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Hsu CY, Jasim SA, Rasool KH, H M, Kaur J, Jabir MS, Alhajlah S, Kumar A, Jawad SF, Husseen B. Divergent functions of TLRs in gastrointestinal (GI) cancer: Overview of their diagnostic, prognostic and therapeutic value. Semin Oncol 2025; 52:152344. [PMID: 40347779 DOI: 10.1016/j.seminoncol.2025.152344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 03/10/2025] [Accepted: 03/15/2025] [Indexed: 05/14/2025]
Abstract
The relationship between the innate immune signal and the start of the adaptive immune response is the central idea of this theory. By controlling the inflammatory and tissue-repair reactions to damage, the Toll-like receptors (TLRs), as a family of PRRs, have attracted increasing attention for its function in protecting the host against infection and preserving tissue homeostasis. Microbial infection, damage, inflammation, and tissue healing have all been linked to the development of malignancies, especially gastrointestinal (GI) cancers. Recently, increased studies on TLR recognition and binding, as well as their ligands, have significantly advanced our knowledge of the various TLR signaling pathways and offered therapy options for GI malignancies. Upon activation by pathogen-associated or damage-associated molecular patterns (DAMPs and PAMPs), TLRs trigger key pathways like NF-κB, MAPK, and IRF. NF-κB activation promotes inflammation, cell survival, and proliferation, often contributing to tumor growth, metastasis, and therapy resistance. MAPK pathways similarly drive uncontrolled cell growth and invasion, while IRF pathways modulate interferon production, yielding both anti-tumor and protumor effects. The resulting chronic inflammatory environment within tumors can foster progression, yet TLR activation can also stimulate beneficial anti-tumor immune responses. However, the functions of TLR expression in GI cancers and their diagnostic and prognostic along with therapeutic value have not yet entirely been elucidated. Understanding how TLR activation contributes to anti-cancer immunity against GI malignancies may hasten immunotherapy developments and increase patient survival.
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Affiliation(s)
- Chou-Yi Hsu
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, Arizona, USA
| | - Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, Al-maarif University College, Anbar, Iraq; Biotechnology Department, College of Applied Science, Fallujah University, Fallujah, Iraq
| | - Khetam Habeeb Rasool
- Department of Biology, College of Science, University of Mustansiriyah, Mustansiriyah, Iraq
| | - Malathi H
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Jaswinder Kaur
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Mohali, Punjab, India
| | - Majid S Jabir
- Department of Applied Sciences, University of Technology, Anbar, Iraq
| | - Sharif Alhajlah
- Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Shaqra, Saudi Arabia.
| | - Abhinav Kumar
- Department of Nuclear and Renewable Energy, Ural Federal University Named after the First President of Russia Boris Yeltsin, Ekaterinburg, Russia; Centre for Research Impact & Outcome, Chitkara University, Rajpura, Punjab, India; Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, India
| | - Sabrean F Jawad
- Department of Pharmacy, Al-Mustaqbal University College, Hillah, Babylon, Iraq
| | - Beneen Husseen
- Medical Laboratory Technique College, the Islamic University, Najaf, Iraq; Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; Medical Laboratory Technique College, the Islamic University of Babylon, Babylon, Iraq
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Ionescu VA, Diaconu CC, Gheorghe G, Mihai MM, Diaconu CC, Bostan M, Bleotu C. Gut Microbiota and Colorectal Cancer: A Balance Between Risk and Protection. Int J Mol Sci 2025; 26:3733. [PMID: 40332367 PMCID: PMC12028331 DOI: 10.3390/ijms26083733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 04/11/2025] [Accepted: 04/14/2025] [Indexed: 05/08/2025] Open
Abstract
The gut microbiome, a complex community of microorganisms residing in the intestinal tract, plays a dual role in colorectal cancer (CRC) development, acting both as a contributing risk factor and as a protective element. This review explores the mechanisms by which gut microbiota contribute to CRC, emphasizing inflammation, oxidative stress, immune evasion, and the production of genotoxins and microbial metabolites. Fusobacterium nucleatum, Escherichia coli (pks+), and Bacteroides fragilis promote tumorigenesis by inducing chronic inflammation, generating reactive oxygen species, and producing virulence factors that damage host DNA. These microorganisms can also evade the antitumor immune response by suppressing cytotoxic T cell activity and increasing regulatory T cell populations. Additionally, microbial-derived metabolites such as secondary bile acids and trimethylamine-N-oxide (TMAO) have been linked to carcinogenic processes. Conversely, protective microbiota, including Lactobacillus, Bifidobacterium, and Faecalibacterium prausnitzii, contribute to intestinal homeostasis by producing short-chain fatty acids (SCFAs) like butyrate, which exhibit anti-inflammatory and anti-carcinogenic properties. These beneficial microbes enhance gut barrier integrity, modulate immune responses, and inhibit tumor cell proliferation. Understanding the dynamic interplay between pathogenic and protective microbiota is essential for developing microbiome-based interventions, such as probiotics, prebiotics, and fecal microbiota transplantation, to prevent or treat CRC. Future research should focus on identifying microbial biomarkers for early CRC detection and exploring personalized microbiome-targeted therapies. A deeper understanding of host-microbiota interactions may lead to innovative strategies for CRC management and improved patient outcomes.
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Affiliation(s)
- Vlad Alexandru Ionescu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania; (V.A.I.); (G.G.); (M.-M.M.)
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Camelia Cristina Diaconu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania; (V.A.I.); (G.G.); (M.-M.M.)
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
- Academy of Romanian Scientists, 050085 Bucharest, Romania;
| | - Gina Gheorghe
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania; (V.A.I.); (G.G.); (M.-M.M.)
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Mara-Madalina Mihai
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania; (V.A.I.); (G.G.); (M.-M.M.)
- Department of Oncologic Dermathology, “Elias” University Emergency Hospital, 010024 Bucharest, Romania
| | - Carmen Cristina Diaconu
- Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (C.C.D.); (M.B.)
| | - Marinela Bostan
- Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (C.C.D.); (M.B.)
- Department of Immunology, “Victor Babes” National Institute of Pathology, 050096 Bucharest, Romania
| | - Coralia Bleotu
- Academy of Romanian Scientists, 050085 Bucharest, Romania;
- Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (C.C.D.); (M.B.)
- Research Institute of the University of Bucharest (ICUB), University of Bucharest, 060023 Bucharest, Romania
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Chung KY, Kim S, Yoon HT, Kwon SH, Park HS, Im JP, Kim JS, Kim JW, Han YM, Koh SJ. Toll-like receptor 3 signaling attenuated colitis-associated cancer development in mice. Sci Rep 2024; 14:30308. [PMID: 39639064 PMCID: PMC11621332 DOI: 10.1038/s41598-024-76954-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 10/18/2024] [Indexed: 12/07/2024] Open
Abstract
Inflammatory bowel disease is associated with a high risk of colitis-associated cancer (CAC). We evaluated the role of TLR3 in CAC using a murine model. Wild-type (WT) and TLR3-knockout (TLR3-/-) mice received azoxymethane (AOM) 12.5 mg/kg intraperitoneally on day zero, followed by three cycles of 2% dextran sulfate sodium (DSS) for five days and free water for two weeks. We evaluated clinical indices, such as weight change, colon length, histological severity of colitis, and tumor number. We performed immunofluorescence assays for phospho-IκB kinase and β-catenin in colon tissues. To elucidate the antitumorigenic mechanism of TLR3 signaling, we injected poly(I: C) or phosphate-buffered saline intraperitoneally into an AOM/DSS-induced tumorigenesis model in WT mice. We also evaluate the direct antitumor effect of TLR signaling in AOM-treated WT and TLR3-/- mice without DSS. TLR3 deficiency increased tumor burden and colitis severity in the colon tissue than in the WT mice. β-catenin immunoreactivity was higher in TLR3-/- mice, while phospho-IκB kinase expression was similar. TLR3 activation by poly(I: C) did not reduce tumor burden in WT mice, but long-term AOM administration without DSS significantly increased tumor burden in TLR3-/- mice. TLR3 signaling attenuates CAC development, suggesting it may be a target for preventing CAC in inflammatory bowel disease.
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Affiliation(s)
- Kee Young Chung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
- Laboratory of Intestinal Mucosa and Skin Immunology, Seoul National University College of Medicine, Seoul, Korea
| | - Seulji Kim
- Division of Gastroenterology, Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
- Laboratory of Intestinal Mucosa and Skin Immunology, Seoul National University College of Medicine, Seoul, Korea
| | - Hee Tae Yoon
- Laboratory of Intestinal Mucosa and Skin Immunology, Seoul National University College of Medicine, Seoul, Korea
| | - So Hyun Kwon
- Laboratory of Intestinal Mucosa and Skin Immunology, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Sun Park
- Laboratory of Intestinal Mucosa and Skin Immunology, Seoul National University College of Medicine, Seoul, Korea
- Department of Dermatology, SMG-SNU Boramae Medical Center, Seoul, Korea
| | - Jong Pil Im
- Division of Gastroenterology, Department of Internal medicine, Seoul National University Hospital, Seoul, Korea
| | - Joo Sung Kim
- Division of Gastroenterology, Department of Internal medicine, Seoul National University Hospital, Seoul, Korea
| | - Ji Won Kim
- Division of Gastroenterology, Department of Internal medicine, SMG-SNU Boramae Medical Center, Seoul, Korea
| | - Yoo Min Han
- Laboratory of Intestinal Mucosa and Skin Immunology, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine and Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea
| | - Seong-Joon Koh
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
- Laboratory of Intestinal Mucosa and Skin Immunology, Seoul National University College of Medicine, Seoul, Korea.
- Division of Gastroenterology, Department of Internal medicine, Seoul National University Hospital, Seoul, Korea.
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Rafique A, Ali I, Kim S, Farooq A, Manzoor U, Moon J, Arooj M, Ahn M, Park Y, Hyun CL, Koh YS. Toll-like receptor 13-mediated signaling protects against the development of colon cancer. Int J Cancer 2024; 155:1858-1873. [PMID: 38989970 DOI: 10.1002/ijc.35089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 05/22/2024] [Accepted: 06/25/2024] [Indexed: 07/12/2024]
Abstract
Appropriate host-microbiota interactions are essential for maintaining intestinal homeostasis; hence, an imbalance in these interactions leads to inflammation-associated intestinal diseases. Toll-like receptors (TLRs) recognize microbial ligands and play a key role in host-microbe interactions in health and disease. TLR13 has a well-established function in enhancing host defenses against pathogenic bacteria. However, its role in maintaining intestinal homeostasis and controlling colitis-associated colon cancer (CAC) is largely unknown. This study aimed to investigate the involvement of TLR13-mediated signaling in intestinal homeostasis and colonic tumorigenesis using ex vivo cell and in vivo CAC animal model. Tlr13-deficient mice were prone to dextran sodium sulfate (DSS)-induced colitis. During the early stages of the CAC regimen (AOM/DSS-treated), Tlr13 deficiency led to severe ulcerative colitis. Moreover, Tlr13-deficient mice exhibited increased intestinal permeability, as evidenced by elevated levels of fluorescein isothiocyanate (FITC)-dextran, endotoxins, and bacterial translocation. Enhanced cell survival and proliferation of colonic intestinal cells were observed in Tlr13-deficient mice. A transcriptome analysis revealed that Tlr13 deficiency is associated with substantial changes in gene expression profile of colonic tumor tissue. Tlr13-deficient mice were more susceptible to CAC, with increased production of interleukin (IL)-6, IL-12, and TNF-α cytokines and enhanced STAT3, NF-κB, and MAPK signaling in colon tissues. These findings suggest that TLR13 plays a protective role in maintaining intestinal homeostasis and controlling CAC. Our study provides a novel perspective on intestinal health via TLR13-mediated signaling, which is crucial for deciphering the role of host-microbiota interactions in health and disease.
