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Bai X, Guo YR, Zhao ZM, Li XY, Dai DQ, Zhang JK, Li YS, Zhang CD. Macrophage polarization in cancer and beyond: from inflammatory signaling pathways to potential therapeutic strategies. Cancer Lett 2025; 625:217772. [PMID: 40324582 DOI: 10.1016/j.canlet.2025.217772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/30/2025] [Accepted: 05/02/2025] [Indexed: 05/07/2025]
Abstract
Macrophages are innate immune cells distributed throughout the body that play vital roles in organ development, tissue homeostasis, and immune surveillance. Macrophages acquire a binary M1/M2 polarized phenotype through signaling cascades upon sensing different signaling molecules in the environment, thereby playing a core role in a series of immune tasks, rendering precise regulation essential. M1/M2 macrophage phenotypes regulate inflammatory responses, while controlled activation of inflammatory signaling pathways is involved in regulating macrophage polarization. Among the relevant signaling pathways, we focus on the six well-characterized NF-κB, MAPK, JAK-STAT, PI3K/AKT, inflammasome, and cGAS-STING inflammatory pathways, and elucidate their roles and crosstalk in macrophage polarization. Furthermore, the effects of many environmental signals that influence macrophage polarization are investigated by modulating these pathways in vivo and in vitro. We thus detail the physiological and pathophysiological status of these six inflammatory signaling pathways and involvement in regulating macrophage polarization in cancer and beyond, as well as describe potential therapeutic approaches targeting these signaling pathways. In this review, the latest research advances in inflammatory signaling pathways regulating macrophage polarization are reviewed, as targeting these inflammatory signaling pathways provides suitable strategies to intervene in macrophage polarization and various tumor and non-tumor diseases.
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Affiliation(s)
- Xiao Bai
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Yun-Ran Guo
- Health Sciences Institute of China Medical University, Shenyang 110122, China
| | - Zhe-Ming Zhao
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Xin-Yun Li
- Clinical Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Dong-Qiu Dai
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China; Cancer Center, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Jia-Kui Zhang
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Yong-Shuang Li
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Chun-Dong Zhang
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China; Central Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
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2
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Zhang R, Zhang X, Lau HCH, Yu J. Gut microbiota in cancer initiation, development and therapy. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1283-1308. [PMID: 39821827 DOI: 10.1007/s11427-024-2831-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 12/12/2024] [Indexed: 01/19/2025]
Abstract
Cancer has long been associated with genetic and environmental factors, but recent studies reveal the important role of gut microbiota in its initiation and progression. Around 13% of cancers are linked to infectious agents, highlighting the need to identify the specific microorganisms involved. Gut microbiota can either promote or inhibit cancer growth by influencing oncogenic signaling pathways and altering immune responses. Dysbiosis can lead to cancer, while certain probiotics and their metabolites may help reestablish micro-ecological balance and improve anti-tumor immune responses. Research into targeted approaches that enhance therapy with probiotics is promising. However, the effects of probiotics in humans are complex and not yet fully understood. Additionally, methods to counteract harmful bacteria are still in development. Early clinical trials also indicate that modifying gut microbiota may help manage side effects of cancer treatments. Ongoing research is crucial to understand better how gut microbiota can be used to improve cancer prevention and treatment outcomes.
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Affiliation(s)
- Ruyi Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiang Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Harry Cheuk Hay Lau
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
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3
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Nobels A, van Marcke C, Jordan BF, Van Hul M, Cani PD. The gut microbiome and cancer: from tumorigenesis to therapy. Nat Metab 2025; 7:895-917. [PMID: 40329009 DOI: 10.1038/s42255-025-01287-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 03/20/2025] [Indexed: 05/08/2025]
Abstract
The gut microbiome has a crucial role in cancer development and therapy through its interactions with the immune system and tumour microenvironment. Although evidence links gut microbiota composition to cancer progression, its precise role in modulating treatment responses remains unclear. In this Review, we summarize current knowledge on the gut microbiome's involvement in cancer, covering its role in tumour initiation and progression, interactions with chemotherapy, radiotherapy and targeted therapies, and its influence on cancer immunotherapy. We discuss the impact of microbial metabolites on immune responses, the relationship between specific bacterial species and treatment outcomes, and potential microbiota-based therapeutic strategies, including dietary interventions, probiotics and faecal microbiota transplantation. Understanding these complex microbiota-immune interactions is critical for optimizing cancer therapies. Future research should focus on defining microbial signatures associated with treatment success and developing targeted microbiome modulation strategies to enhance patient outcomes.
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Affiliation(s)
- Amandine Nobels
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute (LDRI), Metabolism and Nutrition Research Group (MNUT), Brussels, Belgium
- UCLouvain, Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique (IREC), Pole of Medical Imaging, Radiotherapy and Oncology (MIRO), Brussels, Belgium
| | - Cédric van Marcke
- UCLouvain, Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique (IREC), Pole of Medical Imaging, Radiotherapy and Oncology (MIRO), Brussels, Belgium
- Department of Medical Oncology, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Brussels, Belgium
- Breast Clinic, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Bénédicte F Jordan
- UCLouvain, Université catholique de Louvain, Biomedical Magnetic Resonance group (REMA), Louvain Drug Research Institute (LDRI), Brussels, Belgium
| | - Matthias Van Hul
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute (LDRI), Metabolism and Nutrition Research Group (MNUT), Brussels, Belgium.
- Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), WELBIO department, WEL Research Institute, Wavre, Belgium.
| | - Patrice D Cani
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute (LDRI), Metabolism and Nutrition Research Group (MNUT), Brussels, Belgium.
- Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), WELBIO department, WEL Research Institute, Wavre, Belgium.
- UCLouvain, Université catholique de Louvain, Institute of Experimental and Clinical Research (IREC), Brussels, Belgium.
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4
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Wizenty J, Sigal M. Helicobacter pylori, microbiota and gastric cancer - principles of microorganism-driven carcinogenesis. Nat Rev Gastroenterol Hepatol 2025; 22:296-313. [PMID: 40011753 DOI: 10.1038/s41575-025-01042-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/16/2025] [Indexed: 02/28/2025]
Abstract
The demonstration that Helicobacter pylori is a pathogenic bacterium with marked carcinogenic potential has paved the way for new preventive approaches for gastric cancer. Although decades of research have uncovered complex interactions of H. pylori with epithelial cells, current insights have refined our view on H. pylori-associated carcinogenesis. Specifically, the cell-type-specific effects on gastric stem and progenitor cells deep in gastric glands provide a new view on the ability of the bacteria to colonize long-term, manipulate host responses and promote gastric pathology. Furthermore, new, large-scale epidemiological data have shed light on factors that determine why only a subset of carriers progress to gastric cancer. Currently, technological advances have brought yet another revelation: H. pylori is far from the only microorganism able to colonize the stomach. Instead, the stomach is colonized by a diverse gastric microbiota, and there is emerging evidence for the occurrence and pathological effect of dysbiosis resulting from an aberrant interplay between H. pylori and the gastric mucosa. With the weight of this evidence mounting, here we consider how the lessons learned from H. pylori research inform and synergize with this emerging field to bring a more comprehensive understanding of the role of microbes in gastric carcinogenesis.
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Affiliation(s)
- Jonas Wizenty
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy and BIH Charité Clinician Scientist Program, Berlin, Germany
| | - Michael Sigal
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
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Ge Y, Janson V, Dong Z, Liu H. Role and mechanism of IL-33 in bacteria infection related gastric cancer continuum: From inflammation to tumor progression. Biochim Biophys Acta Rev Cancer 2025; 1880:189296. [PMID: 40058506 DOI: 10.1016/j.bbcan.2025.189296] [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: 09/04/2024] [Revised: 03/02/2025] [Accepted: 03/03/2025] [Indexed: 03/22/2025]
Abstract
Gastric cancer, a globally prevalent malignant tumor, is characterized by low early diagnosis rate, high metastasis rate, and poor prognosis, particularly in East Asia, Eastern Europe, and South America. Helicobacter pylori (H. pylori) is recognized as the primary risk factor for gastric cancer. However, the fact that fewer than 3 % of infected individuals develop cancer suggests that other bacteria may also influence gastric carcinogenesis. A diverse community of microorganisms may interact with H. pylori, thereby driving disease progression. Here, the role of the cytokine IL-33, a member of the IL-1 family, is scrutinized. Its production can be induced by H. pylori through the activation of specific signaling pathways, and it contributes to the inflammatory environment by promoting the release of pro-inflammatory cytokines. This article reviews the conflicting evidence regarding IL-33's role in the progression from gastritis to gastric cancer and discusses the potential therapeutic implications of targeting the IL-33/ST2 axis, with various antibodies and inhibitors in development or undergoing clinical trials for inflammatory diseases. However, the role of IL-33 in gastric cancer treatment remains to be fully elucidated, with its effects potentially dependent on the cellular context and stage of cancer progression. In summary, this review provides a comprehensive overview of the intricate relationship between gastric microbiota, IL-33, and gastritis - gastric cancer transition, offering insights into potential therapeutic targets and the development of novel treatment strategies.
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Affiliation(s)
- Yunxiao Ge
- Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Victor Janson
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Zigang Dong
- Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, China; China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, Henan 450008, China
| | - Hui Liu
- Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, China; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, Henan 450008, China.
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6
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Ye Y, Bin B, Chen P, Chen J, Meng A, Yu L, Yang F, Cui H. Advances in the study of the role of gastric microbiota in the progression of gastric cancer. Microb Pathog 2025; 199:107240. [PMID: 39708981 DOI: 10.1016/j.micpath.2024.107240] [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: 07/10/2024] [Revised: 12/17/2024] [Accepted: 12/18/2024] [Indexed: 12/23/2024]
Abstract
Gastric cancer (GC) is a common malignant tumor and the third most common cancer in China in terms of mortality. Stomach microorganisms play complex roles in the development of GC. The carcinogenic mechanism of Helicobacter pylori has been elucidated, and there is much evidence that other microorganisms in the gastric mucosa are also heavily involved in the disease progression of this cancer. However, their carcinogenic mechanisms have not yet been fully elucidated. The microbial compositions associated with the normal stomach, precancerous lesions, and GC are distinctly different and have a complex evolutionary mechanism. The dysregulation of gastric microbiota may play a key role in the oncogenic process from precancerous lesions to malignant gastric tumors. In this review, we explore the potential translational and clinical implications of intragastric microbes in the diagnosis, prognosis, and treatment of GC. Finally, we summarize the research dilemmas and solutions concerning intragastric microbes, emphasizing that they should be at the forefront of strategies for GC prevention and treatment.
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Affiliation(s)
- Yu Ye
- Inner Mongolia Medical University, No 60, Xi Lin Guo Le South Road, Hohhot, 010020, Inner Mongolia Autonomous Region, PR China
| | - Ba Bin
- Department of Oncology, Ordos Hospital of Traditional Chinese Medicine, No 5, Yongning Street, Kangbashi District, Ordos City, Inner Mongolia Autonomous Region, PR China
| | - Pengfei Chen
- The Affiliated Hospital of Inner Mongolia Medical University, PR China
| | - Jing Chen
- Medical Department of Ordos College of Applied Technology, PR China
| | - Aruna Meng
- Inner Mongolia Medical University, No 60, Xi Lin Guo Le South Road, Hohhot, 010020, Inner Mongolia Autonomous Region, PR China
| | - Lei Yu
- Department of Pharmacy, Traditional Chinese Medicine Hospital of Inner Mongolia Autonomous Region, Hohhot, Inner Mongolia Autonomous Region, 010020, PR China
| | - Fan Yang
- Inner Mongolia Autonomous Region Blood Central, PR China.
| | - Hongwei Cui
- Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, No 42, Zhao Wu Da Road, Hohhot, 010020, Inner Mongolia Autonomous Region, PR China.
