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Jing Z, Yinhang W, Jian C, Zhanbo Q, Xinyue W, Shuwen H. Interaction between gut microbiota and T cell immunity in colorectal cancer. Autoimmun Rev 2025; 24:103807. [PMID: 40139455 DOI: 10.1016/j.autrev.2025.103807] [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: 07/02/2024] [Revised: 02/26/2025] [Accepted: 03/22/2025] [Indexed: 03/29/2025]
Abstract
This review delves into the complex and multi-layered mechanisms that govern the interaction between gut microbiota and T cells in the context of colorectal cancer (CRC), revealing a novel "microbiota-immune regulatory landscape" within the tumor microenvironment. As CRC progresses, the gut microbiota experiences a significant transformation in both its composition and metabolic patterns. On one hand, specific microbial entities within the gut microbiota can directly engage with T cells, functioning as "immunological triggers" that shape T-cell behavior. Simultaneously, microbial metabolites, such as short-chain fatty acids and bile acids, serve as "molecular regulators" that intricately govern T-cell function and differentiation, fine-tuning the immune response. On the other hand, the quorum-sensing mechanism, a recently recognized communication network among bacteria, also plays a pivotal role in orchestrating T-cell immunity. Additionally, the gut microbiota forms an intriguing connection with the neuro-immune regulatory axis, a largely unexplored "territory" in CRC research. Regarding treatment strategies, a diverse array of intervention approaches-including dietary modifications, the utilization of probiotics, bacteriophages, and targeted antibiotic therapies-offer promising prospects for restoring the equilibrium of the gut microbiota, thereby acting as "ecosystem renovators" that impede tumor initiation and progression. Nevertheless, the current research landscape in this field is fraught with challenges. These include significant variations in microbial composition, dietary preferences, and tumor microenvironments among individuals, a lack of large-scale cohort studies, and insufficient research that integrates tumor mutation analysis, gut microbiota investigations, and immune microenvironment evaluations. This review emphasizes the necessity for future research efforts to seamlessly incorporate multiple factors and utilize bioinformatics analysis to construct a more comprehensive "interactive map" of the gut microbiota-T cell relationship in CRC. The aim is to establish a solid theoretical basis for the development of highly effective and personalized treatment regimens, ultimately transforming the therapeutic approach to CRC.
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Affiliation(s)
- Zhuang Jing
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China
| | - Wu Yinhang
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China
| | - Chu Jian
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China
| | - Qu Zhanbo
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China
| | - Wu Xinyue
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China
| | - Han Shuwen
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; ASIR (Institute - Association of intelligent systems and robotics), 14B rue Henri Sainte Claire Deville, 92500 Rueil-Malmaison, France.
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Han B, Zhang Y, Feng X, Yang J, Wang B, Fang J, Wang Z, Zhu J, Niu G, Guo Y. The power of microbes: the key role of gut microbiota in the initiation and progression of colorectal cancer. Front Oncol 2025; 15:1563886. [PMID: 40297806 PMCID: PMC12034544 DOI: 10.3389/fonc.2025.1563886] [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: 01/21/2025] [Accepted: 03/24/2025] [Indexed: 04/30/2025] Open
Abstract
Colorectal cancer (CRC) is ranked as the third most prevalent malignancy and is a leading cause of cancer-related mortality globally, significantly affecting the health and longevity of middle-aged individuals and the elderly. The primary risk factors for CRC are mainly due to unhealthy dietary habits and lifestyle choices, and they have been shown to profoundly influence the composition of the gut microbiota. Given that dietary patterns are critical determinants of gut microbial diversity, a compelling association exists between gut microbiota and the pathogenesis of CRC. Recent research has increasingly focused on the intricate interplay between gut microbiota and CRC, exploring its role in disease initiation, progression, and the modulation of host immune responses. Investigations have demonstrated that certain specific microbial communities can promote inflammation, disrupt metabolic pathways, and produce carcinogenic compounds, thereby contributing to the development of CRC. Conversely, a diverse and balanced gut microbiome may confer protective effects against cancer through mechanisms such as the production of short-chain fatty acids and the enhancement of intestinal barrier integrity. This article provides a comprehensive overview of the characteristics of the gut microbial community and its complex relationship with CRC. It highlights potential mechanisms through which gut microbiota may influence CRC pathogenesis, including chronic inflammation, toxins, metabolites, epigenetic dysregulation, and immune regulatory dysfunction. Additionally, this review summarizes innovative strategies for CRC prevention and treatment, emphasizing the therapeutic potential of probiotics and natural plant extracts. By elucidating these connections, this work aims to enhance the understanding of the gut microbiome's role in CRC.
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Affiliation(s)
- Bo Han
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Yongfeng Zhang
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Xue Feng
- Department of Cardiology, 63650 Military Hospital, Urumqi, China
| | - Jun Yang
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Baolin Wang
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Jiang Fang
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Zhigang Wang
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Jun Zhu
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Ge Niu
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Youxiang Guo
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
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Abken H. CAR T cell therapies in gastrointestinal cancers: current clinical trials and strategies to overcome challenges. Nat Rev Gastroenterol Hepatol 2025:10.1038/s41575-025-01062-y. [PMID: 40229574 DOI: 10.1038/s41575-025-01062-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/10/2025] [Indexed: 04/16/2025]
Abstract
Despite multimodal treatment options, most gastrointestinal cancers are still associated with high mortality rates and poor responsiveness to immunotherapy. The unprecedented efficacy of chimeric antigen receptor (CAR)-engineered T cells in the treatment of haematological malignancies raised interest in translating CAR T cell therapies to the treatment of gastrointestinal cancers. Treatment of solid cancers with canonical CAR T cells faces substantial challenges, including the dense architecture of the tumour tissue, the tolerogenic environment with low tumour-intrinsic immunogenicity, the rareness of targetable tumour-selective antigens, the antigenic heterogeneity of cancer cells, and the profound metabolic and immune cell disbalances. This Review provides an overview of CAR T cell trials in the treatment of gastrointestinal cancers, discussing considerations relating to safety, efficacy, potential reasons for failure and options for improving CAR T cells for the future. In addition, lessons regarding how to improve efficacy are drawn from CAR T cells armed with adjuvants that sustain their activation within the hostile environment and activate resident immune cells. As the field is rapidly evolving, current treatment modalities and editing CAR T cell functionalities are being refined towards a potentially more successful CAR T cell therapy for gastrointestinal cancers.