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Affiliation(s)
- Asma Rafique
- College of Medicine, and Jeju Research Center for Natural Medicine, Jeju National University, Jeju, South Korea
| | - Irshad Ali
- College of Medicine, and Jeju Research Center for Natural Medicine, Jeju National University, Jeju, South Korea
| | - Seukchan Kim
- Department of Animal Science, College of Life Science, Sangji University, Wonju, South Korea
| | - Adeel Farooq
- Research Institute for Basic Sciences, Jeju National University, Jeju, South Korea
| | - Umar Manzoor
- Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju, South Korea
| | - Jeungho Moon
- Department of Animal Science, College of Life Science, Sangji University, Wonju, South Korea
| | - Madeeha Arooj
- College of Medicine, and Jeju Research Center for Natural Medicine, Jeju National University, Jeju, South Korea
| | - Meejung Ahn
- Department of Animal Science, College of Life Science, Sangji University, Wonju, South Korea
| | - Youngjun Park
- Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju, South Korea
- Laboratory of Immune and Inflammatory Disease, Jeju Research Institute of Pharmaceutical Sciences, College of Pharmacy, Jeju National University, Jeju, South Korea
| | - Chang Lim Hyun
- College of Medicine, and Jeju Research Center for Natural Medicine, Jeju National University, Jeju, South Korea
| | - Young-Sang Koh
- College of Medicine, and Jeju Research Center for Natural Medicine, Jeju National University, Jeju, South Korea
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Li Y, Peng J, Meng X. Gut bacteria, host immunity, and colorectal cancer: From pathogenesis to therapy. Eur J Immunol 2024; 54:e2451022. [PMID: 38980275 DOI: 10.1002/eji.202451022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 06/18/2024] [Accepted: 06/25/2024] [Indexed: 07/10/2024]
Abstract
The emergence of 16S rRNA and metagenomic sequencing has gradually revealed the close relationship between dysbiosis and colorectal cancer (CRC). Recent studies have confirmed that intestinal dysbiosis plays various roles in the occurrence, development, and therapeutic response of CRC. Perturbation of host immunity is one of the key mechanisms involved. The intestinal microbiota, or specific bacteria and their metabolites, can modulate the progression of CRC through pathogen recognition receptor signaling or via the recruitment, polarization, and activation of both innate and adaptive immune cells to reshape the protumor/antitumor microenvironment. Therefore, the administration of gut bacteria to enhance immune homeostasis represents a new strategy for the treatment of CRC. In this review, we cover recent studies that illuminate the role of gut bacteria in the progression and treatment of CRC through orchestrating the immune response, which potentially offers insights for subsequent transformative research.
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Affiliation(s)
- Yuyi Li
- Department of Gastroenterology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Shanghai, China
- Digestive Disease Research and Clinical Translation Center, Shanghai Jiao Tong University, Shanghai, China
| | - Jinjin Peng
- Department of Gastroenterology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Shanghai, China
- Digestive Disease Research and Clinical Translation Center, Shanghai Jiao Tong University, Shanghai, China
| | - Xiangjun Meng
- Department of Gastroenterology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Shanghai, China
- Digestive Disease Research and Clinical Translation Center, Shanghai Jiao Tong University, Shanghai, China
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González A, Fullaondo A, Odriozola A. Microbiota-associated mechanisms in colorectal cancer. ADVANCES IN GENETICS 2024; 112:123-205. [PMID: 39396836 DOI: 10.1016/bs.adgen.2024.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, ranking third in terms of incidence and second as a cause of cancer-related death. There is growing scientific evidence that the gut microbiota plays a key role in the initiation and development of CRC. Specific bacterial species and complex microbial communities contribute directly to CRC pathogenesis by promoting the neoplastic transformation of intestinal epithelial cells or indirectly through their interaction with the host immune system. As a result, a protumoural and immunosuppressive environment is created conducive to CRC development. On the other hand, certain bacteria in the gut microbiota contribute to protection against CRC. In this chapter, we analysed the relationship of the gut microbiota to CRC and the associations identified with specific bacteria. Microbiota plays a key role in CRC through various mechanisms, such as increased intestinal permeability, inflammation and immune system dysregulation, biofilm formation, genotoxin production, virulence factors and oxidative stress. Exploring the interaction between gut microbiota and tumourigenesis is essential for developing innovative therapeutic approaches in the fight against CRC.
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Affiliation(s)
- Adriana González
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain.
| | - Asier Fullaondo
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | - Adrian Odriozola
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
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Tan S, Yu H, Zhang Z, Liu Y, Lou G. Hypoxic tumour-derived exosomal miR-1225-5p regulates M2 macrophage polarisation via toll-like receptor 2 to promote ovarian cancer progress. Autoimmunity 2023; 56:2281226. [PMID: 38010845 DOI: 10.1080/08916934.2023.2281226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 11/05/2023] [Indexed: 11/29/2023]
Abstract
Tumor-secreted exosomes are critical for the functional regulation of tumor-associated macrophages (TAMs). This study aimed to explore how exosomes secreted by ovarian carcinoma cells regulate the phenotype and function of macrophages. Hypoxic treatment of A2780 cells was postulated to mimic the tumor microenvironment, and exosomes were co-cultured with TAMs. miR-1225-5p was enriched in hypoxic exosomes and contributed to M2 macrophage polarizationby modulating Toll-like receptor 2 expression (TLR2). Furthermore, hypoxia-treated macrophages promote ovarian cancer cell viability, migration, and invasion via the wnt/β-catenin pathway. This study clarified that exosomal miR-1225-5p promotes macrophage M2-like polarization by targeting TLR2 to promote ovarian cancer, which may via the wnt/β-catenin pathway.
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Affiliation(s)
- Shu Tan
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Hao Yu
- Nangang District of Heilongjiang Provincial Hospital, Harbin, China
| | - Zhaocong Zhang
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yiming Liu
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ge Lou
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, China
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Mukherjee S, Patra R, Behzadi P, Masotti A, Paolini A, Sarshar M. Toll-like receptor-guided therapeutic intervention of human cancers: molecular and immunological perspectives. Front Immunol 2023; 14:1244345. [PMID: 37822929 PMCID: PMC10562563 DOI: 10.3389/fimmu.2023.1244345] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 09/07/2023] [Indexed: 10/13/2023] Open
Abstract
Toll-like receptors (TLRs) serve as the body's first line of defense, recognizing both pathogen-expressed molecules and host-derived molecules released from damaged or dying cells. The wide distribution of different cell types, ranging from epithelial to immune cells, highlights the crucial roles of TLRs in linking innate and adaptive immunity. Upon stimulation, TLRs binding mediates the expression of several adapter proteins and downstream kinases, that lead to the induction of several other signaling molecules such as key pro-inflammatory mediators. Indeed, extraordinary progress in immunobiological research has suggested that TLRs could represent promising targets for the therapeutic intervention of inflammation-associated diseases, autoimmune diseases, microbial infections as well as human cancers. So far, for the prevention and possible treatment of inflammatory diseases, various TLR antagonists/inhibitors have shown to be efficacious at several stages from pre-clinical evaluation to clinical trials. Therefore, the fascinating role of TLRs in modulating the human immune responses at innate as well as adaptive levels directed the scientists to opt for these immune sensor proteins as suitable targets for developing chemotherapeutics and immunotherapeutics against cancer. Hitherto, several TLR-targeting small molecules (e.g., Pam3CSK4, Poly (I:C), Poly (A:U)), chemical compounds, phytocompounds (e.g., Curcumin), peptides, and antibodies have been found to confer protection against several types of cancers. However, administration of inappropriate doses of such TLR-modulating therapeutics or a wrong infusion administration is reported to induce detrimental outcomes. This review summarizes the current findings on the molecular and structural biology of TLRs and gives an overview of the potency and promises of TLR-directed therapeutic strategies against cancers by discussing the findings from established and pipeline discoveries.
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Affiliation(s)
- Suprabhat Mukherjee
- Integrative Biochemistry & Immunology Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol, West Bengal, India
| | - Ritwik Patra
- Integrative Biochemistry & Immunology Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol, West Bengal, India
| | - Payam Behzadi
- Department of Microbiology, Shahr-e-Qods Branch, Islamic Azad University, Tehran, Iran
| | - Andrea Masotti
- Research Laboratories, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
| | - Alessandro Paolini
- Research Laboratories, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
| | - Meysam Sarshar
- Research Laboratories, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
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Iyer K, Erkert L, Becker C. Know your neighbors: microbial recognition at the intestinal barrier and its implications for gut homeostasis and inflammatory bowel disease. Front Cell Dev Biol 2023; 11:1228283. [PMID: 37519301 PMCID: PMC10375050 DOI: 10.3389/fcell.2023.1228283] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/07/2023] [Indexed: 08/01/2023] Open
Abstract
Intestinal epithelial cells (IECs) perform several physiological and metabolic functions at the epithelial barrier. IECs also play an important role in defining the overall immune functions at the mucosal region. Pattern recognition receptors (PRRs) on the cell surface and in other cellular compartments enable them to sense the presence of microbes and microbial products in the intestinal lumen. IECs are thus at the crossroads of mediating a bidirectional interaction between the microbial population and the immune cells present at the intestinal mucosa. This communication between the microbial population, the IECs and the underlying immune cells has a profound impact on the overall health of the host. In this review, we focus on the various PRRs present in different cellular compartments of IECs and discuss the recent developments in the understanding of their role in microbial recognition. Microbial recognition and signaling at the epithelial barrier have implications in the maintenance of intestinal homeostasis, epithelial barrier function, maintenance of commensals, and the overall tolerogenic function of PRRs in the gut mucosa. We also highlight the role of an aberrant microbial sensing at the epithelial barrier in the pathogenesis of inflammatory bowel disease (IBD) and the development of colorectal cancer.
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Affiliation(s)
- Krishna Iyer
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, United States
| | - Lena Erkert
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christoph Becker
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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Wang J, Zhang J, Wang J, Hu X, Ouyang L, Wang Y. Small-Molecule Modulators Targeting Toll-like Receptors for Potential Anticancer Therapeutics. J Med Chem 2023; 66:6437-6462. [PMID: 37163340 DOI: 10.1021/acs.jmedchem.2c01655] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Toll-like receptors (TLRs) are key components of the innate immune system and serve as a crucial link between innate and acquired immunity. In addition to immune function, TLRs are involved in other important pathological processes, including tumorigenesis. TLRs have dual regulatory effects on tumor immunity by activating nuclear factor κ-B signaling pathways, which induce tumor immune evasion or enhance the antitumor immune response. Therefore, TLRs have become a popular target for cancer prevention and treatment, and TLR agonists and antagonists offer considerable potential for drug development. The TLR7 agonist imiquimod (1) has been approved by the U.S. Food and Drug Administration as a treatment for malignant skin cancer. Herein, the structure, signaling pathways, and function of the TLR family are summarized, and the structure-activity relationships associated with TLR selective and multitarget modulators and their potential application in tumor therapy are systematically discussed.
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Affiliation(s)
- Jiayu Wang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
- College of Life Sciences, Sichuan University, Chengdu 610064, Sichuan, China
| | - Jifa Zhang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Jiaxing Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Xinyue Hu
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
- College of Life Sciences, Sichuan University, Chengdu 610064, Sichuan, China
| | - Liang Ouyang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Yuxi Wang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
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Pandey H, Tang DWT, Wong SH, Lal D. Gut Microbiota in Colorectal Cancer: Biological Role and Therapeutic Opportunities. Cancers (Basel) 2023; 15:cancers15030866. [PMID: 36765824 PMCID: PMC9913759 DOI: 10.3390/cancers15030866] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 02/03/2023] Open
Abstract
Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths worldwide. While CRC is thought to be an interplay between genetic and environmental factors, several lines of evidence suggest the involvement of gut microbiota in promoting inflammation and tumor progression. Gut microbiota refer to the ~40 trillion microorganisms that inhabit the human gut. Advances in next-generation sequencing technologies and metagenomics have provided new insights into the gut microbial ecology and have helped in linking gut microbiota to CRC. Many studies carried out in humans and animal models have emphasized the role of certain gut bacteria, such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and colibactin-producing Escherichia coli, in the onset and progression of CRC. Metagenomic studies have opened up new avenues for the application of gut microbiota in the diagnosis, prevention, and treatment of CRC. This review article summarizes the role of gut microbiota in CRC development and its use as a biomarker to predict the disease and its potential therapeutic applications.