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Liang C, Wang S, Wu C, Wang J, Xu L, Wan S, Zhang X, Hou Y, Xia Y, Xu L, Huang X, Xie H. Role of the AKT signaling pathway in regulating tumor-associated macrophage polarization and in the tumor microenvironment: A review. Medicine (Baltimore) 2025; 104:e41379. [PMID: 39889181 PMCID: PMC11789917 DOI: 10.1097/md.0000000000041379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 01/02/2025] [Accepted: 01/10/2025] [Indexed: 02/02/2025] Open
Abstract
Tumor-associated macrophages (TAMs) are present in and are important components of the tumor microenvironment (TME). TAMs differentiate into 2 functionally distinct morphologies, classically activated (M1)-type TAMs and alternatively activated (M2)-type TAMs, when stimulated by different cytokines. The 2 types of TAMs exhibit distinct properties and functions. M1 TAMs secrete high levels of pro-inflammatory and chemotactic factors, exerting proinflammatory, antitumor effects. Conversely, M2 TAMs alter the extracellular matrix, facilitate cellular immune escape, and stimulate tumor angiogenesis, thereby promoting anti-inflammatory responses and tumor growth. The ratio of M1 TAMs to M2 TAMs in the TME is closely related to the prognosis of the tumor. Tumor cells and other cells in the TME can regulate the polarization of TAMs and thus promote tumor progression through the secretion of various substances; however, polarized TAMs can also act on various cells in the TME through the secretion of exosomes, thus forming a positive feedback loop. Therefore, modulating the phenotype of TAMs in the TME or blocking the polarization of M2 TAMs might be a new approach for cancer treatment. However, the intracellular signaling pathways involved in the polarization of TAMs are poorly understood. The AKT signaling pathway is an important signaling pathway involved in the polarization, growth, proliferation, recruitment, and apoptosis of TAMs, as well as the action of TAMs on other cells within the TME. This paper reviews the AKT signaling pathway in the polarization of TAMs and the regulation of the TME and provides new ideas for tumor immunotherapy.
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Affiliation(s)
- Changming Liang
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Song Wang
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Chengwei Wu
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Jiawei Wang
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Lishuai Xu
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Senlin Wan
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Xu Zhang
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Yinfen Hou
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Yabin Xia
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Li Xu
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Xiaoxu Huang
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Hao Xie
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
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Zhang Z, Liu J, Wang Y, Zhang L, Zhou T, Huang Y, Zhu T. Toll-like Receptor 4 Signaling Mediates Gastritis and Gastric Cancer. Curr Mol Med 2025; 25:388-398. [PMID: 38204278 DOI: 10.2174/0115665240276139231206071742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/02/2023] [Accepted: 10/25/2023] [Indexed: 01/12/2024]
Abstract
The stomach is a crucial digestive organ in the human body, highly susceptible to inflammation or pathogen invasion, which can lead to various gastric diseases, including gastric cancer. Toll-like receptors (TLRs) are the first line of defense against pathogen invasion. TLR4, a member of the TLRs family, recognizes pathogen and danger-related molecular patterns to induce inflammatory responses. Helicobacter pylori (H. pylori) is a significant factor in gastric health, and TLR4 recognizes H. pylori -LPS to trigger an inflammatory response. Downstream TLR4 signaling generates proinflammatory cytokines that initiate inflammation in the gastric mucosa. In addition, TLR4 gene polymorphisms can increase health risks. This study aims to investigate the contribution of TLR4 to the inflammatory response in gastric diseases and the relation between TLR4 and H. pylori, TLR4 gene polymorphisms, and how TLR4 affects gastric diseases' possible pathways to provide further insight for future prevention and clinical treatment strategies.
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Affiliation(s)
- Zepeng Zhang
- Department of pharmacy, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, China
| | - Ju Liu
- Department of pharmacy, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, China
| | - Yi Wang
- Department of pharmacy, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, China
| | - Lei Zhang
- Department of pharmacy, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, China
| | - Tong Zhou
- Department of pharmacy, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, China
| | - Yu Huang
- Department of pharmacy, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, China
| | - Tongtong Zhu
- Department of pharmacy, Kunshan Hospital of Integrated Traditional Chinese and Western Medicine, Suzhou, China
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Nguyen DK, Kang MJ, Oh SJ, Park HJ, Kim SH, Yu JH, Lee Y, Lee HS, Yang JW, Seo Y, Ahn JS, Kim HS. Parvimonas micra-polarized M2-like tumor-associated macrophages accelerate colorectal cancer development via IL-8 secretion. Anim Cells Syst (Seoul) 2024; 29:24-34. [PMID: 39777026 PMCID: PMC11703389 DOI: 10.1080/19768354.2024.2442401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 10/27/2024] [Accepted: 11/29/2024] [Indexed: 01/11/2025] Open
Abstract
Parvimonas micra (Pm), a periodontal pathogen, has been implicated in the impairment of anti-tumor responses in colorectal cancer (CRC). The tumor microenvironment in CRC involves tumor-associated macrophages (TAMs), which are pivotal in modulating tumor-associated immune responses. The polarization of TAMs towards an M2-like phenotype promotes CRC progression by suppressing the immune system. However, the mechanisms by which Pm affects the progression of CRC remain inadequately elucidated. In this study, we explored the impact of Pm infection on CRC cell characteristics, including proliferation, chemoresistance, migration, and macrophage polarization. We found that Pm-infected THP-1-derived macrophages exhibited elevated interleukin-10 levels, a well-established M2 marker. Conditioned media from Pm-treated THP-1 cells significantly enhanced CRC cell proliferation, cisplatin resistance, and migration, and interleukin-8 was identified as a key factor. Consistent with the in vitro results, an azoxymethane/dextran sodium sulfate mouse model treated with oral Pm showed accelerated CRC tumor growth. These results offer mechanistic insights into the influence of Pm infection on tumor microenvironment in CRC through M2-like macrophage polarization. The identified pathways may serve as potential targets for therapeutic interventions for CRC.
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Affiliation(s)
- Dang Khoa Nguyen
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan, Republic of Korea
| | - Min-Jung Kang
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
| | - Su-Jeong Oh
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan, Republic of Korea
| | - Hee-Jeong Park
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan, Republic of Korea
| | - Seong Hui Kim
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan, Republic of Korea
| | - Jeong Hyun Yu
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan, Republic of Korea
| | - Yunji Lee
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan, Republic of Korea
| | - Hyeon Seo Lee
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan, Republic of Korea
| | - Ji Won Yang
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
| | - Yoojin Seo
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
| | - Ji-Su Ahn
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
| | - Hyung-Sik Kim
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, Republic of Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan, Republic of Korea
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10
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Li Y, He C, Lu N. Impacts of Helicobacter pylori infection and eradication on gastrointestinal microbiota: An up-to-date critical review and future perspectives. Chin Med J (Engl) 2024; 137:2833-2842. [PMID: 39501846 DOI: 10.1097/cm9.0000000000003348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Indexed: 12/17/2024] Open
Abstract
ABSTRACT Helicobacter pylori ( H. pylori ) infects approximately half of the population worldwide and causes chronic gastritis, peptic ulcers, and gastric cancer. Test-and-treat strategies have been recommended for the prevention of H. pylori -associated diseases. Advancements in high-throughput sequencing technologies have broadened our understanding of the complex gastrointestinal (GI) microbiota and its role in maintaining host homeostasis. Recently, an increasing number of studies have indicated that the colonization of H. pylori induces dramatic alterations in the gastric microbiota, with a predominance of H. pylori and a reduction in microbial diversity. Dysbiosis of the gut microbiome has also been observed after H. pylori infection, which may play a role in the development of colorectal cancer. However, there is concern regarding the impact of antibiotics on the gut microbiota during H. pylori eradication. In this review, we summarize the current literature concerning how H. pylori infection reshapes the GI microbiota and the underlying mechanisms, including changes in the gastric environment, immune responses, and persistent inflammation. Additionally, the impacts of H. pylori eradication on GI microbial homeostasis and the use of probiotics as adjuvant therapy are also discussed. The shifts in the GI microbiota and their crosstalk with H. pylori may provide potential targets for H. pylori -related gastric diseases and extragastric manifestations.
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Affiliation(s)
- Yu Li
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- HuanKui Academy, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Cong He
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Nonghua Lu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
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11
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Zeng R, Gou H, Lau HCH, Yu J. Stomach microbiota in gastric cancer development and clinical implications. Gut 2024; 73:2062-2073. [PMID: 38886045 PMCID: PMC11672014 DOI: 10.1136/gutjnl-2024-332815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 06/05/2024] [Indexed: 06/20/2024]
Abstract
Gastric cancer (GC) is one of the most common malignancies and a prominent cause of cancer mortality worldwide. A distinctive characteristic of GC is its intimate association with commensal microbial community. Although Helicobacter pylori is widely recognised as an inciting factor of the onset of gastric carcinogenesis, increasing evidence has indicated the substantial involvement of microbes that reside in the gastric mucosa during disease progression. In particular, dysregulation in gastric microbiota could play pivotal roles throughout the whole carcinogenic processes, from the development of precancerous lesions to gastric malignancy. Here, current understanding of the gastric microbiota in GC development is summarised. Potential translational and clinical implications of using gastric microbes for GC diagnosis, prognosis and therapeutics are also evaluated, with further discussion on conceptual haziness and limitations at present. Finally, we highlight that modulating microbes is a novel and promising frontier for the prevention and management of GC, which necessitates future in-depth investigations.
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Affiliation(s)
- Ruijie Zeng
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Hongyan Gou
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Harry Cheuk Hay Lau
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
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12
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Liu MM, Zhu HH, Bai J, Tian ZY, Zhao YJ, Boekhout T, Wang QM. Breast cancer colonization by Malassezia globosa accelerates tumor growth. mBio 2024; 15:e0199324. [PMID: 39235230 PMCID: PMC11481877 DOI: 10.1128/mbio.01993-24] [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: 07/02/2024] [Accepted: 07/18/2024] [Indexed: 09/06/2024] Open
Abstract
Malassezia globosa is a lipophilic basidiomycetous yeast that occurs abundantly in breast tumors and that may contribute to a shortened overall survival of breast cancer (BRAC) patients, suggesting that the yeast may participate in the carcinogenesis of BRAC. However, the mechanisms involved in the M. globosa-based acceleration of BRAC are unknown. Here, we show that M. globosa can colonize mammary tissue in 7,12-dimethylbenz[a] anthracene-induced mice. The abundance of M. globosa shortened the overall survival and increased the tumor incidence. Transcriptome data illustrated that IL-17A plays a key role in tumor growth due to M. globosa colonization, and tumor-associated macrophage infiltration was elevated during M. globosa colonization which triggers M2 polarization of macrophages via toll-like receptors 4/nuclear factor kappa-B (Nf-κB) signaling. Our results show that the expression of sphingosine kinase 1 (Sphk1) is increased in breast tumors after inoculation with M. globosa. Moreover, we discovered that Sphk1-specific small interfering RNA blocked the formation of lipid droplets, which can effectively alleviate the expression of the signal transducer and activator of the transcription 3 (STAT3)/Nf-κB pathway. Taken together, our results demonstrate that M. globosa could be a possible factor for the progression of BRAC. The mechanisms by which M. globosa promotes BRAC development involve the IL-17A/macrophage axis. Meanwhile, Sphk1 overexpression was induced by M. globosa infection, which also promoted the proliferation of MCF-7 cells.IMPORTANCELiterature has suggested that Malassezia globosa is associated with breast tumors; however, this association has not been confirmed. Here, we found that M. globosa colonizes in breast fat pads leading to tumor growth. As a lipophilic yeast, the expression of sphingosine kinase 1 (Sphk1) was upregulated to promote tumor growth after M. globosa colonization. Moreover, the IL-17A/macrophages axis plays a key role in mechanisms involved in the M. globosa-induced breast cancer acceleration from the tumor immune microenvironment perspective.