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Affiliation(s)
- Hinrich Abken
- Leibniz Institute for Immunotherapy, Genetic Immunotherapy Division, Regensburg, Germany.
- Genetic Immunotherapy, University of Regensburg, Regensburg, Germany.
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Zitvogel L, Derosa L, Routy B, Loibl S, Heinzerling L, de Vries IJM, Engstrand L, Segata N, Kroemer G. Impact of the ONCOBIOME network in cancer microbiome research. Nat Med 2025; 31:1085-1098. [PMID: 40217075 DOI: 10.1038/s41591-025-03608-8] [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: 08/02/2024] [Accepted: 02/24/2025] [Indexed: 04/18/2025]
Abstract
The European Union-sponsored ONCOBIOME network has spurred an international effort to identify and validate relevant gut microbiota-related biomarkers in oncology, generating a unique and publicly available microbiome resource. ONCOBIOME explores the effects of the microbiota on gut permeability and metabolism as well as on antimicrobial and antitumor immune responses. Methods for the diagnosis of gut dysbiosis have been developed based on oncomicrobiome signatures associated with the diagnosis, prognosis and treatment responses in patients with cancer. The mechanisms explaining how dysbiosis compromises natural or therapy-induced immunosurveillance have been explored. Through its integrative approach of leveraging multiple cohorts across populations, cancer types and stages, ONCOBIOME has laid the theoretical and practical foundations for the recognition of microbiota alterations as a hallmark of cancer. ONCOBIOME has launched microbiota-centered interventions and lobbies in favor of official guidelines for avoiding diet-induced or iatrogenic (for example, antibiotic- or proton pump inhibitor-induced) dysbiosis. Here, we review the key advances of the ONCOBIOME network and discuss the progress toward translating these into oncology clinical practice.
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Affiliation(s)
- Laurence Zitvogel
- INSERM U1015, Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France.
- Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
- Clinicobiome, Gustave Roussy, Villejuif, France.
- Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France.
| | - Lisa Derosa
- INSERM U1015, Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France
- Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France
- Clinicobiome, Gustave Roussy, Villejuif, France
| | - Bertrand Routy
- University of Montreal Research Center (CR-CHUM), Montreal, Quebec, Canada
- Department of Hematology-Oncology, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Quebec, Canada
| | - Sibylle Loibl
- German Breast Group c/ GBG Forschungs GmbH, Neu-Isenburg, Goethe University, Frankfurt, Germany
| | - Lucie Heinzerling
- Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
- Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - I Jolanda M de Vries
- Medical Biosciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Lars Engstrand
- Department of Microbiology Tumor and Cell Biology, Centre for Translational Microbiome Research, Karolinska Institutet, Stockholm, Sweden
| | - Nicola Segata
- Department CIBIO, University of Trento, Trento, Italy
- European Institute of Oncology IRCCS, Milan, Italy
| | - Guido Kroemer
- Equipe labellisée par la Ligue contre le Cancer, Université de Paris Cité, Sorbonne Université, Institut Universitaire de France, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
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Alves Costa Silva C, Almonte AA, Zitvogel L. Oncobiomics: Leveraging Microbiome Translational Research in Immuno-Oncology for Clinical-Practice Changes. Biomolecules 2025; 15:504. [PMID: 40305219 PMCID: PMC12024955 DOI: 10.3390/biom15040504] [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: 01/26/2025] [Revised: 03/16/2025] [Accepted: 03/28/2025] [Indexed: 05/02/2025] Open
Abstract
Growing evidence suggests that cancer should not be viewed solely as a genetic disease but also as the result of functional defects in the metaorganism, including disturbances in the gut microbiota (i.e., gut dysbiosis). The human microbiota plays a critical role in regulating epithelial barrier function in the gut, airways, and skin, along with host metabolism and systemic immune responses against microbes and cancer. Collaborative international networks, such as ONCOBIOME, are essential in advancing research equity and building microbiome resources to identify and validate microbiota-related biomarkers and therapies. In this review, we explore the intricate relationship between the microbiome, metabolism, and cancer immunity, and we propose microbiota-based strategies to improve outcomes for individuals at risk of developing cancer or living with the disease.
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Affiliation(s)
- Carolina Alves Costa Silva
- Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif, France; (C.A.C.S.); (A.A.A.)
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale Contre le Cancer, 94800 Villejuif, France
| | - Andrew A. Almonte
- Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif, France; (C.A.C.S.); (A.A.A.)
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale Contre le Cancer, 94800 Villejuif, France
| | - Laurence Zitvogel
- Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif, France; (C.A.C.S.); (A.A.A.)
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale Contre le Cancer, 94800 Villejuif, France
- Faculté de Médecine, Université Paris-Saclay, 94270 Kremlin-Bicêtre, France
- Center of Clinical Investigations BIOTHERIS, INSERM CIC1428, 94805 Villejuif, France
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Li H, Meng H, Dang C, Liu P, Liu J, Yu X, Wang Z, Lilv, Sui X. Exploring potential causal relationships between gut microbiota, inflammatory factors, and postpartum depression: a Mendelian randomization analysis. BMC Pregnancy Childbirth 2025; 25:177. [PMID: 39962387 PMCID: PMC11834640 DOI: 10.1186/s12884-025-07304-w] [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: 05/03/2024] [Accepted: 02/07/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Recent studies have suggested a potential correlation between ecological dysregulation of the gut microbiota (GM) and the onset and development of postpartum depression (PPD). In addition, inflammatory factors (IFs) have been reported to play an important role in the development of PPD. However, the causal connections among GM, IFs, and PPD remain to be understood. OBJECTIVE This study sought to determine if genetically predicted GM and IFs exert a causal effect on PPD and to study whether IFs mediate the causal effect of GM on PPD. METHODS Two-step and two-sample Mendelian randomization (MR) analyses, primarily employing the inverse variance weighted (IVW) method, were conducted to evaluate the causal relationship between GM, IFs, and PPD, and to assess potential mediating effects. Heterogeneity and horizontal pleiotropy tests were performed to evaluate the robustness of the findings and the strength of the causal associations. RESULTS Class Alphaproteobacteria, genus Family XIII AD3011 group exhibited a positive association with PPD risk; whereas, the family Clostridiales vadin BB60 group, family Veillonellaceae, genus Ruminococcaceae UCG011, and the inflammatory factors C-C motif chemokine ligand 5 (CCL5) and C-C motif chemokine ligand 3 (CCL3) demonstrated negative correlations with PPD risk. IFs did not exhibit a mediating role. No heterogeneity or horizontal pleiotropy was observed. CONCLUSIONS Our MR study offered genetic evidence that GM and IFs contribute to the pathogenesis of PPD, with no mediating effect of IFs. This enhances our understanding of PPD's pathological mechanisms and offers new perspectives for developing novel preventative and therapeutic strategies.