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Affiliation(s)
- Himani Pandey
- Redcliffe Labs, Electronic City, Noida 201301, India
| | - Daryl W. T. Tang
- School of Biological Sciences, Nanyang Technological University, Singapore 308232, Singapore
| | - Sunny H. Wong
- Centre for Microbiome Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
- Correspondence: (S.H.W.); (D.L.)
| | - Devi Lal
- Department of Zoology, Ramjas College, University of Delhi, Delhi 110007, India
- Correspondence: (S.H.W.); (D.L.)
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12
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Zhuang T, Hu M, Wang J, Mei L, Zhu X, Zhang H, Jin F, Shao J, Wang T, Wang C, Niu X, Wu D. Sodium houttuyfonate effectively treats acute pulmonary infection of Pseudomonas aeruginosa by affecting immunity and intestinal flora in mice. Front Cell Infect Microbiol 2022; 12:1022511. [PMID: 36530439 PMCID: PMC9751016 DOI: 10.3389/fcimb.2022.1022511] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 11/14/2022] [Indexed: 12/04/2022] Open
Abstract
Introduction Pseudomonas aeruginosa is a major nosocomial pathogen that frequently causes ventilator-associated pneumonia in specific populations. Sodium houttuyfonate (SH) has shown mild antibacterial activity against P. aeruginosa in vitro, but the mechanism of potent antimicrobial activity of SH against P. aeruginosa infection in vivo remains unclear. Methods Here, using the mouse pneumonia model induced by P. aeruginosa nasal drip to explore the therapeutic effects of SH. Results We found that SH exhibits dose-dependent therapeutic effects of reducing P. aeruginosa burden and systemic inflammation in pneumonia mice. SH ameliorates inflammatory gene expression and production of inflammatory proteins, such as interleukin-6 (IL-6), nuclear factor kappa-B (NF-κB) and toll-like receptor 4 (TLR4), associated with the TLR4/NF-κB pathway in mice with P. aeruginosa pneumonia. Furthermore, we analyzed the intestinal flora of mice and found that compared with the model group, the abundance and diversity of beneficial bacterial flora of SH treatment groups increased significantly, suggesting that SH can improve the intestinal flora disorder caused by inflammation. In addition, SH improves alpha and beta diversity index and reduces species abundance differences of intestinal flora in pneumonia mice. Discussion Taken together, our presented results indicate that SH may effectively alleviate the acute pulmonary infection induced by P. aeruginosa by reducing the disturbance of regulating immunity and intestinal flora in mice.
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Affiliation(s)
- Tian Zhuang
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China,Research Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China
| | - Mengxue Hu
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China,Research Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China
| | - Jian Wang
- Key Laboratory of Xin’an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China,Pathology Department, First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Longfei Mei
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China,Research Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China
| | - Xiaoxiao Zhu
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China,Research Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China
| | - Haitao Zhang
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China,Research Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China
| | - Feng Jin
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China,Research Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China
| | - Jing Shao
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China,Research Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China,Key Laboratory of Xin’an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China
| | - Tianming Wang
- Key Laboratory of Xin’an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China
| | - Changzhong Wang
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China,Research Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China,Key Laboratory of Xin’an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China
| | - Xiaojia Niu
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China,Research Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China,Key Laboratory of Xin’an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China,*Correspondence: Daqiang Wu, ; Xiaojia Niu,
| | - Daqiang Wu
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China,Key Laboratory of Xin’an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China,*Correspondence: Daqiang Wu, ; Xiaojia Niu,
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13
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Yang Y, Li H, Fotopoulou C, Cunnea P, Zhao X. Toll-like receptor-targeted anti-tumor therapies: Advances and challenges. Front Immunol 2022; 13:1049340. [PMID: 36479129 PMCID: PMC9721395 DOI: 10.3389/fimmu.2022.1049340] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 10/31/2022] [Indexed: 11/22/2022] Open
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors, originally discovered to stimulate innate immune reactions against microbial infection. TLRs also play essential roles in bridging the innate and adaptive immune system, playing multiple roles in inflammation, autoimmune diseases, and cancer. Thanks to the immune stimulatory potential of TLRs, TLR-targeted strategies in cancer treatment have proved to be able to regulate the tumor microenvironment towards tumoricidal phenotypes. Quantities of pre-clinical studies and clinical trials using TLR-targeted strategies in treating cancer have been initiated, with some drugs already becoming part of standard care. Here we review the structure, ligand, signaling pathways, and expression of TLRs; we then provide an overview of the pre-clinical studies and an updated clinical trial watch targeting each TLR in cancer treatment; and finally, we discuss the challenges and prospects of TLR-targeted therapy.
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Affiliation(s)
- Yang Yang
- Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University, Chengdu, China
| | - Hongyi Li
- Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University, Chengdu, China
| | - Christina Fotopoulou
- Division of Cancer, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Paula Cunnea
- Division of Cancer, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Xia Zhao
- Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University, Chengdu, China
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14
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Fonseca S, Carvalho AL, Miquel-Clopés A, Jones EJ, Juodeikis R, Stentz R, Carding SR. Extracellular vesicles produced by the human gut commensal bacterium Bacteroides thetaiotaomicron elicit anti-inflammatory responses from innate immune cells. Front Microbiol 2022; 13:1050271. [PMID: 36439842 PMCID: PMC9684339 DOI: 10.3389/fmicb.2022.1050271] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 10/25/2022] [Indexed: 07/24/2023] Open
Abstract
Bacterial extracellular vesicles (BEVs) produced by gut commensal bacteria have been proposed to play an important role in maintaining host homeostasis via interactions with the immune system. Details of the mediators and pathways of BEV-immune cell interactions are however incomplete. In this study, we provide evidence for the anti-inflammatory and immunomodulatory properties of extracellular vesicles produced by the prominent human gut commensal bacterium Bacteroides thetaiotaomicron (Bt BEVs) and identify the molecular mechanisms underlying their interaction with innate immune cells. Administration of Bt BEVs to mice treated with colitis-inducing dextran sodium sulfate (DSS) ameliorates the symptoms of intestinal inflammation, improving survival rate and reducing weight loss and disease activity index scores, in association with upregulation of IL-10 production in colonic tissue and in splenocytes. Pre-treatment (conditioning) of murine bone marrow derived monocytes (BMDM) with Bt BEVs resulted in higher ratio of IL-10/TNFα production after an LPS challenge when compared to LPS pre-conditioned or non-conditioned BMDM. Using the THP-1 monocytic cell line the interactions between Bt BEVs and monocytes/macrophages were shown to be mediated primarily by TLR2. Histone (H3K4me1) methylation analysis showed that Bt BEVs induced epigenetic reprogramming which persisted after infectious challenge, as revealed by increased levels of H3K4me1 in Bt BEV-conditioned LPS-challenged BMDM. Collectively, our findings highlight the important role of Bt BEVs in maintaining host immune homeostasis and raise the promising possibility of considering their use in immune therapies.
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Affiliation(s)
- Sonia Fonseca
- Gut Microbes and Health, Quadram Institute Bioscience, Norwich, United Kingdom
| | - Ana L. Carvalho
- Gut Microbes and Health, Quadram Institute Bioscience, Norwich, United Kingdom
- Department of Women’s and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | | | - Emily J. Jones
- Gut Microbes and Health, Quadram Institute Bioscience, Norwich, United Kingdom
| | - Rokas Juodeikis
- Gut Microbes and Health, Quadram Institute Bioscience, Norwich, United Kingdom
| | - Régis Stentz
- Gut Microbes and Health, Quadram Institute Bioscience, Norwich, United Kingdom
| | - Simon R. Carding
- Gut Microbes and Health, Quadram Institute Bioscience, Norwich, United Kingdom
- Norwich Medical School, University of East Anglia, Norwich, United Kingdom
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15
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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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16
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Yinhang W, Wei W, Jing Z, Qing Z, Yani Z, Yangyanqiu W, Shuwen H. Biological roles of toll-like receptors and gut microbiota in colorectal cancer. Future Microbiol 2022; 17:1071-1089. [PMID: 35916158 DOI: 10.2217/fmb-2021-0072] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most considerably common malignancies of the alimentary system, with high mortality and incidence rates. The present study suggested that the occurrence of CRC is closely related to bacteria, as the large intestine is a gathering place for human micro-organisms. However, the nosogenesis of bacteria leading to tumorigenesis is still obscure. Recently, many studies have reported that toll-like receptors and their related molecular pathways are involved in the process of gut micro-organisms generating CRC. Gut micro-organisms can promote or inhibit the development of CRC via binding to special toll-like receptors. In this paper, the authors review the relationship among toll-like receptors, gut micro-organisms and CRC in order to provide a reference for future tumor immunotherapy and targeted therapy.
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Affiliation(s)
- Wu Yinhang
- Huzhou Central Hospital, Affiliated Central Hospital, Huzhou University, 1558 Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, China.,The Second School of Clinical Medicine, Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang Province, 310053, China.,Key Laboratory of Multiomics Research & Clinical Transformation of Digestive Cancer of Huzhou,1558 Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, China
| | - Wu Wei
- Huzhou Central Hospital, Affiliated Central Hospital, Huzhou University, 1558 Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, China.,Key Laboratory of Multiomics Research & Clinical Transformation of Digestive Cancer of Huzhou,1558 Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, China
| | - Zhuang Jing
- Huzhou Central Hospital, Affiliated Central Hospital, Huzhou University, 1558 Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, China.,Key Laboratory of Multiomics Research & Clinical Transformation of Digestive Cancer of Huzhou,1558 Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, China
| | - Zhou Qing
- Huzhou Central Hospital, Affiliated Central Hospital, Huzhou University, 1558 Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, China.,Key Laboratory of Multiomics Research & Clinical Transformation of Digestive Cancer of Huzhou,1558 Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, China
| | - Zhou Yani
- Huzhou Central Hospital, Affiliated Central Hospital, Huzhou University, 1558 Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, China.,Graduate School of Medicine Faculty, Zhejiang University, 866 Yuhangtang Road, Xihu District, Hangzhou, Zhejiang Province, 310058, China
| | - Wang Yangyanqiu
- Huzhou Central Hospital, Affiliated Central Hospital, Huzhou University, 1558 Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, China.,Graduate School of Medicine Faculty, Zhejiang University, 866 Yuhangtang Road, Xihu District, Hangzhou, Zhejiang Province, 310058, China
| | - Han Shuwen
- Huzhou Central Hospital, Affiliated Central Hospital, Huzhou University, 1558 Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, China.,Key Laboratory of Multiomics Research & Clinical Transformation of Digestive Cancer of Huzhou,1558 Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, China
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17
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Man SM, Jenkins BJ. Context-dependent functions of pattern recognition receptors in cancer. Nat Rev Cancer 2022; 22:397-413. [PMID: 35355007 DOI: 10.1038/s41568-022-00462-5] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/01/2022] [Indexed: 02/07/2023]
Abstract
The immune system plays a critical role in shaping all facets of cancer, from the early initiation stage through to metastatic disease and resistance to therapy. Our understanding of the importance of the adaptive arm of the immune system in antitumour immunity has led to the implementation of immunotherapy with immune checkpoint inhibitors in numerous cancers, albeit with differing efficacy. By contrast, the clinical utility of innate immunity in cancer has not been exploited, despite dysregulated innate immunity being a feature of at least one-third of all cancers associated with tumour-promoting chronic inflammation. The past two decades have seen innate immune pattern recognition receptors (PRRs) emerge as critical regulators of the immune response to microbial infection and host tissue damage. More recently, it has become apparent that in many cancer types, PRRs play a central role in modulating a vast array of tumour-inhibiting and tumour-promoting cellular responses both in immune cells within the tumour microenvironment and directly in cancer cells. Herein, we provide a comprehensive overview of the fast-evolving field of PRRs in cancer, and discuss the potential to target PRRs for drug development and biomarker discovery in a wide range of oncology settings.
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Affiliation(s)
- Si Ming Man
- Division of Immunity, Inflammation and Infection, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
- Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, VIC, Australia.
