studies of MGN1703 have confirmed that this TLR-9 agonist has therapeutic potential in a variety of solid tumors, while long-term treatment with high doses was very well tolerated. A pivotal trial of first-line maintenance treatment with MGN1703 in patients with metastatic colorectal cancer is underway.
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Chang LC, Fan CW, Tseng WK, Chein HP, Hsieh TY, Chen JR, Hwang CC, Hua CC. IFNAR1 is a predictor for overall survival in colorectal cancer and its mRNA expression correlated with IRF7 but not TLR9. Medicine (Baltimore) 2014; 93:e349. [PMID: 25546690 PMCID: PMC4602595 DOI: 10.1097/md.0000000000000349] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Toll-like receptor (TLR) 9 plays a role in intestinal inflammation that, in turn, is related to the tumorigenesis of colorectal cancer. Nuclear factor κB (NFκB), and interferon regulatory factor (IRF) 5 and IRF7 can be activated by TLR9 and induce the production of proinflammatory cytokines and type I interferon, respectively. This study investigated the mRNA expressions of TLR9 and its downstream signaling molecules in both the tumor and the normal tissues of colorectal cancer. Eighty-four subjects with colorectal cancer were consecutively recruited at a community-based hospital, and the mRNA expression of TLR9, NFκB, IRF5, IRF7, interleukin 6 (IL6), and interferon α/β/ω receptor 1 (IFNAR1) in the tumor and normal tissue were determined by real-time reverse transcription polymerase chain reaction using TaqMan FAM-labeled MGB probes (Life Technologies, Carlsbad, CA). The tumor had higher percentages of detection of TLR9, IFNAR1, and IL6 mRNA expressions than normal tissue. The absence of detectable TLR9 mRNA expression was associated with an absence of significance in the correlation between IL6 and NFκB or IRF5, but not that between IRF7 and IFNAR1 in both the tumor and the normal tissues. An absence of detectable IFNAR1 mRNA expression in the tumor (hazard ratio: 3.77; 95% confidence interval: 1.22-11.60) and advanced stage (stages III and IV, 7.86; 1.76-35.40) were significant predictors for overall survival. IFNAR1 is a predictor for overall survival and mRNA expression is correlated to IRF7, but not TLR9 in colorectal cancer. The results cast doubt on the usefulness of TLR9 agonist in treating colorectal cancer.
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Affiliation(s)
- Liang-Che Chang
- From the Department of Pathology (L-CC, T-YH, H-PC, J-RC, C-CH); Division of Colon and Rectal Surgery (C-WF, W-KT); and Department of Internal Medicine (C-CH), Chang Gung Memorial Hospital, Keelung, and Chang Gung University, Taoyuan, Taiwan
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Eiró N, Altadill A, Juárez LM, Rodríguez M, González LO, Atienza S, Bermúdez S, Fernandez-Garcia B, Fresno-Forcelledo MF, Rodrigo L, Vizoso FJ. Toll-like receptors 3, 4 and 9 in hepatocellular carcinoma: Relationship with clinicopathological characteristics and prognosis. Hepatol Res 2014; 44:769-78. [PMID: 23742263 DOI: 10.1111/hepr.12180] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2012] [Revised: 05/03/2013] [Accepted: 05/29/2013] [Indexed: 12/12/2022]
Abstract
AIM Hepatocellular carcinoma (HCC) is in the 10 leading cancer types, being difficult to detect as most of patients who develop this tumor have no symptoms other than those related to their long-standing liver disease. The liver is constantly exposed to bacterial products, viral infection, alcohol or other products, which may be the cause of chronic liver damage, and thus an increasing risk for HCC. Toll-like receptors (TLR) have gained an extraordinary interest in cancer research due to their role in several biological processes such as innate immune responses, the induction of adaptive immune responses, regulation of inflammation, would healing and carcinogenesis. Therefore, the aim of this study was to investigate the expression and clinical relevance of TLR3, 4 and 9 in HCC. METHODS The expression levels of TLR3, TLR4 and TLR9 were analyzed in tumors from 30 patients with HCC. The analysis was performed by immunohistochemistry. Results were correlated with various clinicopathological findings and with overall survival. RESULTS TLR3 was significantly high in large tumors (>4 cm in diameter) compared with small tumors (P < 0.05). Our results demonstrated that patients whose tumors showed both TLR4 and TLR9 positive immunostaining had poor prognosis. In addition, TLR9 expression by fibroblast-like cells was significantly associated with a shortened overall survival (P = 0.015). CONCLUSION The results demonstrated an association between TLR3, TLR4 and TLR9 expression and tumor aggressiveness and poor prognosis in HCC.