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Affiliation(s)
- Hui Li
- Shandong University of Traditional Chinese Medicine, Jingshi Road, Jinan, Shandong, 250014, China
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jingshi Road, Jinan, Shandong, 250014, China
| | - Hongyan Meng
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jingshi Road, Jinan, Shandong, 250014, China
| | - Chunxiao Dang
- Shandong University of Traditional Chinese Medicine, Jingshi Road, Jinan, Shandong, 250014, China
| | - Pengfei Liu
- Shandong University of Traditional Chinese Medicine, Jingshi Road, Jinan, Shandong, 250014, China
| | - Jinxing Liu
- Shandong University of Traditional Chinese Medicine, Jingshi Road, Jinan, Shandong, 250014, China
| | - Xiao Yu
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jingshi Road, Jinan, Shandong, 250014, China
| | - Zhonglin Wang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jingshi Road, Jinan, Shandong, 250014, China.
| | - Lilv
- Qilu Hospital of Shandong University, Wenhua West Road, Jinan, Shandong, 250014, China.
| | - Xiaohui Sui
- Shandong University of Traditional Chinese Medicine, Jingshi Road, Jinan, Shandong, 250014, China
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Lei H, Hu J, Zhu J, Li R, Zhao Y, Zhao Y, He G, Song T, Lu C, Zheng W, Li L, Liu C, Chen H. Global research prospects and trends in TFH cells and tumors: a bibliometric analysis. Front Oncol 2025; 15:1443890. [PMID: 40027134 PMCID: PMC11867951 DOI: 10.3389/fonc.2025.1443890] [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: 07/10/2024] [Accepted: 01/24/2025] [Indexed: 03/05/2025] Open
Abstract
Background T follicular helper (TFH) cells, a subset of CD4+Th cells, play a critical role in B cell activation, proliferation, and differentiation primarily within B follicles in secondary lymphoid organs, essential processes for effective antibody responses. TFH cells are also implicated in various conditions, including autoimmune diseases, cancer, infectious diseases, allergies, and vaccine reactions. Despite their broad impact, a review of the literature on TFH cells and tumors has not been conducted. We aimed to fill this gap by providing a detailed analysis of the research landscape concerning TFH cells and tumors. Method We conducted a bibliometric analysis of literature on TFH cells and tumors from 2012 to 2024 using the Web of Science Core Collection (WoSCC). For an analysis of the global research landscape, we employed VOSviewer (version 1.6.20), CiteSpace 6.2.R6 software, and the "bibliometric" package in R language (version 4.3.2) to evaluate data on countries/regions, authors and cited authors, institutions, journals, references, and keywords. We also conducted a systematic review to summarize the global research trends, prospects, and hotspots in this field. Results Our analysis included contributions from 60 countries/regions, 7,864 authors, 35,853 cited authors, 1,756 institutions, 385 academic journals, 50883 references, 222 keywords, and 1,181published papers. Over the past decade, the volume of research on TFH cells and tumors had consistently increased. China published the most papers, more than double that of the United States. The top 2 authors ranked by publication volume were Gaulard, Philippe (14 articles, 379 citations), and De leval, Laurence (12 articles, 236 citations) Notably, 9 of the top 10 most published institutions were from China. Frontiers in Immunology and Immunity were the leading journals in publications and citations. A cluster analysis revealed a shift in research focus from "expression","B cells" and "survival" to "tumor microenvironment", "tumor infiltrating immune cells" and "immune infiltration" in recent years. Conclusion This bibliometric analysis suggests that TFH cells hold significant research value and potential clinical applications in tumor immunotherapy. Moreover, the bibliometric analysis offers valuable references and guidance for related research endeavors. It also points out the prevailing issues and challenges in TFH cell research, and underscores the need for further basic and clinical research to advance the related fields.
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Affiliation(s)
- Hao Lei
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Jin Hu
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Junpeng Zhu
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Runze Li
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Zhao
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaqi Zhao
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guisheng He
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Tao Song
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Chong Lu
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wuping Zheng
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Lei Li
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chunping Liu
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hengyu Chen
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
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Valciukiene J, Lastauskiene E, Laurinaviciene A, Jakubauskas M, Kryzauskas M, Valkiuniene RB, Augulis R, Garnelyte A, Kavoliunas J, Silinskaite U, Poskus T. Interaction of human gut microbiota and local immune system in progression of colorectal adenoma (MIMICA-1): a protocol for a prospective, observational cohort study. Front Oncol 2025; 14:1495635. [PMID: 39834942 PMCID: PMC11743970 DOI: 10.3389/fonc.2024.1495635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 12/11/2024] [Indexed: 01/22/2025] Open
Abstract
INTRODUCTION The current understanding of colorectal carcinogenesis is based on the adenoma-carcinoma sequence, where genetics, intestinal microbiota changes and local immunity shifts seem to play the key roles. Despite the emerging evidence of dysbiotic intestinal state and immune-cell infiltration changes in patients with colorectal adenocarcinoma, early and advanced adenoma as precursors of colorectal cancer, and carcinoma in situ as the following progression, are rather less studied. The newly colon-site adapted AI-based analysis of immune infiltrates is able to predict long-term outcomes of colon carcinoma. Though it could also facilitate the pathologic evaluation of precancerous lesion's potential to progress. Therefore, the purpose of this prospective cohort study (MIMICA-1) is, firstly, to identify the intestinal microbiota and immune infiltration patterns around the normal bowel tissue, early and advanced adenoma, carcinoma in situ, and adenocarcinoma, and secondly, to analyze the immune - microbiome interplay along the steps of conventional colorectal tumorigenesis. METHODS AND ANALYSES This study aims to prospectively recruit 40 patients (10 per group) with confirmed colorectal dysplasia undergoing endoscopic polypectomy, endoscopic mucosal resection for colorectal small (≤1cm), and large (>1cm) adenoma or carcinoma in situ, or biopsy and subsequent colon resection for invasive colorectal cancer, and 10 healthy patients undergoing screening colonoscopy. Stool samples will be collected prior to bowel preparation for the analysis of fecal (luminal) microbiota composition. Biopsy specimens will be taken from the terminal ileum, right colon, left colon, and a pathological lesion in the colon (if present) to assess mucosa-associated microbiota composition and intestinal immunity response. DNA will be extracted from all samples and sequenced using the Illumina MiSeq platform. Unifrac and Bray-Curtis methods will be used to assess microbial diversity. The intestinal immune system response will be examined using digital image analysis where primarily immunohistochemistry procedures for CD3, CD8, CD20 and CD68 immune cell markers will be performed. Thereafter, the count, density and distribution of immunocompetent cells in epithelial and stromal tissue compartments will be evaluated using AI-based platform. The interaction between the microbial shifts and intestinal immune system response in adenoma-carcinoma sequence and the healthy patients will be examined. In addition, fecal samples will be explored for gut microbiota's composition, comparing fecal- and tissue-derived bacterial patterns in healthy gut and along the adenoma-carcinoma sequence. DISCUSSION We hypothesize that changes within the human gut microbiota led to detectable alterations of the local immune response and correlate with the progression from normal mucosa to colorectal adenoma and invasive carcinoma. It is expectable to find more severe gut immune infiltration at dysplasia site, though analyzing invasive colorectal cancer we expect to detect broader mucosa-associated and luminal microbiota changes with subsequent local immune response at near-lesion site and possibly throughout the entire colon. We believe that specific compositional differences detected around premalignant colorectal lesions are critically important for its primary role in initiation and acceleration of colorectal carcinogenesis. Thus, these microbial patterns could potentially supplement fecal immunohistochemical tests for the early non-invasive detection of colorectal adenoma. Moreover, AI-based analysis of immune infiltrates could become additional diagnostic and prognostic tool in precancerous lesions prior to the development of colorectal cancer. REGISTRATION The study is registered at the Australian New Zealand Clinical Trials Registry (ACTRN12624000976583) https://www.anzctr.org.au/.