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18
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Nagao-Kitamoto H, Kitamoto S, Kamada N. Inflammatory bowel disease and carcinogenesis. Cancer Metastasis Rev 2022; 41:301-316. [PMID: 35416564 DOI: 10.1007/s10555-022-10028-4] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 03/27/2022] [Indexed: 11/24/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer mortality worldwide. Colitis-associated colorectal cancer (CAC) is a subtype of CRC associated with inflammatory bowel disease (IBD). It is well known that individuals with IBD have a 2-3 times higher risk of developing CRC than those who do not, rendering CAC a major cause of death in this group. Although the etiology and pathogenesis of CAC are incompletely understood, animal models of chronic inflammation and human cohort data indicate that changes in the intestinal environment, including host response dysregulation and gut microbiota perturbations, may contribute to the development of CAC. Genomic alterations are a hallmark of CAC, with patterns that are distinct from those in sporadic CRC. The discovery of the biological changes that underlie the development of CAC is ongoing; however, current data suggest that chronic inflammation in IBD increases the risk of developing CAC. Therefore, a deeper understanding of the precise mechanisms by which inflammation triggers genetic alterations and disrupts intestinal homeostasis may provide insight into novel therapeutic strategies for the prevention of CAC.
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Affiliation(s)
- Hiroko Nagao-Kitamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA.
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
| | - Sho Kitamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
| | - Nobuhiko Kamada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA.
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
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19
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Toll-Like Receptors (TLRs): Structure, Functions, Signaling, and Role of Their Polymorphisms in Colorectal Cancer Susceptibility. BIOMED RESEARCH INTERNATIONAL 2021; 2021:1157023. [PMID: 34552981 PMCID: PMC8452412 DOI: 10.1155/2021/1157023] [Citation(s) in RCA: 168] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/04/2021] [Accepted: 08/19/2021] [Indexed: 12/14/2022]
Abstract
Toll-like receptors (TLRs) are the important mediators of inflammatory pathways in the gut which play a major role in mediating the immune responses towards a wide variety of pathogen-derived ligands and link adaptive immunity with the innate immunity. Numerous studies in different populations across the continents have reported on the significant roles of TLR gene polymorphisms in modulating the risk of colorectal cancer (CRC). CRC is one of the major malignancies affecting the worldwide population and is currently ranking the third most common cancer in the world. In this review, we have attempted to discuss the structure, functions, and signaling of TLRs in comprehensive detail together with the role played by various TLR gene SNPs in CRC susceptibility.
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20
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Ferguson M, Foley E. Microbial recognition regulates intestinal epithelial growth in homeostasis and disease. FEBS J 2021; 289:3666-3691. [PMID: 33977656 DOI: 10.1111/febs.15910] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 04/06/2021] [Accepted: 04/30/2021] [Indexed: 12/13/2022]
Abstract
The intestine is constantly exposed to a dynamic community of microbes. Intestinal epithelial cells respond to microbes through evolutionarily conserved recognition pathways, such as the immune deficiency (IMD) pathway of Drosophila, the Toll-like receptor (TLR) response of flies and vertebrates, and the vertebrate nucleotide-binding oligomerization domain (NOD) pathway. Microbial recognition pathways are tightly controlled to respond effectively to pathogens, tolerate the microbiome, and limit intestinal disease. In this review, we focus on contributions of different model organisms to our understanding of how epithelial microbe recognition impacts intestinal proliferation and differentiation in homeostasis and disease. In particular, we compare how microbes and subsequent recognition by the intestine influences barrier integrity, intestinal repair and tumorigenesis in Drosophila, zebrafish, mice, and organoids. In addition, we discuss the importance of microbial recognition in homeostatic intestinal growth and discuss how immune pathways directly impact stem cell and crypt dynamics.
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Affiliation(s)
- Meghan Ferguson
- Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.,Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Edan Foley
- Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.,Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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21
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Hangai S, Kimura Y, Taniguchi T, Yanai H. Signal-transducing innate receptors in tumor immunity. Cancer Sci 2021; 112:2578-2591. [PMID: 33570784 PMCID: PMC8253268 DOI: 10.1111/cas.14848] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 02/05/2021] [Accepted: 02/09/2021] [Indexed: 12/15/2022] Open
Abstract
The signal‐transducing innate receptors represent classes of pattern recognition receptors (PRRs) that play crucial roles in the first line of the host defense against infections by the recognition of pathogen‐derived molecules. Because of their poorly discriminative nature compared with antigen receptors of the adaptive immune system, they also recognize endogenous molecules and evoke immune responses without infection, resulting in the regulation of tumor immunity. Therefore, PRRs may be promising targets for effective cancer immunotherapy, either by activating or inhibiting them. Here, we summarize our current knowledge of signal‐transducing PRRs in the regulation of tumor immunity.
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Affiliation(s)
- Sho Hangai
- Department of Inflammology, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Yoshitaka Kimura
- Department of Inflammology, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Tadatsugu Taniguchi
- Department of Inflammology, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Hideyuki Yanai
- Department of Inflammology, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
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22
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Reilly F, Burke JP, Lennon G, Kay EW, McNamara DA, Cullen G, Doherty GA, Mulcahy H, Martin S, Winter DC, Sheahan K, O'Connell PR. A case-control study examining the association of smad7 and TLR single nucleotide polymorphisms on the risk of colorectal cancer in ulcerative colitis. Colorectal Dis 2021; 23:1043-1048. [PMID: 33512737 DOI: 10.1111/codi.15550] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 01/20/2021] [Accepted: 01/21/2021] [Indexed: 01/01/2023]
Abstract
AIM Ulcerative colitis (UC) is characterized by chronic mucosal inflammation and an increased risk of colorectal cancer. smad7, TLR2 and TLR4 modulate intestinal inflammation and their polymorphisms affect the risk of development of sporadic colorectal cancer. The aim of the current study was to examine the association between single nucleotide polymorphisms (SNPs) in smad7, TLR2 and TLR4 and the development of colorectal cancer in patients with UC. METHOD DNA was extracted from formalin-fixed, paraffin-embedded tissue from 90 patients with UC who had undergone panproctocolectomy between 1985 and 2013 (30 with UC-associated colorectal cancer and 60 control UC patients). Control cases were matched 2:1 for age at diagnosis of colitis, duration of disease and gender. Genotyping was performed for the smad7 rs4464148, rs11874392, rs12953717 and rs4939827 SNPs, the TLR2 rs5743704 and rs5743708 SNPs and the TLR4 rs4986790 and rs4986791 SNPs. RESULTS Sixty three of the 90 patients (70%) were men and the mean age at diagnosis of UC was 38.6 ± 1.6 years. The mean time to the diagnosis of UC-associated colorectal cancer was 13.5 ± 1.9 years. The 5-year recurrence-free and cancer-specific survival rates were 76% and 88%, respectively. All eight SNPs were in Hardy-Weinberg equilibrium. None of the eight SNPs assessed in smad7, TLR2 or TLR4 were associated with the development of UC-associated colorectal cancer at an allelic or genotypic level. CONCLUSIONS These data do not support an association between polymorphisms in smad7, TLR2 or TLR4 and the development of UC-associated colorectal cancer.
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Affiliation(s)
- Frank Reilly
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, Ireland
| | - John P Burke
- Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland
| | - Grainne Lennon
- School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland
| | - Elaine W Kay
- Department of Pathology, Beaumont Hospital, Dublin, Ireland
| | | | - Garret Cullen
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, Ireland
| | - Glen A Doherty
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, Ireland
| | - Hugh Mulcahy
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, Ireland
| | - Sean Martin
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, Ireland
| | - Desmond C Winter
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, Ireland
| | - Kieran Sheahan
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, Ireland
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Duan X, Iwanowycz S, Ngoi S, Hill M, Zhao Q, Liu B. Molecular Chaperone GRP94/GP96 in Cancers: Oncogenesis and Therapeutic Target. Front Oncol 2021; 11:629846. [PMID: 33898309 PMCID: PMC8062746 DOI: 10.3389/fonc.2021.629846] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/10/2021] [Indexed: 12/16/2022] Open
Abstract
During tumor development and progression, intrinsic and extrinsic factors trigger endoplasmic reticulum (ER) stress and the unfolded protein response, resulting in the increased expression of molecular chaperones to cope with the stress and maintain tumor cell survival. Heat shock protein (HSP) GRP94, also known as GP96, is an ER paralog of HSP90 and has been shown to promote survival signaling during tumor-induced stress and modulate the immune response through its multiple clients, including TLRs, integrins, LRP6, GARP, IGF, and HER2. Clinically, elevated expression of GRP94 correlates with an aggressive phenotype and poor clinical outcome in a variety of cancers. Thus, GRP94 is a potential molecular marker and therapeutic target in malignancies. In this review, we will undergo deep molecular profiling of GRP94 in tumor development and summarize the individual roles of GRP94 in common cancers, including breast cancer, colon cancer, lung cancer, liver cancer, multiple myeloma, and others. Finally, we will briefly review the therapeutic potential of selectively targeting GRP94 for the treatment of cancers.
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Affiliation(s)
- Xiaofeng Duan
- Department of Microbiology & Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
| | - Stephen Iwanowycz
- Department of Microbiology & Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
| | - Soo Ngoi
- Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Megan Hill
- Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Qiang Zhao
- Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Clinical Research Center for Cancer, Tianjin, China
| | - Bei Liu
- Department of Microbiology & Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
- Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
- The Pelotonia Institute for Immuno-Oncology at The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
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Gubernatorova EO, Polinova AI, Petropavlovskiy MM, Namakanova OA, Medvedovskaya AD, Zvartsev RV, Telegin GB, Drutskaya MS, Nedospasov SA. Dual Role of TNF and LTα in Carcinogenesis as Implicated by Studies in Mice. Cancers (Basel) 2021; 13:1775. [PMID: 33917839 PMCID: PMC8068266 DOI: 10.3390/cancers13081775] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 03/30/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023] Open
Abstract
Tumor necrosis factor (TNF) and lymphotoxin alpha (LTα) are two related cytokines from the TNF superfamily, yet they mediate their functions in soluble and membrane-bound forms via overlapping, as well as distinct, molecular pathways. Their genes are encoded within the major histocompatibility complex class III cluster in close proximity to each other. TNF is involved in host defense, maintenance of lymphoid tissues, regulation of cell death and survival, and antiviral and antibacterial responses. LTα, known for some time as TNFβ, has pleiotropic functions including control of lymphoid tissue development and homeostasis cross talk between lymphocytes and their environment, as well as lymphoid tissue neogenesis with formation of lymphoid follicles outside the lymph nodes. Along with their homeostatic functions, deregulation of these two cytokines may be associated with initiation and progression of chronic inflammation, autoimmunity, and tumorigenesis. In this review, we summarize the current state of knowledge concerning TNF/LTα functions in tumor promotion and suppression, with the focus on the recently uncovered significance of host-microbiota interplay in cancer development that may explain some earlier controversial results.