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Affiliation(s)
- Miao-Miao Liu
- School of Life Sciences, Institute of Life Sciences and Green Development, Hebei University, Baoding, Hebei, China
| | - Hui-Hui Zhu
- School of Life Sciences, Institute of Life Sciences and Green Development, Hebei University, Baoding, Hebei, China
| | - Jie Bai
- School of Life Sciences, Institute of Life Sciences and Green Development, Hebei University, Baoding, Hebei, China
| | - Zi-Ye Tian
- School of Life Sciences, Institute of Life Sciences and Green Development, Hebei University, Baoding, Hebei, China
| | - Yu-Jing Zhao
- School of Life Sciences, Institute of Life Sciences and Green Development, Hebei University, Baoding, Hebei, China
| | - Teun Boekhout
- College of Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Qi-Ming Wang
- School of Life Sciences, Institute of Life Sciences and Green Development, Hebei University, Baoding, Hebei, China
- Hebei Basic Science Center for Biotic Interaction, Hebei University, Baoding, Hebei, China
- Engineering Research Center of Ecological Safety and Conservation in Beijing-Tianjin-Hebei (Xiong’an New Area) of MOE, Xiong’an, China
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13
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Liu C, Fu L, Wang Y, Yang W. Influence of the gut microbiota on immune cell interactions and cancer treatment. J Transl Med 2024; 22:939. [PMID: 39407240 PMCID: PMC11476117 DOI: 10.1186/s12967-024-05709-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 09/26/2024] [Indexed: 10/20/2024] Open
Abstract
The tumour microenvironment represents a novel frontier in oncological research. Over the past decade, accumulating evidence has underscored the importance of the tumour microenvironment (TME), including tumour cells, stromal cells, immune cells, and various secreted factors, which collectively influence tumour growth, invasion, and responses to therapeutic agents. Immune cells within the TME are now widely acknowledged to play pivotal roles in tumour development and treatment. While some perspectives have posited that immune cells within the TME facilitate tumour progression and confer resistance to therapeutic interventions, contrasting conclusions also exist. Affirmative and negative conclusions appear to be context dependent, and a unified consensus has yet to be reached. The burgeoning body of research on the relationship between the gut microbiota and tumours in recent years has led to a growing understanding. Most studies have indicated that specific components of the gut microbiota, such as unique bacterial communities or specific secretory factors, play diverse roles in regulating immune cells within the TME, thereby influencing the prognosis and outcomes of cancer treatments. A detailed understanding of these factors could provide novel insights into the TME and cancer therapy. In this study, we aimed to synthesise information on the interactions between the gut microbiota and immune cells within the TME, providing an in-depth exploration of the potential guiding implications for future cancer therapies.
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Affiliation(s)
- Chunxiao Liu
- Department of Gastroenterological Surgery, Hengqin Hospital, First Affiliated Hospital of Guangzhou Medical University, No. 118 Baoxing Road, Hengqin, Guangdong, 519031, China
| | - Lingfeng Fu
- Department of Gastroenterological Surgery, Hengqin Hospital, First Affiliated Hospital of Guangzhou Medical University, No. 118 Baoxing Road, Hengqin, Guangdong, 519031, China
| | - Yuxin Wang
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, No. 1838, North Guangzhou Avenue, Guangzhou, Guangdong, 510515, China.
- Central Laboratory, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
| | - Weijun Yang
- Department of Gastroenterological Surgery, Hengqin Hospital, First Affiliated Hospital of Guangzhou Medical University, No. 118 Baoxing Road, Hengqin, Guangdong, 519031, China.
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14
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Tong J, Yao G, Chen Y, Xie H, Zheng X, Sun L, Huang Z, Xie Z. Mesenchymal Stem Cells Regulate Microglial Polarization via Inhibition of the HMGB1/TLR4 Signaling Pathway in Diabetic Retinopathy. Inflammation 2024; 47:1728-1743. [PMID: 38625640 DOI: 10.1007/s10753-024-02005-6] [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: 01/05/2024] [Revised: 02/29/2024] [Accepted: 03/05/2024] [Indexed: 04/17/2024]
Abstract
Diabetic retinopathy (DR) is recognized as the most prevalent retinal degenerative disorder. Inflammatory response usually precedes microvascular alteration and is the primary factor of diabetic retinopathy. Activated microglia express many pro-inflammatory cytokines that exacerbate retina inflammation and disruption. In the present study, we found that MSCs alleviated blood-retina barrier (BRB) breakdown in diabetic rats, as evidenced by reduced retinal edema, decreased vascular leakage, and increased occludin expression. The MSC-treated retinal microglia exhibited reduced expression of M1-phenotype markers in the diabetic rats, including inducible nitric oxide synthase (iNOS), CD16, and pro-inflammatory cytokines. On the other hand, MSCs increased the expression of M2-phenotype markers, such as arginase-1 (Arg-1), CD206, and anti-inflammatory cytokines. HMGB1/TLR4 signaling pathway is activated in DR and inhibited after MSC treatment. Consistent with in vivo evidence, MSCs drove BV2 microglia toward M2 phenotype in vitro. Overexpression of HMGB1 in microglia reversed the effects of MSC treatment, suggesting HMGB1/TLR4 pathway is necessary for MSCs' regulatory effects on microglia polarization. Collectively, MSCs exert beneficial effects on DR by polarizing microglia from M1 toward M2 phenotype via inhibiting the HMGB1/TLR4 signaling pathway.
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Affiliation(s)
- Jun Tong
- Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Department of Ophthalmology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Genhong Yao
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yueqin Chen
- Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Hairong Xie
- Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xinyu Zheng
- Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Lingyun Sun
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Zhenping Huang
- Department of Ophthalmology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Zhenggao Xie
- Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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15
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Vásquez Martínez IP, Pérez-Campos E, Pérez-Campos Mayoral L, Cruz Luis HI, Pina Canseco MDS, Zenteno E, Bazán Salinas IL, Martínez Cruz M, Pérez-Campos Mayoral E, Hernández-Huerta MT. O-GlcNAcylation: Crosstalk between Hemostasis, Inflammation, and Cancer. Int J Mol Sci 2024; 25:9896. [PMID: 39337387 PMCID: PMC11432004 DOI: 10.3390/ijms25189896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/03/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
O-linked β-N-acetylglucosamine (O-GlcNAc, O-GlcNAcylation) is a post-translational modification of serine/threonine residues of proteins. Alterations in O-GlcNAcylation have been implicated in several types of cancer, regulation of tumor progression, inflammation, and thrombosis through its interaction with signaling pathways. We aim to explore the relationship between O-GlcNAcylation and hemostasis, inflammation, and cancer, which could serve as potential prognostic tools or clinical predictions for cancer patients' healthcare and as an approach to combat cancer. We found that cancer is characterized by high glucose demand and consumption, a chronic inflammatory state, a state of hypercoagulability, and platelet hyperaggregability that favors thrombosis; the latter is a major cause of death in these patients. Furthermore, we review transcription factors and pathways associated with O-GlcNAcylation, thrombosis, inflammation, and cancer, such as the PI3K/Akt/c-Myc pathway, the nuclear factor kappa B pathway, and the PI3K/AKT/mTOR pathway. We also review infectious agents associated with cancer and chronic inflammation and potential inhibitors of cancer cell development. We conclude that it is necessary to approach both the diagnosis and treatment of cancer as a network in which multiple signaling pathways are integrated, and to search for a combination of potential drugs that regulate this signaling network.
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Affiliation(s)
- Itzel Patricia Vásquez Martínez
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - Eduardo Pérez-Campos
- National Institute of Technology of Mexico, Technological Institute of Oaxaca, Oaxaca 68033, Mexico; (E.P.-C.); (M.M.C.)
| | - Laura Pérez-Campos Mayoral
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - Holanda Isabel Cruz Luis
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - María del Socorro Pina Canseco
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - Edgar Zenteno
- Department of Biochemistry, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico;
| | - Irma Leticia Bazán Salinas
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - Margarito Martínez Cruz
- National Institute of Technology of Mexico, Technological Institute of Oaxaca, Oaxaca 68033, Mexico; (E.P.-C.); (M.M.C.)
| | - Eduardo Pérez-Campos Mayoral
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - María Teresa Hernández-Huerta
- National Council of Humanities, Sciences and Technologies (CONAHCYT), Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68120, Mexico
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16
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Jingushi K, Kawashima A, Tanikawa S, Saito T, Yamamoto A, Uemura T, Sassi N, Ishizuya Y, Yamamoto Y, Kato T, Hatano K, Hase H, Nonomura N, Tsujikawa K. Cutibacterium acnes-derived extracellular vesicles promote tumor growth in renal cell carcinoma. Cancer Sci 2024; 115:2578-2587. [PMID: 38682309 PMCID: PMC11309925 DOI: 10.1111/cas.16202] [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: 02/07/2024] [Revised: 04/08/2024] [Accepted: 04/17/2024] [Indexed: 05/01/2024] Open
Abstract
Bacterial flora are present in various parts of the human body, including the intestine, and are thought to be involved in the etiology of various diseases such as multiple sclerosis, intestinal diseases, cancer, and uterine diseases. In recent years, the presence of bacterial 16S rRNA genes has been revealed in blood, which was previously thought to be a sterile environment, and characteristic blood microbiomes have been detected in various diseases. However, the mechanism and the origin of the bacterial information are unknown. In this study, we performed 16S rRNA metagenomic analysis of bacterial DNA in serum extracellular vesicles from five healthy donors and seven patients with renal cell carcinoma and detected Cutibacterium acnes DNA as a characteristic bacterial DNA in the serum extracellular vesicles of patients with renal cell carcinoma. In addition, C. acnes DNA was significantly reduced in postoperative serum extracellular vesicles from patients with renal cell carcinoma compared with that in preoperative serum extracellular vesicles from these patients and was also detected in tumor tissue and extracellular vesicles from tumor tissue-associated microbiota, suggesting an association between C. acnes extracellular vesicles and renal cell carcinoma. C. acnes extracellular vesicles were taken up by renal carcinoma cells to enhance their proliferative potential. C. acnes extracellular vesicles also exhibited tumor-promoting activity in a mouse model of renal cancer allografts with enhanced angiogenesis. These results suggest that extracellular vesicles released by C. acnes localized in renal cell carcinoma tissues act in a tumor-promoting manner.