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Affiliation(s)
- Noemí Eiró
- Research Unit, Foundation Hospital of Jove, Gijón, Spain
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Tchórzewski M, Lewkowicz P, Dziki A, Tchórzewski H. Expression of toll-like receptors on human rectal adenocarcinoma cells. Arch Immunol Ther Exp (Warsz) 2014; 62:247-51. [PMID: 24390484 PMCID: PMC4024133 DOI: 10.1007/s00005-013-0260-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2013] [Accepted: 10/28/2013] [Indexed: 12/16/2022]
Abstract
The innate immune system uses Toll-like receptors (TLR) to detect the presence of pathogen patterns thus allowing for rapid host defense responses. Stimulation of TLR results in inflammatory response and regulatory cytokine production affecting acquired immunity. The aim of the study was an evaluation of TLR2 and TLR4 expression on the surface of human colon cancer cells in primary culture with or without autologous peripheral blood mononuclear cells. Surgical specimens of colon cancer were processed to obtain cancer cells. Cancer cells separation was conducted first by mechanical tissue disintegration and than by gradient centrifugation to obtain 95 % cell confluence. By staining the isolated cells the pathologist determined them as adenocarcinoma. Colon cancer cells were then co-cultured in 24 h culture alone or together with autologous lymphocytes. Reverse-transcription polymerase chain reaction was performed for detection of TLR2 and TLR4 mRNA in colon cancer and normal colon epithelial cells using commercially available primers. Resting as well as phytohemagglutinin or lipopolysaccharide (LPS) stimulated cells were tested. Receptor proteins on cancer cells were examined by immunohistochemistry. TLR4 mRNA was detected in cancer cells. Autologous lymphocytes do not exert any effect on these receptors expression. TLR4 mRNA expression was not observed in normal colon epithelial cells. TLR2 mRNA was present on LPS stimulated cancer cells as well as on resting and stimulated lymphocytes. Expression of TLR2 and TLR4 receptor proteins on colon cancer cells were confirmed by immunohistochemistry. TLR4 may be responsible for uncontrolled tumor growth under LPS stimulation in human colon environment.
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Affiliation(s)
- Marcin Tchórzewski
- Department of General and Colorectal Surgery, Medical University of Lodz, Lodz, Poland,
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Zhang HT, Zhao XZ, Sun H, Li K. Endoscopic and pathological features of colorectal polyps and risk factors for their malignant transformation. Shijie Huaren Xiaohua Zazhi 2013; 21:2886-2889. [DOI: 10.11569/wcjd.v21.i27.2886] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To summarize the endoscopic and pathological characteristics of colorectal polyps and to analyze risk factors for their malignant transformation.
METHODS: A total of 406 patients with colorectal polyps treated at our hospital were included in this study. The endoscopic and pathological characteristics of colorectal polyps (including age, size, shape, location, and pathological type) were explored and risk factors for their malignant transformation were analyzed.
RESULTS: The elderly group was associated with the highest incidence of colorectal polyps, followed by the middle-aged group and young group. Colorectal polyps were most commonly seen in the sigmoid colon and rectum, and ileocecal polyps were relatively rarely seen. Polyps with a diameter ≤ 1 cm were most commonly seen, and most of them were hyperplastic polyps. Polyps with a diameter of 1-2 cm were mostly adenomas. Polyps with a diameter > 2 cm were mostly juvenile polyps. Non-lobulated colorectal polyps were more commonly seen. Lobulated polyps were mostly adenomatous, while non-lobulated ones were mostly proliferative. The rate of malignant transformation was significantly higher in the elderly group than in the young and middle-aged groups (χ2 = 10.317, P < 0.05). Malignant transformation was more commonly seen in the ileocecal junction, rectum, sigmoid colon than in other locations (χ2 = 5.787, P < 0.05). With the increase in polyp diameter, the probability of malignant transformation increased. The probability of malignant transformation was more commonly seen in adenomas than in other pathologic types (χ2 = 67.183, P < 0.05), and in lobulated adenomas than in non-lobulated ones.