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Affiliation(s)
- Jurate Valciukiene
- Clinic of Gastroenterology, Nephro-Urology, and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Egle Lastauskiene
- Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Aida Laurinaviciene
- National Center of Pathology, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
- Department of Pathology, Forensic Medicine and Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Matas Jakubauskas
- Clinic of Gastroenterology, Nephro-Urology, and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Marius Kryzauskas
- Clinic of Gastroenterology, Nephro-Urology, and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Ruta Barbora Valkiuniene
- National Center of Pathology, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
- Department of Pathology, Forensic Medicine and Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Renaldas Augulis
- National Center of Pathology, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
- Department of Pathology, Forensic Medicine and Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Ausra Garnelyte
- National Center of Pathology, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
| | - Justinas Kavoliunas
- Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | | | - Tomas Poskus
- Clinic of Gastroenterology, Nephro-Urology, and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
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9
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Kaviyarasan V, Das A, Deka D, Saha B, Banerjee A, Sharma NR, Duttaroy AK, Pathak S. Advancements in immunotherapy for colorectal cancer treatment: a comprehensive review of strategies, challenges, and future prospective. Int J Colorectal Dis 2024; 40:1. [PMID: 39731596 DOI: 10.1007/s00384-024-04790-w] [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] [Accepted: 12/15/2024] [Indexed: 12/30/2024]
Abstract
PURPOSE Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Metastatic colorectal cancer (mCRC) continues to present significant challenges, particularly in patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors. This narrative review aims to provide recent developments in immunotherapy for CRC treatment, focusing on its efficacy and challenges. METHODS This review discussed the various immunotherapeutic strategies for CRC treatment, including immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1, combination therapies involving ICIs with other modalities, chimeric antigen receptor T-cell (CAR-T) cell therapy, and cancer vaccines. The role of the tumor microenvironment and immune evasion mechanisms was also explored to understand their impact on the effectiveness of these therapies. RESULTS This review provides a comprehensive update of recent advancements in immunotherapy for CRC, highlighting the potential of various immunotherapeutic approaches, including immune checkpoint inhibitors, combination therapies, CAR-T therapy, and vaccination strategies. The results of checkpoint inhibitors, particularly in patients with MSI-H/dMMR tumors, which have significant improvements in survival rates have been observed. Furthermore, this review also addresses the challenges faced in treating pMMR/MSS CRC, which remains resistant to immunotherapy. CONCLUSION Immunotherapy plays a significant role in the treatment of CRC, particularly in patients with MSI-H/dMMR tumors. However, many challenges remain, especially in treating pMMR/MSS CRC. This review discussed the need for further research into combination therapies, biomarker development, CAR-T cell therapy, and a deeper understanding of immune evasion mechanisms for CRC treatment.
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Affiliation(s)
- Vaishak Kaviyarasan
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Alakesh Das
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Dikshita Deka
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Biki Saha
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Antara Banerjee
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India.
| | - Neeta Raj Sharma
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India
| | - Asim K Duttaroy
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India.
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10
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Geremia N, Giovagnorio F, Colpani A, De Vito A, Botan A, Stroffolini G, Toc DA, Zerbato V, Principe L, Madeddu G, Luzzati R, Parisi SG, Di Bella S. Fluoroquinolones and Biofilm: A Narrative Review. Pharmaceuticals (Basel) 2024; 17:1673. [PMID: 39770514 PMCID: PMC11679785 DOI: 10.3390/ph17121673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 12/04/2024] [Accepted: 12/05/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Biofilm-associated infections frequently span multiple body sites and represent a significant clinical challenge, often requiring a multidisciplinary approach involving surgery and antimicrobial therapy. These infections are commonly healthcare-associated and frequently related to internal or external medical devices. The formation of biofilms complicates treatment, as they create environments that are difficult for most antimicrobial agents to penetrate. Fluoroquinolones play a critical role in the eradication of biofilm-related infections. Numerous studies have investigated the synergistic potential of combining fluoroquinolones with other chemical agents to augment their efficacy while minimizing potential toxicity. Comparative research suggests that the antibiofilm activity of fluoroquinolones is superior to that of beta-lactams and glycopeptides. However, their activity remains less effective than that of minocycline and fosfomycin. Noteworthy combinations include fluoroquinolones with fosfomycin and aminoglycosides for enhanced activity against Gram-negative organisms and fluoroquinolones with minocycline and rifampin for more effective treatment of Gram-positive infections. Despite the limitations of fluoroquinolones due to the intrinsic characteristics of this antibiotic, they remain fundamental in this setting thanks to their bioavailability and synergisms with other drugs. Methods: A comprehensive literature search was conducted using online databases (PubMed/MEDLINE/Google Scholar) and books written by experts in microbiology and infectious diseases to identify relevant studies on fluoroquinolones and biofilm. Results: This review critically assesses the role of fluoroquinolones in managing biofilm-associated infections in various clinical settings while also exploring the potential benefits of combination therapy with these antibiotics. Conclusions: The literature predominantly consists of in vitro studies, with limited in vivo investigations. Although real world data are scarce, they are in accordance with fluoroquinolones' effectiveness in managing early biofilm-associated infections. Also, future perspectives of newer treatment options to be placed alongside fluoroquinolones are discussed. This review underscores the role of fluoroquinolones in the setting of biofilm-associated infections, providing a comprehensive guide for physicians regarding the best use of this class of antibiotics while highlighting the existing critical issues.