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Affiliation(s)
- Kentaro Jingushi
- Laboratory of Molecular and Cellular PhysiologyGraduate School of Pharmaceutical Sciences, Osaka UniversitySuitaOsakaJapan
| | - Atsunari Kawashima
- Department of UrologyGraduate School of Medicine, Osaka UniversitySuitaJapan
| | - Sayaka Tanikawa
- Laboratory of Molecular and Cellular PhysiologyGraduate School of Pharmaceutical Sciences, Osaka UniversitySuitaOsakaJapan
| | - Takuro Saito
- Department of SurgeryGraduate School of Medicine, Osaka UniversitySuitaOsakaJapan
- Department of Clinical Research in Tumor ImmunologyGraduate School of Medicine, Osaka UniversitySuitaOsakaJapan
| | - Akinaru Yamamoto
- Department of UrologyGraduate School of Medicine, Osaka UniversitySuitaJapan
| | - Toshihiro Uemura
- Department of UrologyGraduate School of Medicine, Osaka UniversitySuitaJapan
| | - Nesrine Sassi
- Department of UrologyGraduate School of Medicine, Osaka UniversitySuitaJapan
| | - Yu Ishizuya
- Department of UrologyGraduate School of Medicine, Osaka UniversitySuitaJapan
| | - Yoshiyuki Yamamoto
- Department of UrologyGraduate School of Medicine, Osaka UniversitySuitaJapan
| | - Taigo Kato
- Department of UrologyGraduate School of Medicine, Osaka UniversitySuitaJapan
| | - Koji Hatano
- Department of UrologyGraduate School of Medicine, Osaka UniversitySuitaJapan
| | - Hiroaki Hase
- Laboratory of Molecular and Cellular PhysiologyGraduate School of Pharmaceutical Sciences, Osaka UniversitySuitaOsakaJapan
| | - Norio Nonomura
- Department of UrologyGraduate School of Medicine, Osaka UniversitySuitaJapan
| | - Kazutake Tsujikawa
- Laboratory of Molecular and Cellular PhysiologyGraduate School of Pharmaceutical Sciences, Osaka UniversitySuitaOsakaJapan
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Huang S, Zhao H, Lou X, Chen D, Shi C, Ren Z. TM6SF1 suppresses the progression of lung adenocarcinoma and M2 macrophage polarization by inactivating the PI3K/AKT/mtor pathway. Biochem Biophys Res Commun 2024; 718:149983. [PMID: 38718735 DOI: 10.1016/j.bbrc.2024.149983] [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: 02/18/2024] [Revised: 04/14/2024] [Accepted: 04/22/2024] [Indexed: 05/23/2024]
Abstract
Transmembrane 6 superfamily 1 (TM6SF1) is lowly expressed in lung adenocarcinoma (LUAD), but the function and mechanisms of TM6SF1 remain unclear. Thus, we attempt to explore the function of TM6SF1 and its underlying mechanisms in LUAD. qRT-PCR was used for detecting TM6SF1 mRNA expression. Immunohistochemistry staining was used for detecting the expression of MMP-2, TM6SF1, Ki67, MMP-9, and CD163 proteins. E-cadherin, p-PI3K, Vimentin, AKT, N-cadherin, PI3K, p-AKT, mTOR, p-mTOR, and marker proteins of M2 macrophages were evaluated using Western blot. CD206 protein expression was examined via immunofluorescence. The IL-10 concentration was measured via enzyme-linked immunosorbent assay (ELISA). Using CCK-8, colony formation and transwell assays, cell proliferation, migration, and invasion were assessed. A549 cells were injected into the mice's flank for establishing a mouse tumor model and into the tail vein for establishing the lung metastasis model. HE staining was performed to detect pathological changes in lung tissues. Decreased TM6SF1 expression was found in LUAD tissues and cells. TM6SF1 overexpression inhibited cell viability, proliferation, invasion, migration, EMT, and polarization of M2 macrophages in LUAD cells, along with tumor growth and metastasis in xenograft mice. Bioinformatics analysis demonstrated that TM6SF1 was correlated with the tumor microenvironment. TM6SF1 overexpression reduced expression levels of p-mTOR, p-PI3K, p-AKT, mTOR, and AKT. TM6SF1-caused inhibition of proliferation, migration, invasion and EMT, as M2 macrophage polarization was reversed by the PI3K activator in LUAD cells. TM6SF1 inactivated the PI3K/AKT/mTOR pathway to suppress LUAD malignancy and polarization of M2 macrophages, providing insight for developing new LUAD treatments.
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Affiliation(s)
- Shucheng Huang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310000, China
| | - Hengchi Zhao
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310000, China
| | - Xiaolong Lou
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310000, China
| | - Dong Chen
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310000, China
| | - Chengwei Shi
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310000, China
| | - Zhe Ren
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310000, China.
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18
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Wang K, Huang H, Zhan Q, Ding H, Li Y. Toll-like receptors in health and disease. MedComm (Beijing) 2024; 5:e549. [PMID: 38685971 PMCID: PMC11057423 DOI: 10.1002/mco2.549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 03/17/2024] [Accepted: 03/26/2024] [Indexed: 05/02/2024] Open
Abstract
Toll-like receptors (TLRs) are inflammatory triggers and belong to a family of pattern recognition receptors (PRRs) that are central to the regulation of host protective adaptive immune responses. Activation of TLRs in innate immune myeloid cells directs lymphocytes to produce the most appropriate effector responses to eliminate infection and maintain homeostasis of the body's internal environment. Inappropriate TLR stimulation can lead to the development of general autoimmune diseases as well as chronic and acute inflammation, and even cancer. Therefore, TLRs are expected to be targets for therapeutic treatment of inflammation-related diseases, autoimmune diseases, microbial infections, and human cancers. This review summarizes the recent discoveries in the molecular and structural biology of TLRs. The role of different TLR signaling pathways in inflammatory diseases, autoimmune diseases such as diabetes, cardiovascular diseases, respiratory diseases, digestive diseases, and even cancers (oral, gastric, breast, colorectal) is highlighted and summarizes new drugs and related clinical treatments in clinical trials, providing an overview of the potential and prospects of TLRs for the treatment of TLR-related diseases.
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Affiliation(s)
- Kunyu Wang
- Department of Head and Neck Oncology Surgery, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Hanyao Huang
- Department of Oral and Maxillofacial Surgery, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduSichuanChina
| | - Qi Zhan
- Department of Head and Neck Oncology Surgery, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Haoran Ding
- Department of Head and Neck Oncology Surgery, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Yi Li
- Department of Head and Neck Oncology Surgery, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
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Monyók Á, Mansour B, Vadnay I, Makra N, Dunai ZA, Nemes-Nikodém É, Stercz B, Szabó D, Ostorházi E. Change in Tissue Microbiome and Related Human Beta Defensin Levels Induced by Antibiotic Use in Bladder Carcinoma. Int J Mol Sci 2024; 25:4562. [PMID: 38674148 PMCID: PMC11050017 DOI: 10.3390/ijms25084562] [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: 03/15/2024] [Revised: 04/12/2024] [Accepted: 04/21/2024] [Indexed: 04/28/2024] Open
Abstract
It is now generally accepted that the success of antitumor therapy can be impaired by concurrent antibiotic therapy, the presence of certain bacteria, and elevated defensin levels around the tumor tissue. The aim of our current investigation was to identify the underlying changes in microbiome and defensin levels in the tumor tissue induced by different antibiotics, as well as the duration of this modification. The microbiome of the tumor tissues was significantly different from that of healthy volunteers. Comparing only the tumor samples, no significant difference was confirmed between the untreated group and the group treated with antibiotics more than 3 months earlier. However, antibiotic treatment within 3 months of analysis resulted in a significantly modified microbiome composition. Irrespective of whether Fosfomycin, Fluoroquinolone or Beta-lactam treatment was used, the abundance of Bacteroides decreased, and Staphylococcus abundance increased. Large amounts of the genus Acinetobacter were observed in the Fluoroquinolone-treated group. Regardless of the antibiotic treatment, hBD1 expression of the tumor cells consistently doubled. The increase in hBD2 and hBD3 expression was the highest in the Beta-lactam treated group. Apparently, antibiotic treatment within 3 months of sample analysis induced microbiome changes and defensin expression levels, depending on the identity of the applied antibiotic.
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Affiliation(s)
- Ádám Monyók
- Department of Urology, Markhot Ferenc University Teaching Hospital, 3300 Eger, Hungary; (Á.M.); (B.M.)
| | - Bassel Mansour
- Department of Urology, Markhot Ferenc University Teaching Hospital, 3300 Eger, Hungary; (Á.M.); (B.M.)
| | - István Vadnay
- Department of Pathology, Markhot Ferenc University Teaching Hospital, 3300 Eger, Hungary; (I.V.); (D.S.)
| | - Nóra Makra
- Department of Medical Microbiology, Semmelweis University, 1085 Budapest, Hungary; (N.M.); (Z.A.D.); (É.N.-N.); (B.S.)
| | - Zsuzsanna A. Dunai
- Department of Medical Microbiology, Semmelweis University, 1085 Budapest, Hungary; (N.M.); (Z.A.D.); (É.N.-N.); (B.S.)
| | - Éva Nemes-Nikodém
- Department of Medical Microbiology, Semmelweis University, 1085 Budapest, Hungary; (N.M.); (Z.A.D.); (É.N.-N.); (B.S.)
| | - Balázs Stercz
- Department of Medical Microbiology, Semmelweis University, 1085 Budapest, Hungary; (N.M.); (Z.A.D.); (É.N.-N.); (B.S.)
| | - Dóra Szabó
- Department of Pathology, Markhot Ferenc University Teaching Hospital, 3300 Eger, Hungary; (I.V.); (D.S.)
- Neurosurgery and Neurointervention Clinic, Semmelweis University, 1085 Budapest, Hungary
| | - Eszter Ostorházi
- Department of Pathology, Markhot Ferenc University Teaching Hospital, 3300 Eger, Hungary; (I.V.); (D.S.)
- Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, 1085 Budapest, Hungary
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20
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Liu Z, Zhang D, Chen S. Unveiling the gastric microbiota: implications for gastric carcinogenesis, immune responses, and clinical prospects. J Exp Clin Cancer Res 2024; 43:118. [PMID: 38641815 PMCID: PMC11027554 DOI: 10.1186/s13046-024-03034-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 03/29/2024] [Indexed: 04/21/2024] Open
Abstract
High-throughput sequencing has ushered in a paradigm shift in gastric microbiota, breaking the stereotype that the stomach is hostile to microorganisms beyond H. pylori. Recent attention directed toward the composition and functionality of this 'community' has shed light on its potential relevance in cancer. The microbial composition in the stomach of health displays host specificity which changes throughout a person's lifespan and is subject to both external and internal factors. Distinctive alterations in gastric microbiome signature are discernible at different stages of gastric precancerous lesions and malignancy. The robust microbes that dominate in gastric malignant tissue are intricately implicated in gastric cancer susceptibility, carcinogenesis, and the modulation of immunosurveillance and immune escape. These revelations offer fresh avenues for utilizing gastric microbiota as predictive biomarkers in clinical settings. Furthermore, inter-individual microbiota variations partially account for differential responses to cancer immunotherapy. In this review, we summarize current literature on the influence of the gastric microbiota on gastric carcinogenesis, anti-tumor immunity and immunotherapy, providing insights into potential clinical applications.
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Affiliation(s)
- Zhiyi Liu
- Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China
| | - Dachuan Zhang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Siyu Chen
- Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China.
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21
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Lunger C, Shen Z, Holcombe H, Mannion AJ, Dzink-Fox J, Kurnick S, Feng Y, Muthupalani S, Carrasco SE, Wilson KT, Peek RM, Piazuelo MB, Morgan DR, Armijo AL, Mammoliti M, Wang TC, Fox JG. Gastric coinfection with thiopeptide-positive Cutibacterium acnes decreases FOXM1 and pro-inflammatory biomarker expression in a murine model of Helicobacter pylori-induced gastric cancer. Microbiol Spectr 2024; 12:e0345023. [PMID: 38014984 PMCID: PMC10783005 DOI: 10.1128/spectrum.03450-23] [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: 09/21/2023] [Accepted: 10/19/2023] [Indexed: 11/29/2023] Open
Abstract
IMPORTANCE H. pylori infects half of the world population and is the leading cause of gastric cancer. We previously demonstrated that gastric cancer risk is associated with gastric microbiota. Specifically, gastric urease-positive Staphylococcus epidermidis and Streptococcus salivarius had contrasting effects on H. pylori-associated gastric pathology and immune responses in germ-free INS-GAS mice. As gastritis progresses to gastric cancer, the oncogenic transcription factor Foxm1 becomes increasingly expressed. In this study, we evaluated the gastric commensal C. acnes, certain strains of which produce thiopeptides that directly inhibit FOXM1. Thiopeptide-positive C. acnes was isolated from Nicaraguan patient gastric biopsies and inoculated into germ-free INS-GAS mice with H. pylori. We, therefore, asked whether coinfection with C. acnes expressing thiopeptide and H. pylori would decrease gastric Foxm1 expression and pro-inflammatory cytokine mRNA and protein levels. Our study supports the growing literature that specific non-H. pylori gastric bacteria affect inflammatory and cancer biomarkers in H. pylori pathogenesis.