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Affiliation(s)
- Ekaterina O. Gubernatorova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Almina I. Polinova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Mikhail M. Petropavlovskiy
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Olga A. Namakanova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Alexandra D. Medvedovskaya
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Ruslan V. Zvartsev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Georgij B. Telegin
- Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences (BIBCh, RAS), 142290 Pushchino, Russia;
| | - Marina S. Drutskaya
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Sergei A. Nedospasov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Sirius University of Science and Technology, Federal Territory Sirius, 354340 Krasnodarsky Krai, Russia
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Okada F, Izutsu R, Goto K, Osaki M. Inflammation-Related Carcinogenesis: Lessons from Animal Models to Clinical Aspects. Cancers (Basel) 2021; 13:cancers13040921. [PMID: 33671768 PMCID: PMC7926701 DOI: 10.3390/cancers13040921] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/11/2021] [Accepted: 02/12/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary In multicellular organisms, inflammation is the body’s most primitive and essential protective response against any external agent. Inflammation, however, not only causes various modern diseases such as cardiovascular disorders, neurological disorders, autoimmune diseases, metabolic syndrome, infectious diseases, and cancer but also shortens the healthy life expectancy. This review focuses on the onset of carcinogenesis due to chronic inflammation caused by pathogen infections and inhalation/ingestion of foreign substances. This study summarizes animal models associated with inflammation-related carcinogenesis by organ. By determining factors common to inflammatory carcinogenesis models, we examined strategies for the prevention and treatment of inflammatory carcinogenesis in humans. Abstract Inflammation-related carcinogenesis has long been known as one of the carcinogenesis patterns in humans. Common carcinogenic factors are inflammation caused by infection with pathogens or the uptake of foreign substances from the environment into the body. Inflammation-related carcinogenesis as a cause for cancer-related death worldwide accounts for approximately 20%, and the incidence varies widely by continent, country, and even region of the country and can be affected by economic status or development. Many novel approaches are currently available concerning the development of animal models to elucidate inflammation-related carcinogenesis. By learning from the oldest to the latest animal models for each organ, we sought to uncover the essential common causes of inflammation-related carcinogenesis. This review confirmed that a common etiology of organ-specific animal models that mimic human inflammation-related carcinogenesis is prolonged exudation of inflammatory cells. Genotoxicity or epigenetic modifications by inflammatory cells resulted in gene mutations or altered gene expression, respectively. Inflammatory cytokines/growth factors released from inflammatory cells promote cell proliferation and repair tissue injury, and inflammation serves as a “carcinogenic niche”, because these fundamental biological events are common to all types of carcinogenesis, not just inflammation-related carcinogenesis. Since clinical strategies are needed to prevent carcinogenesis, we propose the therapeutic apheresis of inflammatory cells as a means of eliminating fundamental cause of inflammation-related carcinogenesis.
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Affiliation(s)
- Futoshi Okada
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (R.I.); (K.G.); (M.O.)
- Chromosome Engineering Research Center, Tottori University, Yonago 683-8503, Japan
- Correspondence: ; Tel.: +81-859-38-6241
| | - Runa Izutsu
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (R.I.); (K.G.); (M.O.)
| | - Keisuke Goto
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (R.I.); (K.G.); (M.O.)
- Division of Gastrointestinal and Pediatric Surgery, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan
| | - Mitsuhiko Osaki
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (R.I.); (K.G.); (M.O.)
- Chromosome Engineering Research Center, Tottori University, Yonago 683-8503, Japan
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Hossam N, Matboli M, Shehata HH, Aboelhussein MM, Hassan MK, Eissa S. Toll-like receptor immune modulatory role in personalized management of colorectal cancer, review of literature. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2020. [DOI: 10.1080/23808993.2020.1816136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Nourhan Hossam
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Marwa Matboli
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Hanan H. Shehata
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Marwa M. Aboelhussein
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohamed Kamel Hassan
- Zewail city for science and Technology, Helmy Institute for medical science, Center for Genomics, Giza, Egypt
- Department of Biology/Zoology, Biotechnology Program, Port Said University, Port Said, Egypt
| | - Sanaa Eissa
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Galan-Ros J, Ramos-Arenas V, Conesa-Zamora P. Predictive values of colon microbiota in the treatment response to colorectal cancer. Pharmacogenomics 2020; 21:1045-1059. [PMID: 32896201 DOI: 10.2217/pgs-2020-0044] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The crosstalk between the colon mucosa and the microbiota represents a complex and delicate equilibrium. Gastrointestinal diseases such as inflammatory bowel disease and colorectal cancer (CRC) are associated with a state of altered microbiota composition known as dysbiosis, which seems to play a causative role in some of these illnesses. Recent reports have shown that the colorectal microbiome is responsible for the response and safety to treatments against CRC, especially immunotherapy, hence opening the possibility to use bacteria as a predictive marker and also as a therapeutic agent. The review objective is to summarize updated reports about the the implication of the colorectal microbiome in the development of CRC, in treatment response and its potential as a therapeutic approach.
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Affiliation(s)
- Jorge Galan-Ros
- Microbiology Department, Santa Lucia University Hospital (HGUSL), Cartagena, 30202, Spain
| | - Verónica Ramos-Arenas
- Clinical Analysis Department, Santa Lucia University Hospital (HGUSL), Cartagena, 30202, Spain
| | - Pablo Conesa-Zamora
- Clinical Analysis Department, Santa Lucia University Hospital (HGUSL), Cartagena, 30202, Spain.,Department of Histology & Pathology, Faculty of Life Sciences, Universidad Católica de Murcia (UCAM), Murcia, 30107, Spain.,Research Group on Molecular Pathology & Pharmacogenetics, Institute for Biomedical Research of Murcia (IMIB), Calle Mezquita sn, Cartagena, 30202, Spain
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Dawod B, Haidl ID, Azad MB, Marshall JS. Toll-like receptor 2 impacts the development of oral tolerance in mouse pups via a milk-dependent mechanism. J Allergy Clin Immunol 2020; 146:631-641.e8. [DOI: 10.1016/j.jaci.2020.01.049] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 01/05/2020] [Accepted: 01/30/2020] [Indexed: 12/31/2022]
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Babajani A, Soltani P, Jamshidi E, Farjoo MH, Niknejad H. Recent Advances on Drug-Loaded Mesenchymal Stem Cells With Anti-neoplastic Agents for Targeted Treatment of Cancer. Front Bioeng Biotechnol 2020; 8:748. [PMID: 32793565 PMCID: PMC7390947 DOI: 10.3389/fbioe.2020.00748] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 06/11/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs), as an undifferentiated group of adult multipotent cells, have remarkable antitumor features that bring them up as a novel choice to treat cancers. MSCs are capable of altering the behavior of cells in the tumor microenvironment, inducing an anti-inflammatory effect in tumor cells, inhibiting tumor angiogenesis, and preventing metastasis. Besides, MSCs can induce apoptosis and inhibit the proliferation of tumor cells. The ability of MSCs to be loaded with chemotherapeutic drugs and release them in the site of primary and metastatic neoplasms makes them a preferable choice as targeted drug delivery procedure. Targeted drug delivery minimizes unexpected side effects of chemotherapeutic drugs and improves clinical outcomes. This review focuses on recent advances on innate antineoplastic features of MSCs and the effect of chemotherapeutic drugs on viability, proliferation, and the regenerative capacity of various kinds of MSCs. It also discusses the efficacy and mechanisms of drug loading and releasing procedures along with in vivo and in vitro preclinical outcomes of antineoplastic effects of primed MSCs for clinical prospection.
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Affiliation(s)
- Amirhesam Babajani
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pegah Soltani
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elham Jamshidi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Student Research Committee, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hadi Farjoo
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Hu C, Wang Y, Liu C, Shen R, Chen B, Sun K, Rao H, Ye L, Ye J, Tian S. Systematic Profiling of Alternative Splicing for Sarcoma Patients Reveals Novel Prognostic Biomarkers Associated with Tumor Microenvironment and Immune Cells. Med Sci Monit 2020; 26:e924126. [PMID: 32683393 PMCID: PMC7388651 DOI: 10.12659/msm.924126] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background Alternative splicing (AS) events is a novel biomarker of tumor prognosis, but the role of AS events in sarcoma patients remains unclear. Material/Methods RNA-seq and clinicopathologic data of the sarcoma cohort were extracted from the TCGA database and data on AS events were downloaded from the TCGASpliceSeq database. Univariate Cox analysis, LASSO regression analysis, and multivariate Cox analysis were performed to determine the overall survival (OS)- and disease-free survival (DFS)-related AS events. Two nomograms were developed based on the independent variables, and subgroup analysis was performed. The area under the curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the nomograms. Then, we used the CIBERSORT and ESTIMATE package to determine the immune cell proportion and tumor microenvironment (TME) score, respectively. The associations between AS events-based clusters and TME and immune cells were studied. Results We identified 1945 and 1831 AS events as OS- and DFS-related AS events, respectively. Two nomograms based on the AS events and clinical data were established and the AUCs of nomograms ranged from 0.807 to 0.894. The calibration curve and DCA showed excellent performance of nomograms. In addition, the results indicated the distinct relationships between AS events-based clusters and OS, DFS, immune score, stromal score, and 10 immune cells. Conclusions Our study indicated that AS events are novel prognostic biomarkers for sarcoma patients that may be associated with the TME and immune cells.
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Affiliation(s)
- Chuan Hu
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Yuanhe Wang
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Chuan Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Rui Shen
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Bo Chen
- Wenzhou Medical University, Wenzhou, Zhejiang, China (mainland)
| | - Kang Sun
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Huili Rao
- Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China (mainland)
| | - Lin Ye
- Wenzhou Medical University, Wenzhou, Zhejiang, China (mainland)
| | - Jianjun Ye
- Wenzhou Medical University, Wenzhou, Zhejiang, China (mainland)
| | - Shaoqi Tian
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
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Dos Santos UR, Costa MC, de Freitas GJC, de Oliveira FS, Santos BR, Silva JF, Santos DA, Dias AAM, de Carvalho LD, Augusto DG, Dos Santos JL. Exposition to Biological Control Agent Trichoderma stromaticum Increases the Development of Cancer in Mice Injected With Murine Melanoma. Front Cell Infect Microbiol 2020; 10:252. [PMID: 32547964 PMCID: PMC7272596 DOI: 10.3389/fcimb.2020.00252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 04/30/2020] [Indexed: 11/29/2022] Open
Abstract
Biological control agents (BCA) are an alternative to chemical pesticides and an emerging strategy to safely eliminate plant pathogens. Trichoderma spp. are the most common fungi used as BCAs. They produce spores that are released into the air and can potentially interact with immune system of mammals. We previously showed that Trichoderma affects expression of genes encoding pattern recognition receptors (PRRs) and cytokines in mice. PRRs are involved in the recognition of microorganisms and can lead to pro-tumoral signaling. Here, we evaluated if mice injected with low doses of murine melanoma exhibited increased development of lung tumor when treated with conidia of T. stromaticum. Mice treated with T. stromaticum and inoculated with B16-F10 melanoma cells exhibited significant increase in tumor uptake (p = 0.006) and increased number of visible nodules in the lungs (p = 0.015). We also analyzed mRNA expression levels of genes encoding PRRs in lung of mice exposed to T. stromaticum and demonstrated that mice treated with T. stromaticum conidia exhibited lower expression levels of Clec7a and increased expression of Tlr4 (toll like receptor 4) compared to non-treated controls. The expression levels of Clec7a and Tlr2 were increased in mice treated with T. stromaticum and inoculated with murine melanoma compared to controls only inoculated with melanoma. Our results demonstrate that intranasal exposition to T. stromaticum increases tumor in the B16-F10 model, which may raise concerns regarding the safety of its use in agriculture.
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Affiliation(s)
- Uener R Dos Santos
- Departamento de Ciências Biológicas, Universidade Estadual de Santa Cruz, Ilhéus, Brazil
| | - Marliete C Costa
- Departamento de Microbiologia, ICB - Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Gustavo J C de Freitas
- Departamento de Microbiologia, ICB - Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Flávia S de Oliveira
- Departamento de Genética, Ecologia e Evolução - ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Bianca R Santos
- Departamento de Ciências Biológicas, Universidade Estadual de Santa Cruz, Ilhéus, Brazil
| | - Juneo F Silva
- Departamento de Ciências Biológicas, Universidade Estadual de Santa Cruz, Ilhéus, Brazil
| | - Daniel A Santos
- Departamento de Microbiologia, ICB - Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Adriana A M Dias
- Departamento de Genética, Ecologia e Evolução - ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Luciana D de Carvalho
- Departamento de Ciências Biológicas, Universidade Estadual de Santa Cruz, Ilhéus, Brazil
| | - Danillo G Augusto
- Programa de Pós-Graduação em Genética, Universidade Federal Do Paraná, Curitiba, Brazil
| | - Jane L Dos Santos
- Departamento de Ciências Biológicas, Universidade Estadual de Santa Cruz, Ilhéus, Brazil
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Panebianco C, Latiano T, Pazienza V. Microbiota Manipulation by Probiotics Administration as Emerging Tool in Cancer Prevention and Therapy. Front Oncol 2020; 10:679. [PMID: 32523887 PMCID: PMC7261958 DOI: 10.3389/fonc.2020.00679] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 04/09/2020] [Indexed: 12/11/2022] Open
Abstract
A growing body of literature indicates that microbiota plays a significant role in the development and curability of cancer, essentially due to the microbial ability to modulate immune and inflammatory responses to cancer and therapeutic treatments. Probiotics consumption, either in the form of food or supplements, is an easy and feasible way to manipulate microbiota composition and a number of recent researches have shown that it may represent a valid approach to prevent cancer onset and progression, to improve the clinical efficacy of the current anticancer treatments, and to mitigate the harmful adverse events of chemo- and radiotherapy, which often lead to scale drug doses, to delay or interrupt treatments. In this review, we gather the main in vivo studies on the current topic, focusing on the beneficial effects and underlying mechanisms provided by bacterial and yeast probiotics and their combination, in the setting of various types of cancers and different therapeutic protocols. These findings will likely open the way to consider, in future, regular probiotics intake as an adjuvant strategy in cancer prevention and management.