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Affiliation(s)
- Nicholas Geremia
- Unit of Infectious Diseases, Department of Clinical Medicine, Ospedale “dell’Angelo”, 30174 Venice, Italy
- Unit of Infectious Diseases, Department of Clinical Medicine, Ospedale Civile “S.S. Giovanni e Paolo”, 30122 Venice, Italy
| | - Federico Giovagnorio
- Department of Molecular Medicine, University of Padua, 35121 Padua, Italy; (F.G.); (S.G.P.)
| | - Agnese Colpani
- Unit of Infectious Diseases, Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (A.D.V.); (G.M.)
| | - Andrea De Vito
- Unit of Infectious Diseases, Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (A.D.V.); (G.M.)
| | - Alexandru Botan
- Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Giacomo Stroffolini
- Department of Infectious-Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, 37024 Verona, Italy;
| | - Dan-Alexandru Toc
- Department of Microbiology, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Verena Zerbato
- Infectious Diseases Unit, Trieste University Hospital (ASUGI), 34125 Trieste, Italy;
| | - Luigi Principe
- Clinical Microbiology and Virology Unit, Great Metropolitan Hospital “Bianchi-Melacrino-Morelli”, 89128 Reggio di Calabria, Italy;
| | - Giordano Madeddu
- Unit of Infectious Diseases, Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (A.D.V.); (G.M.)
| | - Roberto Luzzati
- Clinical Department of Medical, Surgical and Health Sciences, Trieste University, 34129 Trieste, Italy; (R.L.); (S.D.B.)
| | | | - Stefano Di Bella
- Clinical Department of Medical, Surgical and Health Sciences, Trieste University, 34129 Trieste, Italy; (R.L.); (S.D.B.)
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11
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Ding ZY, Piao Y, Jiang T, Chen J, Wang YN, Yu HY, Zheng ZD. Effects of postoperative treatment with chemotherapy and cellular immunotherapy on patients with colorectal cancer. World J Gastrointest Surg 2024; 16:3202-3210. [PMID: 39575273 PMCID: PMC11577400 DOI: 10.4240/wjgs.v16.i10.3202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 08/30/2024] [Accepted: 09/03/2024] [Indexed: 09/27/2024] Open
Abstract
BACKGROUND The outcome of surgical treatment for colorectal cancer (CRC) remains unsatisfactory and warrants further exploration and optimization.
AIM To clarify the impact of chemotherapy plus cellular immunotherapy [dendritic cell-cytokine-induced killer (DC-CIK) cell immunotherapy] on patients after CRC surgery and to explore the mediating variables.
METHODS A total cohort of 121 patients who underwent CRC surgery between January 2019 and April 2022 were selected. The sample comprised a control group of 55 patients who received the XELOX chemotherapy regimen and a research group of 66 patients who received XELOX + DC-CIK immunotherapy. We performed comparative analyses of the clinical and pathological data of the two groups, including efficacy (2-year disease-free survival [DFS] rate), the incidence of adverse events (diarrhea, myelosuppression, gastrointestinal reactions, and peripheral neuritis), serum levels of tumor markers [carcinoembryonic antigens and carbohydrate antigens (CA)19-9 and CA242], and T-cell subsets [cluster of differentiation (CD)3+, CD3+ CD4+, CD3+ CD8+, natural killer (NK), and NK T cells]. We also conducted preliminary univariate and multivariate analyses of the variables that affected the efficacy of the treatments.
RESULTS We found a significantly higher 2-year DFS rate of treatment efficacy in the research group than in the control group, with a statistically lower incidence of adverse events. Both groups showed a reduction in serum tumor markers after treatment but there was no marked intergroup difference. After treatment, the various T-cell subgroup indicators in the control group were significantly lower than those in the research group. The indices of T-cell subsets in the research group showed no significant change from preoperative levels. Univariate analysis revealed a significant correlation between TNM staging, tumor differentiation, and the rates of nonresponse to treatment in CRC patients after surgery. Multivariate results indicated that the treatment approach significantly affected the efficacy of postoperative CRC treatment.
CONCLUSION We concluded that XELOX + DC-CIK immunotherapy for postsurgical CRC patients offers reduced rates of treatment-induced adverse events, extended 2-year DFS, enhanced immunity, and increased physiological antitumor responses.