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Affiliation(s)
- Courtney Lunger
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Zeli Shen
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Hilda Holcombe
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Anthony J. Mannion
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - JoAnn Dzink-Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Susanna Kurnick
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Yan Feng
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Sureshkumar Muthupalani
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Sebastian E. Carrasco
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Keith T. Wilson
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Richard M. Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M. Blanca Piazuelo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Douglas R. Morgan
- Division of Gastroenterology and Hepatology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Amanda L. Armijo
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Melissa Mammoliti
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Timothy C. Wang
- Division of Gastroenterology and Irvine Cancer Research Center, Columbia University, New York, New York, USA
| | - James G. Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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22
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Wang G, Wang H, Ji X, Wang T, Zhang Y, Jiang W, Meng L, Wu HJ, Xing X, Ji J. Intratumoral microbiome is associated with gastric cancer prognosis and therapy efficacy. Gut Microbes 2024; 16:2369336. [PMID: 38944840 PMCID: PMC11216101 DOI: 10.1080/19490976.2024.2369336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 06/12/2024] [Indexed: 07/02/2024] Open
Abstract
The role of the intratumoral microbiome in gastric cancer (GC) has not been comprehensively assessed. Here, we explored the relationship between the microbial community and GC prognosis and therapy efficacy. Several cancer-associated microbial characteristics were identified, including increased α-diversity, differential β-diversity, and decreased Helicobacter pylori abundance. After adjusting for clinical features, prognostic analysis revealed 2 phyla, 14 genera, and 5 species associated with the overall survival of patients with GC. Additionally, 2 phyla, 14 genera, and 6 species were associated with adjuvant chemotherapy (ACT) efficacy in patients with stage II - III GC. Furthermore, we classified GC microbiome structures into three microbial subtypes (MS1, MS2 and MS3) with distinguishing features. The MS1 subtype exhibited high immune activity and enrichment of microbiota related to immunotherapy and butyric acid-producing, as well as potential benefits in immunotherapy. MS2 featured the highest α-diversity and activation of the TFF pathway, MS3 was characterized by epithelial-mesenchymal transition and was associated with poor prognosis and reduced ACT efficacy. Collectively, the results of this study provide valuable insights into the microbial characteristics associated with GC prognosis and therapy efficacy.
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Affiliation(s)
- Gangjian Wang
- Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital and Institute, Beijing, China
| | - Haojie Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
- Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Xin Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Tong Wang
- Department of General Surgery, Nanjing Medical University Affiliated Wuxi People’s Hospital, Wuxi, Jiangsu, China
| | - Ye Zhang
- Department of General Surgery, Nanjing Medical University Affiliated Wuxi People’s Hospital, Wuxi, Jiangsu, China
| | - Wenjie Jiang
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China
| | - Lin Meng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Hua-Jun Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
- Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Center for Precision Medicine Multi-Omics Research, Institute of Advanced Clinical Medicine, Peking University, Beijing, China
| | - Xiaofang Xing
- Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital and Institute, Beijing, China
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jiafu Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
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23
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Zhang J, Hu C, Zhang R, Xu J, Zhang Y, Yuan L, Zhang S, Pan S, Cao M, Qin J, Cheng X, Xu Z. The role of macrophages in gastric cancer. Front Immunol 2023; 14:1282176. [PMID: 38143746 PMCID: PMC10746385 DOI: 10.3389/fimmu.2023.1282176] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 11/24/2023] [Indexed: 12/26/2023] Open
Abstract
As one of the deadliest cancers of the gastrointestinal tract, there has been limited improvement in long-term survival rates for gastric cancer (GC) in recent decades. The poor prognosis is attributed to difficulties in early detection, minimal opportunity for radical resection and resistance to chemotherapy and radiation. Macrophages are among the most abundant infiltrating immune cells in the GC stroma. These cells engage in crosstalk with cancer cells, adipocytes and other stromal cells to regulate metabolic, inflammatory and immune status, generating an immunosuppressive tumour microenvironment (TME) and ultimately promoting tumour initiation and progression. In this review, we summarise recent advances in our understanding of the origin of macrophages and their types and polarisation in cancer and provide an overview of the role of macrophages in GC carcinogenesis and development and their interaction with the GC immune microenvironment and flora. In addition, we explore the role of macrophages in preclinical and clinical trials on drug resistance and in treatment of GC to assess their potential therapeutic value in this disease.
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Affiliation(s)
- Jiaqing Zhang
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Can Hu
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Ruolan Zhang
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Jingli Xu
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Yanqiang Zhang
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Li Yuan
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Shengjie Zhang
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Siwei Pan
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Mengxuan Cao
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Jiangjiang Qin
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Xiangdong Cheng
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Zhiyuan Xu
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
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24
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Cheng W, He L, Ren W, Yue T, Xie X, Sun J, Chen X, Wu Z, Li F, Piao JG. Bacteria-nanodrug cancer treatment system: The combination of dual swords and the confrontation of needle tips. NANO TRANSMED 2023; 2:100008. [DOI: 10.1016/j.ntm.2023.100008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2023]
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25
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Cheng W, He L, Ren W, Yue T, Xie X, Sun J, Chen X, Wu Z, Li F, Piao JG. Bacteria-nanodrug cancer treatment system: The combination of dual swords and the confrontation of needle tips. NANO TRANSMED 2023; 2:100008. [DOI: 10.1016/j.ntm.2023.100008 received in revised form 24 august 2023; acce] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2023]
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26
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Li J, Sun J, Zeng Z, Liu Z, Ma M, Zheng Z, He Y, Kang W. Tumour-associated macrophages in gastric cancer: From function and mechanism to application. Clin Transl Med 2023; 13:e1386. [PMID: 37608500 PMCID: PMC10444973 DOI: 10.1002/ctm2.1386] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 08/10/2023] [Accepted: 08/14/2023] [Indexed: 08/24/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is a malignant tumour, with high morbidity and mortality rates worldwide. The occurrence and development of GC is a complex process involving genetic changes in tumour cells and the influence of the surrounding tumour microenvironment (TME). Accumulative evidence shows that tumour-associated macrophages (TAMs) play a vital role in GC, acting as plentiful and active infiltrating inflammatory cells in the TME. MAIN BODY In this review, the different functions and mechanisms of TAMs in GC progression, including the conversion of phenotypic subtypes; promotion of tumour proliferation, invasion and migration; induction of chemoresistance; promotion of angiogenesis; modulation of immunosuppression; reprogramming of metabolism; and interaction with the microbial community are summarised. Although the role of TAMs in GC remains controversial in clinical settings, clarifying their significance in the treatment selection and prognostic prediction of GC could support optimising TAM-centred clinicaltherapy. CONCLUSION In summary, we reviewed the the phenotypic polarisation, function and molecular mechanism of TAMs and their potential applications in the treatment selection and prognostic prediction of GC.
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Affiliation(s)
- Jie Li
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Juan Sun
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Ziyang Zeng
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Zhen Liu
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Mingwei Ma
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Zicheng Zheng
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Yixuan He
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Weiming Kang
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
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27
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Cai R, Wang M, Liu M, Zhu X, Feng L, Yu Z, Yang X, Zhang Z, Guo H, Guo R, Zheng Y. An iRGD-conjugated photothermal therapy-responsive gold nanoparticle system carrying siCDK7 induces necroptosis and immunotherapeutic responses in lung adenocarcinoma. Bioeng Transl Med 2023; 8:e10430. [PMID: 37476070 PMCID: PMC10354770 DOI: 10.1002/btm2.10430] [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: 06/29/2022] [Revised: 10/07/2022] [Accepted: 10/10/2022] [Indexed: 07/22/2023] Open
Abstract
Although immunotherapy has improved the clinical treatment of lung adenocarcinoma (LUAD), many tumors have poor responses to immunotherapy. In this study, we confirmed that high expression of Cyclin-Dependent Kinase 7 (CDK7) promoted an immunosuppressive macrophage phenotype and macrophage infiltration in LUAD. Thus, we have developed an internalizing-RGD (iRGD)-conjugated gold nanoparticle (AuNP) system which carries siCDK7 to activate the antitumor immune response. The iRGD-conjugated AuNP/siCDK7 system exhibited good tumor targeting performance and photothermal effects. The AuNP/siCDK7 system with excellent biosafety exerted a significant photothermal antitumor effect by inducing tumor cell necroptosis. Furthermore, the AuNP/siCDK7 system ameliorated the immunosuppressive microenvironment and enhanced the efficacy of anti-PD-1 treatment by increasing CD8+ T cell infiltration and decreasing M2 macrophage infiltration. Hence, this iRGD-conjugated AuNP/siCDK7 system is a potential treatment strategy for lung adenocarcinoma, which exerts its effects by triggering tumor cell necroptosis and immunotherapeutic responses.
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Affiliation(s)
- Rui Cai
- Department of Medical OncologyAffiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhouChina
- State Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Meng Wang
- Department of Medical OncologyAffiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhouChina
- State Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Meiyuan Liu
- Department of Medical OncologyAffiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhouChina
- State Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Xiongjie Zhu
- Department of Medical OncologyAffiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhouChina
- State Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Longbao Feng
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Guangdong Provincial Engineering and Technological Research Center for Drug Carrier Development, Department of Biomedical EngineeringJinan UniversityGuangzhouChina
| | - Zhongjian Yu
- Department of Medical OncologyAffiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhouChina
- State Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Xia Yang
- Department of Medical OncologyAffiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhouChina
- State Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Zhiwu Zhang
- Department of Medical OncologyAffiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhouChina
- State Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Huili Guo
- Department of Medical OncologyAffiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhouChina
- State Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Rui Guo
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Guangdong Provincial Engineering and Technological Research Center for Drug Carrier Development, Department of Biomedical EngineeringJinan UniversityGuangzhouChina
| | - Yanfang Zheng
- Department of Medical OncologyAffiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhouChina
- State Key Laboratory of Respiratory DiseaseGuangzhouChina
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28
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Yang JW, Wan S, Li KP, Chen SY, Yang L. Gut and urinary microbiota: the causes and potential treatment measures of renal cell carcinoma. Front Immunol 2023; 14:1188520. [PMID: 37441065 PMCID: PMC10333567 DOI: 10.3389/fimmu.2023.1188520] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 06/12/2023] [Indexed: 07/15/2023] Open
Abstract
Mounting evidence suggests that the gut microbiota plays a crucial role in the development and treatment of various cancers. Recent research on the urinary microbiota challenges the long-standing belief that urine is sterile, as urinary microbiota has been implicated in the development of bladder and prostate cancers, similar to the role of gut microbiota in cancer development. Although the precise involvement of microbiota in the proliferation and differentiation of renal cell carcinoma (RCC) remains unclear, dysbiosis is considered one possible mechanism by which microbiota may contribute to RCC development and treatment. This review summarizes potential mechanisms by which gut microbiota may contribute to the development of RCC, and provides evidence for the involvement of urinary microbiota in RCC. We also explore the role of gut microbiota in RCC treatment and propose that the composition of gut microbiota could serve as a predictive marker for the potential efficacy of immune checkpoint inhibitors (ICIs) in RCC patients. Additionally, evidence suggests that modulating the abundance and distribution of microbiota can enhance the therapeutic effects of drugs, suggesting that microbiota may serve as a promising adjuvant therapy for RCC. Overall, we believe that further investigation into the gut and urinary microbiome of RCC patients could yield valuable insights and strategies for the prevention and personalized treatment of RCC.