CONCLUSION: Patients with colorectal polyps should undergo endoscopy to examine the whole colon to carefully observe the shape, size, site of polyps and conduct a biopsy. If possible, polyps should be removed to avoid the occurrence of malignant transformation.
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Vacchelli E, Eggermont A, Sautès-Fridman C, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Toll-like receptor agonists for cancer therapy. Oncoimmunology 2013; 2:e25238. [PMID: 24083080 PMCID: PMC3782517 DOI: 10.4161/onci.25238] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 05/31/2013] [Indexed: 12/19/2022] Open
Abstract
Toll-like receptors (TLRs) have long been known for their ability to initiate innate immune responses upon exposure to conserved microbial components such as lipopolysaccharide (LPS) and double-stranded RNA. More recently, this family of pattern recognition receptors has been attributed a critical role in the elicitation of anticancer immune responses, raising interest in the development of immunochemotherapeutic regimens based on natural or synthetic TLR agonists. In spite of such an intense wave of preclinical and clinical investigation, only three TLR agonists are currently licensed by FDA for use in cancer patients: bacillus Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis that operates as a mixed TLR2/TLR4 agonist; monophosphoryl lipid A (MPL), a derivative of Salmonella minnesota that functions as a potent agonist of TLR4; and imiquimod, a synthetic imidazoquinoline that activates TLR7. One year ago, in the August and September issues of OncoImmunology, we described the main biological features of TLRs and discussed the progress of clinical studies evaluating the safety and therapeutic potential of TLR agonists in cancer patients. Here, we summarize the latest developments in this exciting area of research, focusing on preclinical studies that have been published during the last 13 mo and clinical trials launched in the same period to investigate the antineoplastic activity of TLR agonists.
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Affiliation(s)
- Erika Vacchelli
- Institut Gustave Roussy; Villejuif, France
- Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre; Paris, France
- INSERM, U848; Villejuif, France
| | | | - Catherine Sautès-Fridman
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Equipe 13, Centre de Recherche des Cordeliers; Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Paris, France
| | - Jérôme Galon
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Equipe 15, Centre de Recherche des Cordeliers; Paris, France
- INSERM, U872; Paris, France
- Université Pierre et Marie Curie/Paris VI; Paris, France
| | - Laurence Zitvogel
- Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre; Paris, France
- INSERM, U1015; Villejuif, France
| | - Guido Kroemer
- INSERM, U848; Villejuif, France
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Paris, France
- Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Metabolomics and Cell Biology Platform; Institut Gustave Roussy; Villejuif, France
| | - Lorenzo Galluzzi
- Institut Gustave Roussy; Villejuif, France
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
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Fűri I, Sipos F, Germann TM, Kalmár A, Tulassay Z, Molnár B, Műzes G. Epithelial toll-like receptor 9 signaling in colorectal inflammation and cancer: clinico-pathogenic aspects. World J Gastroenterol 2013; 19:4119-4126. [PMID: 23864774 PMCID: PMC3710413 DOI: 10.3748/wjg.v19.i26.4119] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2013] [Revised: 04/23/2013] [Accepted: 04/28/2013] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) recognize specific motifs which are frequently present in bacteria, fungi, prokaryotes and viruses. Amongst TLRs, TLR9 can be activated by such bacterial or viral DNA fragments, immunoglobulin-DNA complexes or synthetic oligonucleotides, which all contain unmethylated cytosine-guanine nucleotide sequences (CpGs). Emerging data indicate that TLR9 signaling has a role in, and may influence, colorectal carcinogenesis and colonic inflammation. CpGs are classified into three groups according to their influence on both the antigen-specific humoral- and cellular immunity, and the production of type 1 interferons and proinflammatory cytokines. TLR9 activation via CpGs may serve as a new therapeutic target for several cancerous and various inflammatory conditions. Due to its probable anti-cancer effects, the application possibilities of TLR9-signaling modulation may be extremely diverse even in colorectal tumors. In this review we aimed to summarize the current knowledge about TLR-signaling in the pathogenesis and therapy of inflammatory bowel diseases and colorectal cancer. Due to the species-specific differences in TLR9 expression, however, one must be careful in translating the animal model data into the human system, because of the differences between CpG-oligodeoxynucleotide-responsive cells. TLR9 agonist DNA-based immunomodulatory sequences could also represent a promising therapeutic alternative in systemic inflammatory conditions and chronic colonic inflammations as their side effects are not significant.