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Affiliation(s)
- Zhen-Yu Ding
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
| | - Ying Piao
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
| | - Tong Jiang
- Laboratory of Military Health in Cold Region, Center for Disease Control and Prevention of Northern Theater Command, Shenyang 110034, Liaoning Province, China
| | - Juan Chen
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
| | - Yi-Nuo Wang
- Department of Clinical Medicine, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China
| | - Hui-Ying Yu
- Basic Medicine Laboratory, General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
| | - Zhen-Dong Zheng
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
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12
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Zhou R, Sun Z, Zhou R, Wang M, Zhuo Q, Deng X, Wang Z, Xu Y. Pancancer analysis of NDUFA4L2 with focused role in tumor progression and metastasis of colon adenocarcinoma. Med Oncol 2024; 41:285. [PMID: 39402288 DOI: 10.1007/s12032-024-02531-1] [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: 08/14/2024] [Accepted: 10/01/2024] [Indexed: 11/14/2024]
Abstract
Colon adenocarcinoma (COAD) is a prevalent gastrointestinal malignant disease with a high mortality rate, and identification of novel prognostic biomarkers and therapeutic targets is urgently needed. Although NDUFA4L2 has high expressions in various tumors and affects tumor progression, its role in COAD remains unclear. The role of NDUFA4L2 in COAD was analyzed utilizing datasets available from public databases including The Cancer Genome Atlas, The Genotype-Tissue Expression (GTEx), Gene Expression Omnibus, Alabama Cancer Database (UALCAN), and The Human Protein Atlas databases. The prognostic value of NDUFA4L2 was determined using Kaplan-Meier analysis and Cox regression analysis. To investigate the possible mechanism underlying the role of NDUFA4L2 in COAD, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were employed. The correlation between NDUFA4L2 expression and immune cell infiltration levels was examined through single-sample gene set enrichment analysis (ssGSEA). The NDUFA4L2 expression levels in COAD patients and cell lines were validated through immunohistochemistry, immunofluorescence, qRT-PCR, and Western blot. Wound healing assay was also performed to evaluate the effect of NDUFA4L2 on COAD metastasis. Furthermore, the NDUFA4L2 mediated competing endogenous RNA (ceRNA) regulatory network was predicted and constructed through a variety of databases. The comprehensive pan-cancer analysis showed that NDUFA4L2 possesses diagnostic and prognostic value in many cancers, especially in COAD. GO-KEGG and GSEA analyses indicated that NDUFA4L2 was associated with multiple biological functions including epithelial-mesenchymal transition and adaptation to hypoxia. The ssGSEA analysis showed that NDUFA4L2 expression was associated with immune infiltration. In vitro experiments confirmed upregulation of NDUFA4L2 in COAD tissues and cell lines, and NDUFA4L2 overexpression significantly promoted migration of COAD cells. In addition, the C9orf139 /miR-194-3p axis was speculated as the possible upstream regulators of NDUFA4L2 in COAD. This study demonstrated that NDUFA4L2 upregulation was correlated with tumor progression, relapsed prognosis and aggressive migration of COAD, suggesting that NDUFA4L2 can act as an effective prognostic biomarker and a promising therapeutic target for COAD treatment.
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Affiliation(s)
- Runlong Zhou
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430081, Hubei, China
| | - Zhe Sun
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
| | - Ruijie Zhou
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430081, Hubei, China
| | - Mengyi Wang
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430081, Hubei, China
| | - Qing Zhuo
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430081, Hubei, China
| | - Xiaotong Deng
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430081, Hubei, China
| | - Zhenrong Wang
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430081, Hubei, China
| | - Yao Xu
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430081, Hubei, China.
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Jandl B, Dighe S, Gasche C, Makristathis A, Muttenthaler M. Intestinal biofilms: pathophysiological relevance, host defense, and therapeutic opportunities. Clin Microbiol Rev 2024; 37:e0013323. [PMID: 38995034 PMCID: PMC11391705 DOI: 10.1128/cmr.00133-23] [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] [Indexed: 07/13/2024] Open
Abstract
SUMMARYThe human intestinal tract harbors a profound variety of microorganisms that live in symbiosis with the host and each other. It is a complex and highly dynamic environment whose homeostasis directly relates to human health. Dysbiosis of the gut microbiota and polymicrobial biofilms have been associated with gastrointestinal diseases, including irritable bowel syndrome, inflammatory bowel diseases, and colorectal cancers. This review covers the molecular composition and organization of intestinal biofilms, mechanistic aspects of biofilm signaling networks for bacterial communication and behavior, and synergistic effects in polymicrobial biofilms. It further describes the clinical relevance and diseases associated with gut biofilms, the role of biofilms in antimicrobial resistance, and the intestinal host defense system and therapeutic strategies counteracting biofilms. Taken together, this review summarizes the latest knowledge and research on intestinal biofilms and their role in gut disorders and provides directions toward the development of biofilm-specific treatments.
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Affiliation(s)
- Bernhard Jandl
- Faculty of Chemistry, Institute of Biological Chemistry, University of Vienna, Vienna, Austria
- Vienna Doctoral School in Chemistry (DoSChem), University of Vienna, Vienna, Austria
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Satish Dighe
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Christoph Gasche
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
- Loha for Life, Center for Gastroenterology and Iron Deficiency, Vienna, Austria
| | - Athanasios Makristathis
- Department of Laboratory Medicine, Division of Clinical Microbiology, Medical University of Vienna, Vienna, Austria
| | - Markus Muttenthaler
- Faculty of Chemistry, Institute of Biological Chemistry, University of Vienna, Vienna, Austria
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
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14
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Gao XC, Zhou BH, Ji ZX, Li Q, Liu HN. Canopy FGF signaling regulator 3 affects prognosis, immune infiltration, and PI3K/AKT pathway in colon adenocarcinoma. World J Gastrointest Oncol 2024; 16:3284-3298. [PMID: 39072149 PMCID: PMC11271795 DOI: 10.4251/wjgo.v16.i7.3284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 05/14/2024] [Accepted: 06/04/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Colon adenocarcinoma (COAD) is a malignant tumor of the digestive system. The mechanisms underlying COAD development and progression are still largely unknown. AIM To identify the role of canopy FGF signaling regulator 3 (CNPY3) in the development and progression of COAD by using bioinformatic tools and functional experiments. METHODS Bioinformatic data were downloaded from public databases. The associations of clinicopathological features, survival, and immune function with the expression of CNPY3 were analyzed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses and Gene Set Enrichment Analysis were used to explore the related pathways. Then, quantitative real-time PCR and immunohistochemistry were used for validation of CNPY3 expression in clinical samples and tumor cell lines. Cell lines with CNPY3 knockdown were constructed to further analyze gene functions. The functional experiments included proliferation, invasion, migration and apoptosis assays. RESULTS In both the TCGA cohort and the merged dataset, elevated CNPY3 expression was observed in tumor tissues. High CNPY3 expression correlated with adverse survival and compromised immune functions. Functional enrichment analysis suggested that the pro-oncogenic properties of CNPY3 might be linked to the PI3K-AKT signaling pathway. CNPY3 expression was validated at both the RNA and protein levels. Functional assays indicated that cell proliferation, invasion, and migration were inhibited and cell apoptosis was promoted after CNPY3 knockdown. Additionally, Western blot results revealed the downregulation of key proteins in the PI3K/AKT pathway following CNPY3 knockdown. PI3K/AKT pathway activator reversed the decrease in proliferation, invasion, and migration and the increase in apoptosis. Notably, CNPY3 knockdown still affected the cells when the pathway was inhibited. CONCLUSION This study showed that CNPY3 is upregulated in COAD and might regulate COAD development and progression by the PI3K/AKT pathway. Thus, CNPY3 might be a promising therapeutic target.