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Affiliation(s)
| | | | | | | | - Li Yang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
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29
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Lin Q, Guan SW, Yu HB. Immuno-oncology-microbiome axis of gastrointestinal malignancy. World J Gastrointest Oncol 2023; 15:757-775. [PMID: 37275452 PMCID: PMC10237027 DOI: 10.4251/wjgo.v15.i5.757] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/15/2023] [Accepted: 04/14/2023] [Indexed: 05/12/2023] Open
Abstract
Research on the relationship between the microbiome and cancer has been controversial for centuries. Recent works have discovered that the intratumor microbiome is an important component of the tumor microenvironment (TME). Intratumor bacteria, the most studied intratumor microbiome, are mainly localized in tumor cells and immune cells. As the largest bacterial reservoir in human body, the gut microbiome may be one of the sources of the intratumor microbiome in gastrointestinal malignancies. An increasing number of studies have shown that the gut and intratumor microbiome play an important role in regulating the immune tone of tumors. Moreover, it has been recently proposed that the gut and intratumor microbiome can influence tumor progression by modulating host metabolism and the immune and immune tone of the TME, which is defined as the immuno-oncology-microbiome (IOM) axis. The proposal of the IOM axis provides a new target for the tumor microbiome and tumor immunity. This review aims to reveal the mechanism and progress of the gut and intratumor microbiome in gastrointestinal malignancies such as esophageal cancer, gastric cancer, liver cancer, colorectal cancer and pancreatic cancer by exploring the IOM axis. Providing new insights into the research related to gastrointestinal malignancies.
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Affiliation(s)
- Quan Lin
- Department of Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Shi-Wei Guan
- Department of Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Hai-Bo Yu
- Department of Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
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Zhou S, Li C, Liu L, Yuan Q, Miao J, Wang H, Ding C, Guan W. Gastric microbiota: an emerging player in gastric cancer. Front Microbiol 2023; 14:1130001. [PMID: 37180252 PMCID: PMC10172576 DOI: 10.3389/fmicb.2023.1130001] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 04/04/2023] [Indexed: 05/16/2023] Open
Abstract
Gastric cancer (GC) is a common cancer worldwide with a high mortality rate. Many microbial factors influence GC, of which the most widely accepted one is Helicobacter pylori (H. pylori) infection. H. pylori causes inflammation, immune reactions and activation of multiple signaling pathways, leading to acid deficiency, epithelial atrophy, dysplasia and ultimately GC. It has been proved that complex microbial populations exist in the human stomach. H. pylori can affect the abundance and diversity of other bacteria. The interactions among gastric microbiota are collectively implicated in the onset of GC. Certain intervention strategies may regulate gastric homeostasis and mitigate gastric disorders. Probiotics, dietary fiber, and microbiota transplantation can potentially restore healthy microbiota. In this review, we elucidate the specific role of the gastric microbiota in GC and hope these data can facilitate the development of effective prevention and therapeutic approaches for GC.
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Affiliation(s)
- Shizhen Zhou
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Chenxi Li
- Laboratory Medicine Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lixiang Liu
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qinggang Yuan
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, Nanjing, Jiangsu, China
| | - Ji Miao
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Hao Wang
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Chao Ding
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Wenxian Guan
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
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Li S, Ding X, Yan X, Qian J, Tan Q. ceAF Ameliorates Diabetic Wound Healing by Alleviating Inflammation and Oxidative Stress via TLR4/NF-κB and Nrf2 Pathways. J Diabetes Res 2023; 2023:2422303. [PMID: 37064758 PMCID: PMC10098416 DOI: 10.1155/2023/2422303] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/24/2022] [Accepted: 03/17/2023] [Indexed: 04/08/2023] Open
Abstract
Background. With the rise in diabetes incidence, diabetic foot ulcers have become the most common clinically chronic refractory wounds. Persistent chronic inflammation is a typical feature of diabetic cutaneous wounds, and diabetic wound healing can be improved by alleviating inflammation and oxidative stress. Chick early amniotic fluids (ceAF) consist of native conglutinant substances with balanced amounts of growth factors, cytokines, and chemokines. However, whether ceAF modulates inflammation and oxidative stress and thus promotes diabetic wound healing remains unknown. Materials and Methods. RAW264.7 cells were categorized into four groups: negative control, LPS, LPS + ceAF, and ceAF. 10% of ceAF was selected to treat different groups of mice with a full-thickness skin defect wound. Then, RT-qPCR, western blot, immunofluorescence, and other assays were carried out to explore the effect of ceAF on wound healing and its molecular mechanism. Results. Topical administration of ceAF improved M2 macrophage polarization and inflammatory response in the wound tissues, thereby ameliorating delayed wound healing. Histological improvement could be observed in the grade of inflammation, collagen deposition, and neovascularization in wound edge tissues. ceAF also increased M2 macrophage-specific markers expression and exogenous ceAF suppressed LPS-induced cellular inflammatory response in vitro high glucose environment. Additionally, ceAF could activate TLR4/NF-κB and Nrf2 signal transductions to promote M2 macrophage polarization in vitro. Conclusions. In summary, ceAF downregulates inflammatory response, regulates M2 macrophage transition via TLR4/NF-κB and Nrf2 signaling pathways, and thus improves diabetic wound healing.
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Affiliation(s)
- Shiyan Li
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, NO. 321, Zhongshan Road, Nanjing, Jiangsu, China
| | - Xiaofeng Ding
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, NO. 321, Zhongshan Road, Nanjing, Jiangsu, China
| | - Xin Yan
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, NO. 321, Zhongshan Road, Nanjing, Jiangsu, China
| | - Jin Qian
- Anhui Hygeiancells BioMedical Co. Ltd., Huangshan, Anhui, China
- Stem Cell Application Research Center, The Hangzhou Branch of Yangtze Delta Region Institute of Tsinghua University, Hangzhou, Zhejiang 310019, China
| | - Qian Tan
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, NO. 321, Zhongshan Road, Nanjing, Jiangsu, China
- Department of Burns and Plastic Surgery, Anqing Shihua Hospital, Nanjing Drum Tower Hospital Group, Anqing 246002, China
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Liu Y, Niu L, Li N, Wang Y, Liu M, Su X, Bao X, Yin B, Shen S. Bacterial-Mediated Tumor Therapy: Old Treatment in a New Context. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2205641. [PMID: 36908053 PMCID: PMC10131876 DOI: 10.1002/advs.202205641] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 02/09/2023] [Indexed: 06/18/2023]
Abstract
Targeted therapy and immunotherapy have brought hopes for precision cancer treatment. However, complex physiological barriers and tumor immunosuppression result in poor efficacy, side effects, and resistance to antitumor therapies. Bacteria-mediated antitumor therapy provides new options to address these challenges. Thanks to their special characteristics, bacteria have excellent ability to destroy tumor cells from the inside and induce innate and adaptive antitumor immune responses. Furthermore, bacterial components, including bacterial vesicles, spores, toxins, metabolites, and other active substances, similarly inherit their unique targeting properties and antitumor capabilities. Bacteria and their accessory products can even be reprogrammed to produce and deliver antitumor agents according to clinical needs. This review first discusses the role of different bacteria in the development of tumorigenesis and the latest advances in bacteria-based delivery platforms and the existing obstacles for application. Moreover, the prospect and challenges of clinical transformation of engineered bacteria are also summarized.
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Affiliation(s)
- Yao Liu
- Key Laboratory of Spine and Spinal Cord Injury Repairand Regeneration of Ministry of EducationOrthopaedic Department of Tongji Hospital, The Institute for Biomedical Engineering and Nano ScienceTongji University School of MedicineShanghai200092P. R. China
- Pharmacy Department and Center for Medical Research and InnovationShanghai Pudong HospitalFudan University Pudong Medical CenterShanghai201399China
| | - Lili Niu
- Central LaboratoryFirst Affiliated HospitalInstitute (College) of Integrative MedicineDalian Medical UniversityDalian116021China
| | - Nannan Li
- Central LaboratoryFirst Affiliated HospitalInstitute (College) of Integrative MedicineDalian Medical UniversityDalian116021China
| | - Yang Wang
- Central LaboratoryFirst Affiliated HospitalInstitute (College) of Integrative MedicineDalian Medical UniversityDalian116021China
| | - Mingyang Liu
- Department of Surgical Oncology and General SurgeryThe First Hospital of China Medical University155 North Nanjing Street, Heping DistrictShenyang110001China
| | - Xiaomin Su
- Central LaboratoryFirst Affiliated HospitalInstitute (College) of Integrative MedicineDalian Medical UniversityDalian116021China
| | - Xuhui Bao
- Institute for Therapeutic Cancer VaccinesFudan University Pudong Medical CenterShanghai201399China
| | - Bo Yin
- Institute for Therapeutic Cancer Vaccines and Department of OncologyFudan University Pudong Medical CenterShanghai201399China
| | - Shun Shen
- Pharmacy Department and Center for Medical Research and InnovationShanghai Pudong HospitalFudan University Pudong Medical CenterShanghai201399China
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Yu MY, Jia HJ, Zhang J, Ran GH, Liu Y, Yang XH. Exosomal miRNAs-mediated macrophage polarization and its potential clinical application. Int Immunopharmacol 2023; 117:109905. [PMID: 36848789 DOI: 10.1016/j.intimp.2023.109905] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 03/01/2023]
Abstract
Macrophages are highly heterogeneous and plastic immune cells that play an important role in the fight against pathogenic microorganisms and tumor cells. After different stimuli, macrophages can polarize to the M1 phenotype to show a pro-inflammatory effect and the M2 phenotype to show an anti-inflammatory effect. The balance of macrophage polarization is highly correlated with disease progression, and therapeutic approaches to reprogram macrophages by targeting macrophage polarization are feasible. There are a large number of exosomes in tissue cells, which can transmit information between cells. In particular, microRNAs (miRNAs) in the exosomes can regulate the polarization of macrophages and further affect the progression of various diseases. At the same time, exosomes are also effective "drug" carriers, laying the foundation for the clinical application of exosomes. This review describes some pathways involved in M1/M2 macrophage polarization and the effects of miRNA carried by exosomes from different sources on the polarization of macrophages. Finally, the application prospects and challenges of exosomes/exosomal miRNAs in clinical treatment are also discussed.
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Affiliation(s)
- Ming Yun Yu
- Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, No. 21 Bohai Road, Caofeidian Eco-city, Tangshan, 063210 Hebei, China
| | - Hui Jie Jia
- School of Basic Medicine, Dali University, Dali, Yunnan 671000, China
| | - Jing Zhang
- Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, No. 21 Bohai Road, Caofeidian Eco-city, Tangshan, 063210 Hebei, China
| | - Guang He Ran
- Department of Medical Laboratory, Chang shou District Hospital of Traditional Chinese Medicine, No. 1 Xinglin Road, Peach Blossom New Town, Changshou District, 401200 Chongqing, China
| | - Yan Liu
- Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, No. 21 Bohai Road, Caofeidian Eco-city, Tangshan, 063210 Hebei, China.
| | - Xiu Hong Yang
- Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, No. 21 Bohai Road, Caofeidian Eco-city, Tangshan, 063210 Hebei, China.