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Affiliation(s)
- Concetta Panebianco
- Division of Gastroenterology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Tiziana Latiano
- Oncology Department, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Valerio Pazienza
- Division of Gastroenterology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
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Antibacterial Monoclonal Antibodies Do Not Disrupt the Intestinal Microbiome or Its Function. Antimicrob Agents Chemother 2020; 64:AAC.02347-19. [PMID: 32152087 PMCID: PMC7179586 DOI: 10.1128/aac.02347-19] [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: 11/25/2019] [Accepted: 03/05/2020] [Indexed: 02/07/2023] Open
Abstract
Antibiotics revolutionized the treatment of infectious diseases; however, it is now clear that broad-spectrum antibiotics alter the composition and function of the host’s microbiome. The microbiome plays a key role in human health, and its perturbation is increasingly recognized as contributing to many human diseases. Widespread broad-spectrum antibiotic use has also resulted in the emergence of multidrug-resistant pathogens, spurring the development of pathogen-specific strategies such as monoclonal antibodies (MAbs) to combat bacterial infection. Antibiotics revolutionized the treatment of infectious diseases; however, it is now clear that broad-spectrum antibiotics alter the composition and function of the host’s microbiome. The microbiome plays a key role in human health, and its perturbation is increasingly recognized as contributing to many human diseases. Widespread broad-spectrum antibiotic use has also resulted in the emergence of multidrug-resistant pathogens, spurring the development of pathogen-specific strategies such as monoclonal antibodies (MAbs) to combat bacterial infection. Not only are pathogen-specific approaches not expected to induce resistance in nontargeted bacteria, but they are hypothesized to have minimal impact on the gut microbiome. Here, we compare the effects of antibiotics, pathogen-specific MAbs, and their controls (saline or control IgG [c-IgG]) on the gut microbiome of 7-week-old, female, C57BL/6 mice. The magnitude of change in taxonomic abundance, bacterial diversity, and bacterial metabolites, including short-chain fatty acids (SCFA) and bile acids in the fecal pellets from mice treated with pathogen-specific MAbs, was no different from that with animals treated with saline or an IgG control. Conversely, dramatic changes were observed in the relative abundance, as well as alpha and beta diversity, of the fecal microbiome and bacterial metabolites in the feces of all antibiotic-treated mice. Taken together, these results indicate that pathogen-specific MAbs do not alter the fecal microbiome like broad-spectrum antibiotics and may represent a safer, more-targeted approach to antibacterial therapy.
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Wieczorska K, Stolarek M, Stec R. The Role of the Gut Microbiome in Colorectal Cancer: Where Are We? Where Are We Going? Clin Colorectal Cancer 2020; 19:5-12. [PMID: 31678050 DOI: 10.1016/j.clcc.2019.07.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 03/01/2019] [Accepted: 07/09/2019] [Indexed: 02/08/2023]
Abstract
Microbiome (microbiota) is a community of all microorganisms inhabiting a specific site of the body, including pathogens, which distinguishes it from the physiological microflora. Intestinal dysbiosis plays a key role in the development of colorectal cancer. In the process of carcinogenesis, inflammation, immune response, and toxic metabolites play a significant role. Specific species of bacteria might affect the risk of colorectal cancer and growth of tumor already present. Assessment of changes in the intestinal microbiome during the development and progression of colorectal cancer might create a simple diagnostic tool, a useful biomarker, or might influence treatment strategies in colorectal cancer patients. Analysis of the gut microbiome provides the potential to develop noninvasive diagnostic tests that would be useful as new protective markers of colorectal cancer, prognostic markers in already present colorectal cancer, and predictive markers of response to treatment, especially immunotherapy.
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Affiliation(s)
| | | | - Rafał Stec
- Department of Oncology, Medical University of Warsaw, Warsaw, Poland.
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35
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Begka C, Pattaroni C, Mooser C, Nancey S, McCoy KD, Velin D, Maillard MH. Toll-Interacting Protein Regulates Immune Cell Infiltration and Promotes Colitis-Associated Cancer. iScience 2020; 23:100891. [PMID: 32114379 PMCID: PMC7049660 DOI: 10.1016/j.isci.2020.100891] [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] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 08/25/2019] [Accepted: 02/04/2020] [Indexed: 12/25/2022] Open
Abstract
Expression of Toll-interacting protein (Tollip), a potent TLR modulator, decreases in patients with inflammatory bowel diseases (IBD), whereas Tollip−/− mice are susceptible to colitis. Tollip expression was shown to be reduced in sporadic adenoma . In contrast, we found variable Tollip expression in patients with colitis-associated adenomas. In Tollip−/− mice challenged to develop colitis-associated cancer (CAC), tumor formation was significantly reduced owing to decreased mucosal proliferative and apoptotic indexes. This protection was associated with blunt inflammatory responses without significant changes in microbial composition. mRNA expression of Cd62l and Ccr5 homing receptors was reduced in colons of untreated Tollip−/− mice, whereas CD62L+ CD8+ T cells accumulated in the periphery. In Tollip-deficient adenomas Ctla-4 mRNA expression and tumor-infiltrating CD4+ Foxp3+ regulatory T cell (Treg) were decreased. Our data show that protection from CAC in Tollip-deficient mice is associated with defects in lymphocyte accumulation and composition in colitis-associated adenomas.
Tollip protects from colitis but promotes colitis-associated cancer onset Tollip-deficient tumors demonstrate decreased cell turnover and inflammation Tollip ablation favors naive CD8+ T cell accumulation in peripheral lymphoid organs Regulatory T cell accumulation is aberrant in Tollip-deficient tumors
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Affiliation(s)
- Christina Begka
- Service of Gastroenterology and Hepatology, Department of Medicine, University Hospital of Lausanne, CHUV-Lausanne, Rue du Bugnon 46, 1011 Lausanne, Switzerland; University of Lausanne, Chemin des Boveresses 155, 1066 Epalinges, Switzerland
| | - Céline Pattaroni
- Service of Pneumology, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Chemin de Boveresses 155, 1066 Epalinges, Switzerland
| | - Catherine Mooser
- Maurice Müller Laboratories (DBMR), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland
| | - Stéphane Nancey
- Lyon Sud Hospital, Hospices Civils de Lyon, CHU, Lyon, France
| | | | - Kathy D McCoy
- Maurice Müller Laboratories (DBMR), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Dominique Velin
- Service of Gastroenterology and Hepatology, Department of Medicine, University Hospital of Lausanne, CHUV-Lausanne, Rue du Bugnon 46, 1011 Lausanne, Switzerland; University of Lausanne, Chemin des Boveresses 155, 1066 Epalinges, Switzerland
| | - Michel H Maillard
- Service of Gastroenterology and Hepatology, Department of Medicine, University Hospital of Lausanne, CHUV-Lausanne, Rue du Bugnon 46, 1011 Lausanne, Switzerland; University of Lausanne, Chemin des Boveresses 155, 1066 Epalinges, Switzerland; Crohn and Colitis Center, Gastroentérologie Beaulieu SA, Lausanne, Switzerland.
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Li B, Hou DQ, Xu SB, Zhang JY, Zhu LF, Wang Q, Pan L, Yu M, Shen WL, Zhu WW, Zhang W, Sun YM, Liu LK. TLR2 deficiency enhances susceptibility to oral carcinogenesis by promoting an inflammatory environment. Am J Cancer Res 2019; 9:2599-2617. [PMID: 31911849 PMCID: PMC6943345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 11/04/2019] [Indexed: 06/10/2023] Open
Abstract
Inflammation is closely related to oral squamous cell carcinoma (OSCC). However, its mechanism is still obscure. Toll-like receptor 2 (TLR2) plays an important role in oral chronic inflammatory diseases, but the role of TLR2 in OSCC is unclear. Here, we investigated the expression of TLR2 expression in OSCCs and examined the potential role of TLR2 in OSCC through its association with clinicopathological features and patient outcome. We used 4-nitroquinoline 1-oxide (4-NQO) to induce a tongue cancer model in TLR2-/- and wild type (WT) mice. Histological and clinical results both indicated that TLR2 played a protective role in oral tumorigenesis. The results of a cytometric bead array (CBA) indicated that TLR2 deficiency resulted in Th1 and Th2 cytokine abnormalities, especially Th2 abnormalities. Immunohistochemistry also showed that TLR2 deficiency increases the number of tongue-infiltrating M2 macrophages. Overall, our results demonstrated that TLR2 plays an important role in the prevention of oral tumorigenesis and affects the levels of Th2 cytokines and tongue-infiltrating M2 macrophages; therefore, it may be used to prevent the development of oral cancer.
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Affiliation(s)
- Bang Li
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, People’s Republic of China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjing, People’s Republic of China
- Department of Stomatology, Wuxi Clinical College of Anhui Medical UniversityWuxi 214044, Jiangsu, People’s Republic of China
| | - De-Qiang Hou
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, People’s Republic of China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjing, People’s Republic of China
| | - Shuang-Bo Xu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, People’s Republic of China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjing, People’s Republic of China
| | - Jia-Yi Zhang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, People’s Republic of China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjing, People’s Republic of China
| | - Li-Fang Zhu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, People’s Republic of China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjing, People’s Republic of China
- Department of Stomatology, The First Affiliated Hospital of Soochow UniversitySuzhou, People’s Republic of China
| | - Qiong Wang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, People’s Republic of China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjing, People’s Republic of China
| | - Lu Pan
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, People’s Republic of China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjing, People’s Republic of China
| | - Miao Yu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, People’s Republic of China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjing, People’s Republic of China
| | - Wei-Li Shen
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, People’s Republic of China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjing, People’s Republic of China
| | - Wei-Wen Zhu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, People’s Republic of China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjing, People’s Republic of China
| | - Wei Zhang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, People’s Republic of China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjing, People’s Republic of China
| | - Ying-Ming Sun
- Department of Stomatology, Wuxi Clinical College of Anhui Medical UniversityWuxi 214044, Jiangsu, People’s Republic of China
| | - Lai-Kui Liu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, People’s Republic of China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjing, People’s Republic of China
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Kim JH, Kordahi MC, Chac D, DePaolo RW. Toll-like Receptor-6 Signaling Prevents Inflammation and Impacts Composition of the Microbiota During Inflammation-Induced Colorectal Cancer. Cancer Prev Res (Phila) 2019; 13:25-40. [PMID: 31771941 DOI: 10.1158/1940-6207.capr-19-0286] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 09/06/2019] [Accepted: 11/13/2019] [Indexed: 11/16/2022]
Abstract
Tightly regulated immune responses must occur in the intestine to avoid unwanted inflammation, which may cause chronic sequela leading to diseases such as colorectal cancer. Toll-like receptors play an important role in preventing aberrant immune responses in the intestine by sensing endogenous commensal microbiota and delivering important regulatory signals to the tissue. However, the role that specific innate receptors may play in the development of chronic inflammation and their impact on the composition of the colonic microbiota is not well understood. Using a model of inflammation-induced colorectal cancer, we found that Lactobacillus species are lost more quickly in wild-type (WT) mice than TLR6-deficient mice resulting in overall differences in bacterial composition. Despite the longer retention of Lactobacillus, the TLR6-deficient mice presented with more tumors and a worse overall outcome. Restoration of the lost Lactobacillus species suppressed inflammation, reduced tumor number, and prevented change in the abundance of Proteobacteria only when given to WT mice, indicating the effect of these Lactobacillus are TLR6 dependent. We found that the TLR6-dependent effects of Lactobacillus could be dissociated from one another via the involvement of IL10, which was necessary to dampen the inflammatory microenvironment, but had no effect on bacterial composition. Altogether, these data suggest that innate immune signals can shape the composition of the microbiota under chronic inflammatory conditions, bias the cytokine milieu of the tissue microenvironment, and influence the response to microbiota-associated therapies.