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Affiliation(s)
- Xu-Can Gao
- Department of Anorectal Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, China
| | - Biao-Huan Zhou
- Department of Anorectal Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, China
| | - Zhou-Xin Ji
- Department of Anorectal Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, China
| | - Qiang Li
- Department of Anorectal Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, China
| | - Hui-Ning Liu
- Department of Anorectal Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, China
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15
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Liu YL, Xiang Z, Zhang BY, Zou YW, Chen GL, Yin L, Shi YL, Xu LL, Bi J, Wang Q. APOA5 alleviates reactive oxygen species to promote oxaliplatin resistance in PIK3CA-mutated colorectal cancer. Aging (Albany NY) 2024; 16:9410-9436. [PMID: 38848145 PMCID: PMC11210231 DOI: 10.18632/aging.205872] [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: 11/15/2023] [Accepted: 03/25/2024] [Indexed: 06/09/2024]
Abstract
Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.
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Affiliation(s)
- Yu-Lin Liu
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250023, China
- Department of Oncology, Shandong Second Provincial General Hospital, Jinan 250023, China
| | - Zhuo Xiang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250023, China
- Department of Oncology, Shandong Second Provincial General Hospital, Jinan 250023, China
| | - Bo-Ya Zhang
- China Key Laboratory of Marine Drugs, The Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
| | - Yu-Wei Zou
- Department of Pathology, Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003, China
| | - Gui-Lai Chen
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250023, China
- Department of Oncology, Shandong Second Provincial General Hospital, Jinan 250023, China
| | - Li Yin
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250023, China
- Department of Oncology, Shandong Second Provincial General Hospital, Jinan 250023, China
| | - Yan-Long Shi
- Department of Oncology, 960 Hospital of People’s Liberation Army, Jinan 250031, China
| | - Li-Li Xu
- Department of Pathology, Navy 971 People’s Liberation Army Hospital, Qingdao 266071, China
| | - Jingwang Bi
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250023, China
- Department of Oncology, Shandong Second Provincial General Hospital, Jinan 250023, China
| | - Qiang Wang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250023, China
- Department of Oncology, Shandong Second Provincial General Hospital, Jinan 250023, China
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Chen J, Wang Z, Zhu Q, Ren S, Xu Y, Wang G, Zhou L. Comprehensive analysis and experimental verification of the mechanism of action of T cell-mediated tumor-killing related genes in Colon adenocarcinoma. Transl Oncol 2024; 43:101918. [PMID: 38412662 PMCID: PMC10907202 DOI: 10.1016/j.tranon.2024.101918] [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: 10/15/2023] [Revised: 02/07/2024] [Accepted: 02/17/2024] [Indexed: 02/29/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a prevalent malignancy of the digestive tract. A new prognostic scoring model for colon adenocarcinoma (COAD) is developed in this study based on the genes involved in tumor cell-mediated killing of T cells (GSTTKs), accurately stratifying COAD patients, thus improving the current status of personalized treatment. METHOD The GEO and TCGA databases served as the sources of the data for the COAD cohort. This study identified GSTTKs-related genes in COAD through single-factor Cox analysis. These genes were used to categorize COAD patients into several subtypes via unsupervised clustering analysis. The biological pathways and tumor microenvironments of different subgroups were compared. We performed intersection analysis between different subtypes to obtain intersection genes. Single-factor Cox regression analysis and Lasso-Cox analysis were conducted to establish clinical prognostic models. Two methods are used to assess the accuracy of model predictions: ROC and Kaplan-Meier analysis. Next, the prediction model was further validated in the validation cohort. Differential immune cell infiltration between various risk categories was identified via single sample gene set enrichment analysis (ssGSEA). The COAD model's gene expression was validated via single-cell data analysis and experiments. RESULT We established two distinct GSTTKs-related subtypes. Biological processes and immune cell tumor invasion differed significantly between various subtypes. Clinical prognostic models were created using five GSTTKs-related genes. The model's risk score independently served as a prognostic factor. COAD patients were classified as low- or high-risk depending on their risk scores. Patients in the low-risk category recorded a greater chance of surviving. The outcomes from the validation cohort match those from the training set. Risk scores and several tumor-infiltrating immune cells were strongly correlated, according to ssGSEA. Single-cell data illustrated that the model's genes were linked to several immune cells. The experimental results demonstrated a significant increase in the expression of HOXC6 in colon cancer tissue. CONCLUSION Our research findings established a new gene signature for COAD. This gene signature helps to accurately stratify the risk of COAD patients and improve the current status of individualized care.
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Affiliation(s)
- Jing Chen
- Department of Medical Laboratory, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, 225009, China
| | - Zhengfang Wang
- Department of Medical Laboratory, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, 225009, China
| | - Qin Zhu
- Department of Trauma Hand Surgery, Dalian Third People's Hospital, Dalian 116000, China
| | - Shiqi Ren
- Department of Hand Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Yanhua Xu
- Department of Medical Laboratory, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, 225009, China
| | - Guangzhou Wang
- Department of Medical Laboratory, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, 225009, China.
| | - Lin Zhou
- Department of Medical Laboratory, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, 225009, China.