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Xu S, Xiong Y, Fu B, Guo D, Sha Z, Lin X, Wu H. Bacteria and macrophages in the tumor microenvironment. Front Microbiol 2023; 14:1115556. [PMID: 36825088 PMCID: PMC9941202 DOI: 10.3389/fmicb.2023.1115556] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 01/12/2023] [Indexed: 02/10/2023] Open
Abstract
Cancer and microbial infections are significant worldwide health challenges. Numerous studies have demonstrated that bacteria may contribute to the emergence of cancer. In this review, we assemble bacterial species discovered in various cancers to describe their variety and specificity. The relationship between bacteria and macrophages in cancer is also highlighted, and we look for ample proof to establish a biological basis for bacterial-induced macrophage polarization. Finally, we quickly go over the potential roles of metabolites, cytokines, and microRNAs in the regulation of the tumor microenvironment by bacterially activated macrophages. The complexity of bacteria and macrophages in cancer will be revealed as we gain a better understanding of their pathogenic mechanisms, which will lead to new therapeutic approaches for both inflammatory illnesses and cancer.
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Affiliation(s)
| | | | - Beibei Fu
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Dong Guo
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Zhou Sha
- School of Life Sciences, Chongqing University, Chongqing, China
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Li M, Tao J, Qian R, Jiang F, Song Y, Zeng Z, Cai C. Development of alternative herbals remedy for gastric cancer based on transcriptomic analysis of immune infiltration and ferroptosis. Front Genet 2023; 14:1086368. [PMID: 36936437 PMCID: PMC10020191 DOI: 10.3389/fgene.2023.1086368] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 02/14/2023] [Indexed: 03/06/2023] Open
Abstract
Objective: Screening out potential herbal medicines and herbal ingredients for the treatment of gastric cancer based on transcriptomic analysis of immune infiltration and ferroptosis. Methods: Gene expression profiles of gastric tumour tissues and normal tissue samples were obtained from the GEO database and the samples were analysed for immune cell infiltration condition and differential expressed genes of ferroptosis. Key genes were screened by protein-protein interaction (PPI) and enrichment analysis, and molecular docking was used to predict and preliminary validate potential herbal and traditional Chinese medicine components for gastric cancer based on the key genes. Finally, RT-QPCR was used to validate the prediction results. Results: Immune cell infiltration analysis revealed high levels of infiltration of activated CD4 memory T cells, monocytes, M0 macrophages in gastric tumor tissues, while plasma cells and resting mast cells had higher levels of infiltration in the paraneoplastic tissues. Differential gene expression analysis identified 1,012 upregulated genes and 880 downregulated genes, of which 84 immune related differentially expressed genes such as CTSB, PGF and PLAU and 10 ferroptosis-related differentially expressed genes such as HSF1, NOX4 and NF2 were highly expressed in gastric cancer tissues. The results of enrichment analysis showed that they mainly involve 343 biological processes such as extracellular matrix organization and extracellular structural organization; 37 cellular components such as complexes of collagen trimer and basement membrane; 35 molecular functions such as signal receptor activator activity and receptor ligand activity; 19 regulatory pathways such as cytokine-cytokine receptor interactions and retinol metabolism. Finally, two key genes, TLR4 and KRAS, were selected and 12 herbal medicines such as Radix Salviae liguliobae, Rhizoma Coptidis, Rhizoma Polygoni cuspidati and 27 herbal ingredients such as resveratrol, salvianolic acid b were predicted on the basis of key genes. Molecular docking results showed that KRAS binds tightly to coumarin and magnolol, while TLR4 can bind tightly to resveratrol, curcumin, salvianolic acid b, shikonin. Subsequently, the effect of resveratrol and magnolol was experimentally verified. Conclusion: Herbal medicines such as S. liguliobae, Rhizoma Coptidis, Rhizoma P. cuspidati and herbal ingredients such as resveratrol, curcumin, salvianolic acid b may provide research directions and alternative therapeutic approaches for immunomodulation of TME and ferroptosis of tumour cells in gastric cancer.
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Affiliation(s)
- Mingyue Li
- Department of Pharmacy, Shenzhen Bao’an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Jie Tao
- Department of Cardiology, Shenzhen Bao’an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Rui Qian
- Department of Gastroenterology, Shenzhen Bao’an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Feng Jiang
- Department of Cardiology, Shenzhen Bao’an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Yinzhi Song
- Department of Cardiology, Shenzhen Bao’an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Zhicong Zeng
- Department of Cardiology, Shenzhen Bao’an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
- *Correspondence: Zhicong Zeng, ; Changlong Cai,
| | - Changlong Cai
- Department of Surgery, Shenzhen Bao’an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
- *Correspondence: Zhicong Zeng, ; Changlong Cai,
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Liu Y, Li C, Lu Y, Liu C, Yang W. Tumor microenvironment-mediated immune tolerance in development and treatment of gastric cancer. Front Immunol 2022; 13:1016817. [PMID: 36341377 PMCID: PMC9630479 DOI: 10.3389/fimmu.2022.1016817] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 10/07/2022] [Indexed: 11/24/2022] Open
Abstract
Tumor microenvironment is the general term for all non-cancer components and their metabolites in tumor tissue. These components include the extracellular matrix, fibroblasts, immune cells, and endothelial cells. In the early stages of tumors, the tumor microenvironment has a tumor suppressor function. As the tumor progresses, tumor immune tolerance is induced under the action of various factors, such that the tumor suppressor microenvironment is continuously transformed into a tumor-promoting microenvironment, which promotes tumor immune escape. Eventually, tumor cells manifest the characteristics of malignant proliferation, invasion, metastasis, and drug resistance. In recent years, stress effects of the extracellular matrix, metabolic and phenotypic changes of innate immune cells (such as neutrophils, mast cells), and adaptive immune cells in the tumor microenvironment have been revealed to mediate the emerging mechanisms of immune tolerance, providing us with a large number of emerging therapeutic targets to relieve tumor immune tolerance. Gastric cancer is one of the most common digestive tract malignancies worldwide, whose mortality rate remains high. According to latest guidelines, the first-line chemotherapy of advanced gastric cancer is the traditional platinum and fluorouracil therapy, while immunotherapy for gastric cancer is extremely limited, including only Human epidermal growth factor receptor 2 (HER-2) and programmed death ligand 1 (PD-L1) targeted drugs, whose benefits are limited. Clinical experiments confirmed that cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), vascular endothelial growth factor receptor (VEGFR) and other targeted drugs alone or in combination with other drugs have limited efficacy in patients with advanced gastric cancer, far less than in lung cancer, colon cancer, and other tumors. The failure of immunotherapy is mainly related to the induction of immune tolerance in the tumor microenvironment of gastric cancer. Therefore, solving the immune tolerance of tumors is key to the success of gastric cancer immunotherapy. In this study, we summarize the latest mechanisms of various components of the tumor microenvironment in gastric cancer for inducing immune tolerance and promoting the formation of the malignant phenotype of gastric cancer, as well as the research progress of targeting the tumor microenvironment to overcome immune tolerance in the treatment of gastric cancer.
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Affiliation(s)
- Yuanda Liu
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Changfeng Li
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
- *Correspondence: Changfeng Li, ; Wei Yang,
| | - Yaoping Lu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Chang Liu
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Wei Yang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
- *Correspondence: Changfeng Li, ; Wei Yang,
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Radej S, Szewc M, Maciejewski R. Prostate Infiltration by Treg and Th17 Cells as an Immune Response to Propionibacterium acnes Infection in the Course of Benign Prostatic Hyperplasia and Prostate Cancer. Int J Mol Sci 2022; 23:ijms23168849. [PMID: 36012113 PMCID: PMC9408129 DOI: 10.3390/ijms23168849] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/04/2022] [Accepted: 08/06/2022] [Indexed: 11/16/2022] Open
Abstract
Benign prostatic hyperplasia (BPH) and prostate cancer (PCa) belong to the most frequent diseases in ageing men. It has been proposed that prostate chronic inflammation is a risk factor for the development of both BPH and PCa. However, potential stimuli that cause or maintain inflammation in the prostate gland are still poorly characterized. Bacterial infections seems to be one of the potential sources of prostatitis. Recent studies show that Propionibacterium acnes (P. acnes) is the most prevalent microorganism in the prostate gland and may be a predisposing factor for inflammation of prostatic tissue. It indicates that P. acnes may contribute to cancer development by enhancing proinflammatory responses, as well as by modifying the prostate extracellular environment. In this review, we discuss the potential role of P. acnes in the development of BPH and PCa and highlight the importance of regulatory T CD4(+)FoxP3(+) (Treg) and Th17 cells in response to P. acnes infection in the context of both prostate diseases.
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Affiliation(s)
- Sebastian Radej
- Department of Normal Anatomy, Medical University of Lublin, 20-090 Lublin, Poland
| | - Monika Szewc
- Department of Normal Anatomy, Medical University of Lublin, 20-090 Lublin, Poland
- Correspondence:
| | - Ryszard Maciejewski
- Department of Normal Anatomy, Medical University of Lublin, 20-090 Lublin, Poland
- Institute of Health Sciences, The John Paul II Catholic University of Lublin, 20-708 Lublin, Poland
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An Electrochemical Immunoassay for Lactobacillus rhamnosus GG Using Cu@Cu2O Nanoparticle-Embedded B, N, Co-doped Porous Carbon. FOOD ANAL METHOD 2022. [DOI: 10.1007/s12161-022-02373-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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Zhang T, Zhang Y, Yang Z, Jiang Y, Sun L, Huang D, Tian M, Shen Y, Deng J, Hou J, Ma Y. Echinococcus multilocularis protoscoleces enhance glycolysis to promote M2 Macrophages through PI3K/Akt/mTOR Signaling Pathway. Pathog Glob Health 2022; 117:409-416. [PMID: 35876088 PMCID: PMC10177676 DOI: 10.1080/20477724.2022.2104055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022] Open
Abstract
Alveolar Echinococcosis (AE) is a zoonotic parasitic disease caused by Echinococcus multilocularis, but its pathogenesis remains unclear. The primary objective of this study is to explore whether Echinococcus multilocularis protoscoleces (PSCs) regulate macrophage polarization and glucose metabolism by PI3K/Akt/mTOR signaling pathway. We found that large numbers of CD68+ macrophages gathered in close liver issue from the lesion in AE patients. PSCs preferentially differentiated into M2 macrophages and the expressions of HK1, PFKL, PKM2, PI3K, Akt, p-Akt, mTOR and p-mTOR increased. The above results show that Echinococcus multilocularis protoscoleces enhance glycolysis to promote M2 macrophages through PI3K/Akt/mTOR signaling pathway.