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Han JH, Park SY, Kim JB, Cho SD, Kim B, Kim BY, Kang MJ, Kim DJ, Park JH, Park JH. TLR7 expression is decreased during tumour progression in transgenic adenocarcinoma of mouse prostate mice and its activation inhibits growth of prostate cancer cells. Am J Reprod Immunol 2013; 70:317-26. [PMID: 23790156 DOI: 10.1111/aji.12146] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Accepted: 06/04/2013] [Indexed: 02/06/2023] Open
Abstract
PROBLEM Although various Toll-like receptors (TLRs) have been associated with immune response and tumorigenesis in the prostate cells, little is known about the role of TLR7. Accordingly, we examined the expression of TLR7 during tumour progression of TRMAP (transgenic mouse model for prostate cancer) mice and its role on cell growth. METHOD OF STUDY Toll-like receptor7 expression was examined by RT-polymerase chain reaction (PCR), Western blot, and immunohistochemistry. Cell growth was examined by MTT assay. Colony formation was investigated by crystal violet staining. RESULTS Strong expression of TLR7 was detected in the normal prostate epithelia of Wild-type (WT) mice, but not in TLR7-deficient mice. In contrast, TLR7 expression was weak in transgenic adenocarcinoma of mouse prostate (TRAMP)-C2 cells, as compared with murine bone marrow-derived macrophages (BMDMs). Moreover, TLR7 mRNA was markedly expressed in RWPE-1 cells (non-cancerous prostate epithelial cells), but not in PC3 and DU145 (prostate cancer cells). Immunohistochemically, TLR7 expression gradually decreased in TRAMP mice depending on the pathologic grade of the prostate cells. TLR7 agonists increased both the gene and protein expression of TLR7 and promoted production of proinflammatory cytokines/chemokines and IFN-β gene expression in prostate cancer cell lines. Moreover, loxoribine inhibited the growth and colony formation of TRAMP-C2 cells dependent of TLR7. CONCLUSION These findings suggest that TLR7 may participate in tumour suppression in the prostate cells.
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Affiliation(s)
- Ju-Hee Han
- Laboratory Animal Medicine, College of Veterinary Medicine, Seoul University, Seoul, Korea
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Moossavi S, Rezaei N. Toll-like receptor signalling and their therapeutic targeting in colorectal cancer. Int Immunopharmacol 2013; 16:199-209. [PMID: 23602501 DOI: 10.1016/j.intimp.2013.03.017] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2012] [Revised: 02/13/2013] [Accepted: 03/13/2013] [Indexed: 12/16/2022]
Abstract
Intestinal homeostasis is dependent on the proper host/microbiota interaction via pattern recognition receptors. Toll-like receptors are a specialised group of membrane receptors which detect pathogen-associated conserved structures. They are present in the intestinal tract and are required for intestinal homeostasis. Dysregulation in the Toll-like receptor signalling can conceivably result in a dysregulated immune response which could contribute to major intestinal pathologies including colorectal cancer. Evidence for the role of microbiota and toll-like receptors in colorectal cancer is emerging. In this report the evidence for the contribution of toll-like receptors to the pathogenesis of colorectal cancer; potential mechanisms affecting toll-like receptor signalling; and their therapeutic targeting in colorectal cancer are reviewed.
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Affiliation(s)
- Shirin Moossavi
- Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Toll-Like Receptor Expression Pattern: Clinical Application. J Clin Immunol 2012; 32:1421-2. [DOI: 10.1007/s10875-012-9719-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Accepted: 06/04/2012] [Indexed: 11/26/2022]
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