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Affiliation(s)
- Jee-Hyun Kim
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Melissa C Kordahi
- Division of Pathology, Department of Medicine, University of Washington, Seattle, Washington
| | - Denise Chac
- Division of Pathology, Department of Medicine, University of Washington, Seattle, Washington
| | - R William DePaolo
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington.
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38
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Sun F, Liang W, Tang K, Hong M, Qian J. Profiling the lncRNA-miRNA-mRNA ceRNA network to reveal potential crosstalk between inflammatory bowel disease and colorectal cancer. PeerJ 2019; 7:e7451. [PMID: 31523496 PMCID: PMC6714963 DOI: 10.7717/peerj.7451] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 07/10/2019] [Indexed: 12/20/2022] Open
Abstract
Background Because of the increasing dysplasia rate in the lifelong course of inflammatory bowel disease (IBD) patients, it is imperative to characterize the crosstalk between IBD and colorectal cancer (CRC). However, there have been no reports revealing the occurrence of the ceRNA network in IBD-related CRC. Methods In this study, we conducted gene expression profile studies of databases and performed an integrated analysis to detect the potential of lncRNA-miRNA-mRNA ceRNA in regulating disease transformation. R packages were used to screen differentially expressed mRNA, lncRNA and miRNA among CRC, IBD and normal tissue. The lncRNA-miRNA-mRNA network was constructed based on predicted miRNA-targeted lncRNAs and miRNA-targeted mRNAs. Functional analyses were then conducted to identify genes involved in the ceRNA network, and key lncRNAs were evaluated based on several clinical outcomes. Results A total of three lncRNAs, 15 miRNAs, and 138 mRNAs were identified as potential mediators in the pathophysiological processes of IBD-related CRC. Gene Ontology annotation enrichment analysis confirmed that the dysplasia process was strongly associated with immune response, response to lipopolysaccharide, and inflammatory response. Survival analysis showed that LINC01106 (HR = 1.7; p < 0.05) were strongly associated with overall survival of colorectal cancer patients. The current study identified a series of IBD-related mRNAs, miRNA, and lncRNAs, and highlighted the important role of ceRNAs in the pathogenesis of IBD-related CRC. Among them, the LINC01106-miRNA-mRNA axis was identified as vital targets for further research.
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Affiliation(s)
- Fangfang Sun
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Zhejiang University School of Medicine, Research Center of Infection and Immunity, ZJU-UCLA Joint Center for Medical Education and Research, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China
| | - Weiwei Liang
- Department of Endocrinology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kejun Tang
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Zhejiang University School of Medicine, Research Center of Infection and Immunity, ZJU-UCLA Joint Center for Medical Education and Research, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China
| | - Mengying Hong
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Zhejiang University School of Medicine, Research Center of Infection and Immunity, ZJU-UCLA Joint Center for Medical Education and Research, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China
| | - Jing Qian
- Zhejiang University School of Medicine, Research Center of Infection and Immunity, ZJU-UCLA Joint Center for Medical Education and Research, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China.,College of Pharmaceutical Sciences, Zhejiang University, Pharmaceutical Informatics Institute, Hangzhou, Zhejiang, China
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39
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Toll-Like Receptors as Therapeutic Targets in Central Nervous System Tumors. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5286358. [PMID: 31240216 PMCID: PMC6556293 DOI: 10.1155/2019/5286358] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 05/08/2019] [Indexed: 12/24/2022]
Abstract
In recent years, progress has been made in understanding the pathological, genetic, and molecular heterogeneity of central nervous system (CNS) tumors. However, improvements in risk classification, prognosis, and treatment have not been sufficient. Currently, great importance has been placed to the tumor microenvironment and the immune system, which are very important components that influence the establishment and development of tumors. Toll-like receptors (TLRs) are innate immunite system sensors of a wide variety of molecules, such as those associated with microorganisms and danger signals. TLRs are expressed on many cells, including immune cells and nonimmune cells such as neurons and cancer cells. In the tumor microenvironment, activation of TLRs plays dual antitumoral (dendritic cells, cytotoxic T cells, and natural killer cells activation) and protumoral effects (tumor cell proliferation, survival, and resistance to chemotherapy) and constitutes an area of opportunities and challenges in the development of new therapeutic strategies. Several clinical trials have been carried out, and others are currently in process; however, the results obtained to date have been contradictory and have not led to a definitive position about the use of TLR agonists in adjuvant therapy during the treatment of central nervous system (CNS) tumors. In this review, we focus on recent advances in TLR agonists as immunotherapies for treatment of CNS tumors.
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40
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Patra MC, Shah M, Choi S. Toll-like receptor-induced cytokines as immunotherapeutic targets in cancers and autoimmune diseases. Semin Cancer Biol 2019; 64:61-82. [PMID: 31054927 DOI: 10.1016/j.semcancer.2019.05.002] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 04/27/2019] [Accepted: 05/01/2019] [Indexed: 12/14/2022]
Abstract
Immune cells of the myeloid and lymphoid lineages express Toll-like receptors (TLRs) to recognize pathogenic components or cellular debris and activate the immune system through the secretion of cytokines. Cytokines are signaling molecules that are structurally and functionally distinct from one another, although their secretion profiles and signaling cascades often overlap. This situation gives rise to pleiotropic cell-to-cell communication pathways essential for protection from infections as well as cancers. Nonetheless, deregulated signaling can have detrimental effects on the host, in the form of inflammatory or autoimmune diseases. Because cytokines are associated with numerous autoimmune and cancerous conditions, therapeutic strategies to modulate these molecules or their biological responses have been immensely beneficial over the years. There are still challenges in the regulation of cytokine function in patients, even in those who take approved biological therapeutics. In this review, our purpose is to discuss the differential expression patterns of TLR-regulated cytokines and their cell type specificity that is associated with cancers and immune-system-related diseases. In addition, we highlight key structural features and molecular recognition of cytokines by receptors; these data have facilitated the development and approval of several biologics for the treatment of autoimmune diseases and cancers.
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Affiliation(s)
- Mahesh Chandra Patra
- Department of Molecular Science and Technology, Ajou University, Suwon, 16499, Republic of Korea
| | - Masaud Shah
- Department of Molecular Science and Technology, Ajou University, Suwon, 16499, Republic of Korea
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon, 16499, Republic of Korea.
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41
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O'Rourke F, Kempf VAJ. Interaction of bacteria and stem cells in health and disease. FEMS Microbiol Rev 2019; 43:162-180. [DOI: 10.1093/femsre/fuz003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 01/11/2019] [Indexed: 12/11/2022] Open
Affiliation(s)
- Fiona O'Rourke
- Institut für Medizinische Mikrobiologie und Krankenhaushygiene, University Hospital, Goethe University, Paul-Ehrlich-Str. 40, D-60596 Frankfurt am Main, Germany
| | - Volkhard A J Kempf
- Institut für Medizinische Mikrobiologie und Krankenhaushygiene, University Hospital, Goethe University, Paul-Ehrlich-Str. 40, D-60596 Frankfurt am Main, Germany
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François S, Usunier B, Forgue-Lafitte ME, L'Homme B, Benderitter M, Douay L, Gorin NC, Larsen AK, Chapel A. Mesenchymal Stem Cell Administration Attenuates Colon Cancer Progression by Modulating the Immune Component within the Colorectal Tumor Microenvironment. Stem Cells Transl Med 2018; 8:285-300. [PMID: 3045139 PMCID: PMC6392393 DOI: 10.1002/sctm.18-0117] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 10/07/2018] [Indexed: 12/17/2022] Open
Abstract
We here determine the influence of mesenchymal stem cell (MSC) therapy on the progression of solid tumors. The influence of MSCs was investigated in human colorectal cancer cells as well as in an immunocompetent rat model of colorectal carcinogenesis representative of the human pathology. Treatment with bone marrow (BM)‐derived MSCs significantly reduced both cancer initiation and cancer progression by increasing the number of tumor‐free animals as well as decreasing the number and the size of the tumors by half, thereby extending their lifespan. The attenuation of cancer progression was mediated by the capacity of the MSCs to modulate the immune component. Specifically, in the adenocarcinomas (ADKs) of MSC‐treated rats, the infiltration of CD68+ monocytes/macrophages was 50% less while the presence of CD3+ lymphocytes increased almost twofold. The MSCs reprogrammed the macrophages to become regulatory cells involved in phagocytosis thereby inhibiting the production of proinflammatory cytokines. Furthermore, the MSCs decreased NK (Natural Killer) and rTh17 cell activities, Treg recruitment, the presence of CD8+ lymphocytes and endothelial cells while restoring Th17 cell activity. The expression of miR‐150 and miR‐7 increased up to fivefold indicating a likely role for these miRNAs in the modulation of tumor growth. Importantly, MSC administration limited the damage of healthy tissues and attenuated tumor growth following radiotherapy. Taken together, we here show that that MSCs have durable action on colon cancer development by modulating the immune component of the tumor microenvironment. In addition, we identify two miRNAs associated with the capacity of MSCs to attenuate cancer growth. stem cells translational medicine2019;8:285&300
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Affiliation(s)
- Sabine François
- Radiobiology of Medical Exposure Laboratory (LRMed), Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France.,Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France
| | - Benoit Usunier
- Radiobiology of Medical Exposure Laboratory (LRMed), Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France
| | - Marie-Elisabeth Forgue-Lafitte
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France
| | - Bruno L'Homme
- Radiobiology of Medical Exposure Laboratory (LRMed), Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France
| | - Marc Benderitter
- Radiobiology of Medical Exposure Laboratory (LRMed), Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France
| | - Luc Douay
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France.,Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France.,Service d'Hématologie Biologique, Hôpital Saint-Antoine/Armand Trousseau, AP-HP, Paris, France.,Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, AP-HP, Paris, France
| | - Norbert-Claude Gorin
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France.,Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France.,Service d'Hématologie Biologique, Hôpital Saint-Antoine/Armand Trousseau, AP-HP, Paris, France.,Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, AP-HP, Paris, France
| | - Annette K Larsen
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France
| | - Alain Chapel
- Radiobiology of Medical Exposure Laboratory (LRMed), Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France.,Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France.,Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France
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Abstract
The incidence of colorectal cancer (CRC) is rapidly growing worldwide, and there is therefore a greater emphasis on studies of the treatment or prevention of CRC pathogenesis. Recent studies suggested that consideration of the microbiota is unavoidable to understand inflammation and tumorigenesis in the gastrointestinal tract. We demonstrate, using a mouse model of colitis-associated CRC, that human commensal B. fragilis protects against colon tumorigenesis. The protective role against tumor formation provided by B. fragilis is associated with inhibition of expression of the chemokine receptor CCR5 in the colon. The molecular mechanism for protection against CRC provided by B. fragilis is dependent on polysaccharide A production and is mediated by TLR2 signaling. Our results suggest that the commensal microorganism B. fragilis can be used to prevent inflammation-associated CRC development and may provide an effective therapeutic strategy for CRC. Many patients with chronic inflammation of the gut, such as that observed in inflammatory bowel disease (IBD), develop colorectal cancer (CRC). Recent studies have reported that the development of IBD and CRC partly results from an imbalanced composition of intestinal microbiota and that intestinal inflammation in these diseases can be modulated by the microbiota. The human commensal Bacteroides fragilis is best exemplified playing a protective role against the development of experimental colitis in several animal disease models. In this study, we found that gut inflammation caused by dextran sulfate sodium (DSS) treatment was inhibited by B. fragilis colonization in mice. Further, we reveal a protective role of B. fragilis treatment against colon tumorigenesis using an azoxymethane (AOM)/DSS-induced model of colitis-associated colon cancer in mice and demonstrate that the decreased tumorigenesis by B. fragilis administration is accompanied by inhibited expression of C-C chemokine receptor 5 (CCR5) in the gut. We show direct evidence that the inhibition of tumor formation provided by B. fragilis in colitis-associated CRC animals was dependent on the production of polysaccharide A (PSA) from B. fragilis and that Toll-like receptor 2 (TLR2) signaling was responsible for the protective function of B. fragilis. IMPORTANCE The incidence of colorectal cancer (CRC) is rapidly growing worldwide, and there is therefore a greater emphasis on studies of the treatment or prevention of CRC pathogenesis. Recent studies suggested that consideration of the microbiota is unavoidable to understand inflammation and tumorigenesis in the gastrointestinal tract. We demonstrate, using a mouse model of colitis-associated CRC, that human commensal B. fragilis protects against colon tumorigenesis. The protective role against tumor formation provided by B. fragilis is associated with inhibition of expression of the chemokine receptor CCR5 in the colon. The molecular mechanism for protection against CRC provided by B. fragilis is dependent on polysaccharide A production and is mediated by TLR2 signaling. Our results suggest that the commensal microorganism B. fragilis can be used to prevent inflammation-associated CRC development and may provide an effective therapeutic strategy for CRC.