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Affiliation(s)
- Tao Zhang
- Research Center for High Altitude Medicine, Qinghai University, Xining, Qinghai province, China.,Key Laboratory of Application of High Altitude Medicine in Qinghai, Qinghai University, Xining, Qinghai province, China.,Department of Rehabilitation Medicine, Qinghai University Affiliated Hospital, Xining, Qinghai province, China
| | - Yaogang Zhang
- Central Laboratory of Qinghai University Affiliated Hospital, Qinghai University Affiliated Hospital, Xining, Qinghai province, China.,Qinghai Province Research Key Laboratory of Echinococcosis, Qinghai University Affiliated Hospital, Xining, Qinghai province, China
| | - Zihan Yang
- Research Center for High Altitude Medicine, Qinghai University, Xining, Qinghai province, China.,Key Laboratory of Application of High Altitude Medicine in Qinghai, Qinghai University, Xining, Qinghai province, China.,Department of Neurology, Qinghai University Affiliated Hospital, Xining, Qinghai province, China
| | - Yuan Jiang
- Central Laboratory of Qinghai University Affiliated Hospital, Qinghai University Affiliated Hospital, Xining, Qinghai province, China
| | - Li Sun
- Central Laboratory of Qinghai University Affiliated Hospital, Qinghai University Affiliated Hospital, Xining, Qinghai province, China
| | - Dengliang Huang
- Central Laboratory of Qinghai University Affiliated Hospital, Qinghai University Affiliated Hospital, Xining, Qinghai province, China
| | - Meiyuan Tian
- Central Laboratory of Qinghai University Affiliated Hospital, Qinghai University Affiliated Hospital, Xining, Qinghai province, China
| | - Yinhong Shen
- Department of Pediatrics, Qinghai University Affiliated Hospital, Xining, Qinghai province, China
| | - Jun Deng
- Department of Pediatrics, Qinghai University Affiliated Hospital, Xining, Qinghai province, China
| | - Jing Hou
- Central Laboratory of Qinghai University Affiliated Hospital, Qinghai University Affiliated Hospital, Xining, Qinghai province, China
| | - Yanyan Ma
- Central Laboratory of Qinghai University Affiliated Hospital, Qinghai University Affiliated Hospital, Xining, Qinghai province, China.,Qinghai Province Research Key Laboratory of Echinococcosis, Qinghai University Affiliated Hospital, Xining, Qinghai province, China.,Department of Pediatrics, Qinghai University Affiliated Hospital, Xining, Qinghai province, China
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Isik Z, Leblebici A, Demir Karaman E, Karaca C, Ellidokuz H, Koc A, Ellidokuz EB, Basbinar Y. In silico identification of novel biomarkers for key players in transition from normal colon tissue to adenomatous polyps. PLoS One 2022; 17:e0267973. [PMID: 35486660 PMCID: PMC9053805 DOI: 10.1371/journal.pone.0267973] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 04/19/2022] [Indexed: 11/18/2022] Open
Abstract
Adenomatous polyps of the colon are the most common neoplastic polyps. Although most of adenomatous polyps do not show malign transformation, majority of colorectal carcinomas originate from neoplastic polyps. Therefore, understanding of this transformation process would help in both preventive therapies and evaluation of malignancy risks. This study uncovers alterations in gene expressions as potential biomarkers that are revealed by integration of several network-based approaches. In silico analysis performed on a unified microarray cohort, which is covering 150 normal colon and adenomatous polyp samples. Significant gene modules were obtained by a weighted gene co-expression network analysis. Gene modules with similar profiles were mapped to a colon tissue specific functional interaction network. Several clustering algorithms run on the colon-specific network and the most significant sub-modules between the clusters were identified. The biomarkers were selected by filtering differentially expressed genes which also involve in significant biological processes and pathways. Biomarkers were also validated on two independent datasets based on their differential gene expressions. To the best of our knowledge, such a cascaded network analysis pipeline was implemented for the first time on a large collection of normal colon and polyp samples. We identified significant increases in TLR4 and MSX1 expressions as well as decrease in chemokine profiles with mostly pro-tumoral activities. These biomarkers might appear as both preventive targets and biomarkers for risk evaluation. As a result, this research proposes novel molecular markers that might be alternative to endoscopic approaches for diagnosis of adenomatous polyps.
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Affiliation(s)
- Zerrin Isik
- Faculty of Engineering, Department of Computer Engineering, Dokuz Eylul University, Izmir, Turkey
| | - Asım Leblebici
- Department of Translational Oncology, Institute of Health Sciences, Dokuz Eylul University, Izmir, Turkey
| | - Ezgi Demir Karaman
- Department of Computer Engineering, Institute of Natural and Applied Sciences, Dokuz Eylul University, Izmir, Turkey
| | - Caner Karaca
- Department of Translational Oncology, Institute of Health Sciences, Dokuz Eylul University, Izmir, Turkey
| | - Hulya Ellidokuz
- Department of Preventive Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Altug Koc
- Gentan Genetic Medical Genetics Diagnosis Center, Izmir, Turkey
| | - Ender Berat Ellidokuz
- Faculty of Medicine, Department of Gastroenterology, Dokuz Eylul University, Izmir, Turkey
| | - Yasemin Basbinar
- Department of Translational Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
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Yang J, Liu X, Cheng Y, Zhang J, Ji F, Ling Z. Roles of Plasmacytoid Dendritic Cells in Gastric Cancer. Front Oncol 2022; 12:818314. [PMID: 35311157 PMCID: PMC8927765 DOI: 10.3389/fonc.2022.818314] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/15/2022] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is the fifth most common neoplasm and the third most deadly cancer in humans worldwide. Helicobacter pylori infection is the most important causative factor of gastric carcinogenesis, and activates host innate and adaptive immune responses. As key constituents of the tumor immune microenvironment, plasmacytoid dendritic cells (pDCs) are increasingly attracting attention owing to their potential roles in immunosuppression. We recently reported that pDCs have vital roles in the development of immunosuppression in GC. Clarifying the contribution of pDCs to the development and progression of GC may lead to improvements in cancer therapy. In this review, we summarize current knowledge regarding immune modulation in GC, especially the roles of pDCs in GC carcinogenesis and treatment strategies.
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Affiliation(s)
- Jinpu Yang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xia Liu
- Department of Intensive Care Unit, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yiwen Cheng
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jingchen Zhang
- Department of Intensive Care Unit, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Feng Ji
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zongxin Ling
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
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Davidsson S, Carlsson J, Greenberg L, Wijkander J, Söderquist B, Erlandsson A. Cutibacterium acnes Induces the Expression of Immunosuppressive Genes in Macrophages and is Associated with an Increase of Regulatory T-Cells in Prostate Cancer. Microbiol Spectr 2021; 9:e0149721. [PMID: 34937192 PMCID: PMC8694172 DOI: 10.1128/spectrum.01497-21] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/30/2021] [Indexed: 12/26/2022] Open
Abstract
Tumors and infectious agents both benefit from an immunosuppressive environment. Cutibacterium acnes (C. acnes) is a bacterium in the normal skin microbiota, which has the ability to survive intracellularly in macrophages and is significantly more common in prostate cancer tissue compared with normal prostate tissue. This study investigated if prostate cancer tissue culture positive for C. acnes has a higher infiltration of regulatory T-cells (Tregs) and if macrophages stimulated with C. acnes induced the expression of immunosuppressive genes that could be linked to an increase of Tregs in prostate cancer. Real-time PCR and enzyme-linked immunosorbent spot assay (ELISA) were used to examine the expression of immunosuppressive genes in human macrophages stimulated in vitro with C. acnes, and associations between the presence of C. acnes and infiltration of Tregs were investigated by statistically analyzing data generated in two previous studies. The in vitro results demonstrated that macrophages stimulated with C. acnes significantly increased their expression of PD-L1, CCL17, and CCL18 mRNA and protein (p <0.05). In the cohort, Tregs in tumor stroma and tumor epithelia were positively associated with the presence of C. acnes (P = 0.0004 and P = 0.046, respectively). Since the macrophages stimulated with C. acnes in vitro increased the expression of immunosuppressive genes, and prostate cancer patients with prostatic C. acnes infection had higher infiltration of Tregs than their noninfected counterparts, we suggest that C. acnes may contribute to an immunosuppressive tumor environment that is vital for prostate cancer progression. IMPORTANCE In an immune suppressive tumor microenvironment constituted by immunosuppressive cells and immunosuppressive mediators, tumors may improve their ability to give rise to a clinically relevant cancer. In the present study, we found that C. acnes might contribute to an immunosuppressive environment by recruiting Tregs and by increasing the expression of immunosuppressive mediators such as PD-L1, CCL17, and CCL18. We believe that our data add support to the hypothesis of a contributing role of C. acnes in prostate cancer development. If established that C. acnes stimulates prostate cancer progression it may open up avenues for targeted prostate cancer treatment.
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Affiliation(s)
- Sabina Davidsson
- Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Jessica Carlsson
- Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Larry Greenberg
- Department of Environmental and Life Sciences/Biology, Faculty of Health, Science and Technology, Karlstad University, Karlstad, Sweden
| | - Jonny Wijkander
- Department of Health Sciences, Faculty of Health, Science and Technology, Karlstad University, Karlstad, Sweden
| | - Bo Söderquist
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Ann Erlandsson
- Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Department of Environmental and Life Sciences/Biology, Faculty of Health, Science and Technology, Karlstad University, Karlstad, Sweden
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Xu T, Yu S, Zhang J, Wu S. Dysregulated tumor-associated macrophages in carcinogenesis, progression and targeted therapy of gynecological and breast cancers. J Hematol Oncol 2021; 14:181. [PMID: 34717710 PMCID: PMC8557603 DOI: 10.1186/s13045-021-01198-9] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 10/19/2021] [Indexed: 12/13/2022] Open
Abstract
Gynecological and breast cancers are a group of heterogeneous malignant tumors. Although existing treatment strategies have ameliorated the clinical outcomes of patients, the overall survival rate of advanced diseases remains unsatisfactory. Increasing evidence has indicated that the development and prognosis of tumors are closely related to the tumor microenvironment (TME), which restricts the immune response and provokes malignant progression. Tumor-associated macrophages (TAMs) are the main component of TME and act as a key regulator in tumor metastasis, immunosuppression and therapeutic resistance. Several preclinical trials have studied potential drugs that target TAMs to achieve potent anticancer therapy. This review focuses on the various functions of TAMs and how they influence the carcinogenesis of gynecological and breast cancers through regulating cancer cell proliferation, tumor angiogenesis and tumor-related immunosuppression. Besides, we also discuss the potential application of disabling TAMs signaling as a part of cancer therapeutic strategies, as well as CAR macrophages, TAMs-based vaccines and TAMs nanobiotechnology. These research advances support that targeting TAMs combined with conventional therapy might be used as effective therapeutics for gynecological and breast cancers in the future.
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Affiliation(s)
- Tianhan Xu
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Sihui Yu
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Jiawen Zhang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China. .,Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
| | - Sufang Wu
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
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Yu X, Yu B, Fang W, Xiong J, Ma M. Identification hub genes of consensus molecular subtype correlation with immune infiltration and predict prognosis in gastric cancer. Discov Oncol 2021; 12:41. [PMID: 35201473 PMCID: PMC8777542 DOI: 10.1007/s12672-021-00434-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/16/2021] [Indexed: 11/19/2022] Open
Abstract
Gastric cancer (GC) has a great fatality rate, meanwhile, there is still a lack of available biomarkers for prognosis. The goal of the research was to discover key and novel potential biomarkers for GC. We screened for the expression of significantly altered genes based on survival rates from two consensus molecular subtypes (CMS) of GC. Subsequently, functional enrichment analysis showed these genes involved in many cancers. And we picked 6 hub genes that could both secreted in the tumor microenvironment and expression enhanced in immune cells. Then, Kaplan Meier survival and expression detected in the tumor pathological stage were utilized to clarify the prognostic of these 6 hub genes. The results indicated that OGN, CHRDL2, C2orf40, THBS4, CHRDL1, and ANGPTL1, respectively, were significantly associated with poor OS in GC patients. And their expression increased with cancer advanced. Moreover, immune infiltration analysis displayed that those hub genes expression positively with M2 macrophage, CD8+ T Cell, most immune inhibitors, and majority immunostimulators. In summary, our results suggested that OGN, CHRDL2, C2orf40, THBS4, CHRDL1, and ANGPTL1 were all potential biomarkers for GC prognosis and might also be potential therapeutic targets for GC.
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Affiliation(s)
- Xin Yu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Bin Yu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Weidan Fang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
| | - Mei Ma
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
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