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Semlali A, Parine NR, Al-Numair NS, Almutairi M, Hawsawi YM, Amri AA, Aljebreen AM, Arafah M, Almadi MA, Azzam NA, Alharbi O, Alanazi MS. Potential role of Toll-like receptor 2 expression and polymorphisms in colon cancer susceptibility in the Saudi Arabian population. Onco Targets Ther 2018; 11:8127-8141. [PMID: 30532554 PMCID: PMC6241690 DOI: 10.2147/ott.s168478] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Inflammation is a fundamental factor that contributes to the development and progression of several types of cancer including colon cancer. Toll-like receptors (TLRs) and their signaling pathways have been reported to be associated with chronic inflammation and thereby induced cancer. Our aim was to investigate the expression and polymorphisms of TLR2 and their association with colon cancer. Methods Real-time PCR and immunohistochemistry were used to investigate TLR2 gene expression and to evaluate the potential risk of predisposition to colon cancer caused by three tagging single-nucleotide polymorphisms (SNPs) on TLR2, including rs3804100, rs4696480, and rs3804099. TaqMan assay was conducted on samples from 115 patients with colon cancer and 102 age- and sex-matched normal individuals. Results We found that, TLR2 was highly expressed in epithelial colon cancer cells and both TLR2 mRNA and protein levels, and significantly decreased in tumor tissues compared to normal tissues. Two of three TLR2 SNPs increased the risk of colon cancer. However, TLR2 rs3804099 increased the risk of colon cancer development by more than 3.8- and 5-fold in female patients and patients aged less than 57 years, respectively. The T allele of TLR2 rs3804100 showed a significant association with patients less than 57 years. In silico analysis of the TLR2 nucleotide substitution in SNP rs3804100 and rs3804099 determined that 67% and 70% probability of these single nucleotide variants alter splicing phenotypes, rs3804100 more specifically result on activating an additional splice site. Genotype and allele frequencies of rs4696480 were similar between the overall study populations. Thus, TLR2 rs4696480 appear to be not involved in colon cancer in our study population. Conclusions There was a significant link between innate immunity deregulation through disruption of the TLRs and potential development of colon cancer. These SNPs can be used as screening markers for predicting colon cancer risk earlier in life to implement necessary prevention.
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Affiliation(s)
- Abdelhabib Semlali
- Groupe de Recherche en Écologie Buccale, Département de stomatologie, Faculté de Médecine Dentaire, Université Laval, Quebec City, QC, Canada, .,Genome Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia,
| | - Narasimha Reddy Parine
- Genome Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia,
| | - Nouf S Al-Numair
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, Kingdom of Saudi Arabia
| | - Mikhlid Almutairi
- Zoology Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Yousef M Hawsawi
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia
| | - Abdullah Al Amri
- Genome Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia,
| | - Abdulrahman M Aljebreen
- College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.,Division of Gastroenterology, King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia
| | - Maha Arafah
- College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Majid A Almadi
- College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.,Division of Gastroenterology, King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia
| | - Nahla Ali Azzam
- College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.,Division of Gastroenterology, King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia
| | - Othman Alharbi
- College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.,Division of Gastroenterology, King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia
| | - Mohammad Saud Alanazi
- Genome Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia,
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Sittipo P, Lobionda S, Choi K, Sari IN, Kwon HY, Lee YK. Toll-Like Receptor 2-Mediated Suppression of Colorectal Cancer Pathogenesis by Polysaccharide A From Bacteroides fragilis. Front Microbiol 2018; 9:1588. [PMID: 30065713 PMCID: PMC6056687 DOI: 10.3389/fmicb.2018.01588] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 06/26/2018] [Indexed: 12/24/2022] Open
Abstract
The beneficial role of gut microbiota in intestinal diseases has been highlighted recently. Bacteroides fragilis found in the human gastrointestinal tract is a well-studied example of a beneficial bacterium that protects against intestinal inflammation. Polysaccharide A (PSA) from B. fragilis induces the production of interleukin (IL)-10 from immune cells via Toll-like receptor 2 (TLR2) signaling in animal colitis models. The direct effect of PSA on human colorectal cancer (CRC) cells has not been studied. Here, we report the effect of PSA from B. fragilis on CRC pathogenesis in SW620 and HT29 CRC cells and the molecular signaling underlying these effects. We demonstrated that PSA induced the production of the pro-inflammatory cytokine, IL-8, but not IL-10, in CRC cells. PSA inhibited CRC cell proliferation by controlling the cell cycle and impaired CRC cell migration and invasion by suppressing epithelial mesenchymal transition. Moreover, as in the case of other animal intestinal diseases, the protective role of PSA against CRC pathogenesis was also mediated by TLR2. Our results reveal that PSA from B. fragilis plays a protective role against CRC via TLR2 signaling.
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Affiliation(s)
| | | | | | | | - Hyog Young Kwon
- Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, Cheonan, South Korea
| | - Yun Kyung Lee
- Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, Cheonan, South Korea
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Evaluation of the detection of Toll-like receptors (TLRs) in cancer development and progression in patients with colorectal cancer. PLoS One 2018; 13:e0197327. [PMID: 29883450 PMCID: PMC5993256 DOI: 10.1371/journal.pone.0197327] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 04/29/2018] [Indexed: 12/22/2022] Open
Abstract
Background Toll-like receptors (TLRs) play essential role in innate and acquired immunity, are expressed in various cell types, and are associated with altered susceptibility to many diseases, and cancers. The aim of this study was to investigate TLR2 (-196 to-174del), TLR4 (Asp299Gly and Thr399Ile) and TLR9 (T1237C and T1486C) gene polymorphisms at risk of colorectal cancer (CRC) development and progression. Methods Peripheral blood was obtained from 397 patients with adjuvant (stage II/III, n = 202) and metastatic (n = 195) CRC. Moreover, blood samples from 50 healthy volunteers and 40 patients with adenomatous polyps were also included as control groups. DNA from patients and controls was analyzed using PCR and PCR-RFLP for genotyping functional polymorphism within TLR2, TLR4 and TLR9 genotypes. Results TLR2–196 to-174del/del genotype was detected in 76.6% of the patients and was significantly higher that the controls groups (p<0.001). TLR4 Asp299Gly, TLR4 Thr399Ile, TLR9 T1237C and T1486C homozygous genotypes were detected in 70.5%, 70.5%, 61.5% and 61.5% of the patients respectively, and were also significantly higher than that in the control groups (p<0.001). All polymorphisms detected were also significantly associated with the metastatic disease (p<0.001) leading to shorter overall survival (p<0.001); whereas, TLR4 Asp299Gly and Thr399Ile polymorphisms were significantly associated with KRAS mutations. Conclusions The detection of higher frequencies of the TLR2, TLR4 and/or TLR9 polymorphisms in CRC patients compared with the control groups highlight the role of these polymorphism in CRC development and cancer progression.
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Role of Pattern Recognition Receptors in KSHV Infection. Cancers (Basel) 2018; 10:cancers10030085. [PMID: 29558453 PMCID: PMC5876660 DOI: 10.3390/cancers10030085] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 03/12/2018] [Accepted: 03/16/2018] [Indexed: 02/06/2023] Open
Abstract
Kaposi’s sarcoma-associated herpesvirus or Human herpesvirus-8 (KSHV/HHV-8), an oncogenic human herpesvirus and the leading cause of cancer in HIV-infected individuals, is a major public health concern with recurring reports of epidemics on a global level. The early detection of KSHV virus and subsequent activation of the antiviral immune response by the host’s immune system are crucial to prevent KSHV infection. The host’s immune system is an evolutionary conserved system that provides the most important line of defense against invading microbial pathogens, including viruses. Viruses are initially detected by the cells of the host innate immune system, which evoke concerted antiviral responses via the secretion of interferons (IFNs) and inflammatory cytokines/chemokines for elimination of the invaders. Type I IFN and cytokine gene expression are regulated by multiple intracellular signaling pathways that are activated by germline-encoded host sensors, i.e., pattern recognition receptors (PRRs) that recognize a conserved set of ligands, known as ‘pathogen-associated molecular patterns (PAMPs)’. On the contrary, persistent and dysregulated signaling of PRRs promotes numerous tumor-causing inflammatory events in various human cancers. Being an integral component of the mammalian innate immune response and due to their constitutive activation in tumor cells, targeting PRRs appears to be an effective strategy for tumor prevention and/or treatment. Cellular PRRs are known to respond to KSHV infection, and KSHV has been shown to be armed with an array of strategies to selectively inhibit cellular PRR-based immune sensing to its benefit. In particular, KSHV has acquired specific immunomodulatory genes to effectively subvert PRR responses during the early stages of primary infection, lytic reactivation and latency, for a successful establishment of a life-long persistent infection. The current review aims to comprehensively summarize the latest advances in our knowledge of role of PRRs in KSHV infections.
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Maisonneuve C, Irrazabal T, Martin A, Girardin SE, Philpott DJ. The Impact of the Gut Microbiome on Colorectal Cancer. ANNUAL REVIEW OF CANCER BIOLOGY-SERIES 2018. [DOI: 10.1146/annurev-cancerbio-030617-050240] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Charles Maisonneuve
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;,
| | - Thergiory Irrazabal
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;,
| | - Alberto Martin
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;,
| | - Stephen E. Girardin
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;,
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Dana J. Philpott
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;,
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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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Zou S, Fang L, Lee MH. Dysbiosis of gut microbiota in promoting the development of colorectal cancer. Gastroenterol Rep (Oxf) 2018; 6:1-12. [PMID: 29479437 PMCID: PMC5806407 DOI: 10.1093/gastro/gox031] [Citation(s) in RCA: 183] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 07/21/2017] [Indexed: 12/11/2022] Open
Abstract
Gastrointestinal microbiome, containing at least 100 trillion bacteria, resides in the mucosal surface of human intestine. Recent studies show that perturbations in the microbiota may influence physiology and link to a number of diseases, including colon tumorigenesis. Colorectal cancer (CRC), the third most common cancer, is the disease resulting from multi-genes and multi-factors, but the mechanistic details between gut microenvironment and CRC remain poorly characterized. Thanks to new technologies such as metagenome sequencing, progress in large-scale analysis of the genetic and metabolic profile of gut microbial has been possible, which has facilitated studies about microbiota composition, taxonomic alterations and host interactions. Different bacterial species and their metabolites play critical roles in the development of CRC. Also, microbiota is important in the inflammatory response and immune processes deregulation during the development and progression of CRC. This review summarizes current studies regarding the association between gastrointestinal microbiota and the development of CRC, which provides insights into the therapeutic strategy of CRC.
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Affiliation(s)
- Shaomin Zou
- Research Institute of Gastroenterology, Sun Yat-sen University, Guangzhou 510020, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510020, China
| | - Lekun Fang
- Research Institute of Gastroenterology, Sun Yat-sen University, Guangzhou 510020, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510020, China
| | - Mong-Hong Lee
- Research Institute of Gastroenterology, Sun Yat-sen University, Guangzhou 510020, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510020, China
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