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Ke S, Lei Y, Guo Y, Xie F, Yu Y, Geng H, Zhong Y, Xu D, Liu X, Yu F, Xia X, Zhang Z, Zhu C, Ling W, Li B, Zhao W. CD177 drives the transendothelial migration of Treg cells enriched in human colorectal cancer. Clin Transl Immunology 2024; 13:e1506. [PMID: 38596253 PMCID: PMC11003710 DOI: 10.1002/cti2.1506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 01/27/2024] [Accepted: 03/28/2024] [Indexed: 04/11/2024] Open
Abstract
Objectives Regulatory T (Treg) cells regulate immunity in autoimmune diseases and cancers. However, immunotherapies that target tumor-infiltrating Treg cells often induce unwanted immune responses and tissue inflammation. Our research focussed on exploring the expression pattern of CD177 in tumor-infiltrating Treg cells with the aim of identifying a potential target that can enhance immunotherapy effectiveness. Methods Single-cell RNA sequencing (scRNA-seq) data and survival data were obtained from public databases. Twenty-one colorectal cancer patient samples, including fresh tumor tissues, peritumoral tissues and peripheral blood mononuclear cells (PBMCs), were analysed using flow cytometry. The transendothelial activity of CD177+ Treg cells was substantiated using in vitro experiments. Results ScRNA-seq and flow cytometry results indicated that CD177 was exclusively expressed in intratumoral Treg cells. CD177+ Treg cells exhibited greater activation status and expressed elevated Treg cell canonical markers and immune checkpoint molecules than CD177- Treg cells. We further discovered that both intratumoral CD177+ Treg cells and CD177-overexpressing induced Treg (iTreg) cells had lower levels of PD-1 than their CD177- counterparts. Moreover, CD177 overexpression significantly enhanced the transendothelial migration of Treg cells in vitro. Conclusions These results demonstrated that Treg cells with higher CD177 levels exhibited an enhanced activation status and transendothelial migration capacity. Our findings suggest that CD177 may serve as an immunotherapeutic target and that overexpression of CD177 may improve the efficacy of chimeric antigen receptor T (CAR-T) cell therapy.
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Affiliation(s)
- Shouyu Ke
- Department of Gastrointestinal Surgery, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yi Lei
- Center for Immune‐Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Thoracic Surgery of Ruijin Hospital, Department of Immunology and MicrobiologyShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yixian Guo
- Department of Gastrointestinal Surgery, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Feng Xie
- Center for Immune‐Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Thoracic Surgery of Ruijin Hospital, Department of Immunology and MicrobiologyShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yimeng Yu
- Center for Immune‐Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Thoracic Surgery of Ruijin Hospital, Department of Immunology and MicrobiologyShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Haigang Geng
- Department of Gastrointestinal Surgery, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yiqing Zhong
- Department of Gastrointestinal Surgery, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Danhua Xu
- Department of Gastrointestinal Surgery, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xu Liu
- Department of Gastrointestinal Surgery, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Fengrong Yu
- Department of Gastrointestinal Surgery, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xiang Xia
- Department of Gastrointestinal Surgery, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Zizhen Zhang
- Department of Gastrointestinal Surgery, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Chunchao Zhu
- Department of Gastrointestinal Surgery, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Wei Ling
- Department of Gastrointestinal Surgery, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Bin Li
- Center for Immune‐Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Thoracic Surgery of Ruijin Hospital, Department of Immunology and MicrobiologyShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Wenyi Zhao
- Department of Gastrointestinal Surgery, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
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Ma M, Zheng Z, Li J, He Y, Kang W, Ye X. Association between the gut microbiota, inflammatory factors, and colorectal cancer: evidence from Mendelian randomization analysis. Front Microbiol 2024; 15:1309111. [PMID: 38562480 PMCID: PMC10982360 DOI: 10.3389/fmicb.2024.1309111] [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: 10/07/2023] [Accepted: 03/06/2024] [Indexed: 04/04/2024] Open
Abstract
Background Colorectal cancer (CRC) is one of the most common malignant tumors primarily affecting individuals over the age of 50 years. Recent studies have suggested that the dysbiosis of the gut microbiota, a community of microorganisms in the human gut, is closely associated with the occurrence and development of CRC. Additionally, inflammatory factors (IFs) have also been reported to play a significant role in the development of CRC. However, the causal relationships between the gut microbiota, IFs, and CRC remain unclear. Methods In this study, we performed Mendelian randomization (MR) analysis using publicly available genome-wide association study (GWAS) data to explore the causal relationship between the gut microbiota, IFs, and CRC. The gut microbiota GWAS data were obtained from the MiBioGen study, while the IFs GWAS data were derived from the comprehensive analysis of three independent cohorts. Causal relationship analysis was conducted using appropriate instrumental variables (IVs) and statistical models. Results MR analysis of the gut microbiota and CRC revealed a negative correlation between the Lachnospiraceae species in the gut and CRC risk, while a positive correlation was observed between Porphyromonadaceae species, Lachnospiraceae UCG010 genus, Lachnospira genus, and Sellimonas genus in the gut, and CRC risk. Additionally, we observed a causal relationship between IL-10 and CRC risk. These findings suggest that the dysbiosis of the gut microbiota might be associated with an increased risk of CRC and that specific bacterial groups may play a crucial role in the occurrence and development of CRC. Conclusion Using MR analysis, this study revealed the causal relationships between the gut microbiota, IFs, and CRC. The negative correlation between the Lachnospiraceae species in the gut and CRC risk, as well as the causal relationship between IL-10 and CRC, provide important clues for the potential roles of gut microbiota regulation and inflammatory factor control in the prevention and treatment of CRC.
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Affiliation(s)
| | | | | | | | - Weiming Kang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xin Ye
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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Guan M, Xu W, Bai H, Geng Z, Yu Z, Li H, Liu T. Potential mechanisms underlying inhibition of xenograft lung cancer models by kaempferol: modulation of gut microbiota in activating immune cell function. J Cancer 2024; 15:1314-1327. [PMID: 38356724 PMCID: PMC10861830 DOI: 10.7150/jca.88038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 12/26/2023] [Indexed: 02/16/2024] Open
Abstract
Context: As a flavonoid compound, kaempferol has great potential in anti-lung cancer therapy, but the mechanism of its therapeutic effect needs further exploration. Objective: To explore the therapeutic effect of kaempferol on lung cancer, as well as its capability to regulate the gut microbiota and stimulate immune function. Materials & methods: Twenty-four BALB/c mice were divided into four groups. The first two groups, consisting of 12 normal mice, were administered either PBS or Kaempferol (Kaem) via gavage. The remaining 12 mice, which were subcutaneously inoculated with Lewis Lung Carcinoma (LLC) cells, were similarly divided and subjected to the same treatments respectively. The inhibitory effect of kaempferol on xenograft lung cancer models was explored with in vivo experiments, the diversity of gut microbiota was investigated by 16S rDNA sequencing, and the treatment effect on immune cells was quantified using flow cytometry. Results: Kaempferol exerted a significant inhibitory effect on xenograft lung cancer models in vivo. It effectively inhibited the proliferation of LLC cells and significantly activated cytotoxic T cells, natural killer cells, and other immune cells in mice. 16S rRNA sequencing of fecal samples from tumor-bearing mice treated with kaempferol showed a significant increase in the abundances of potentially advantageous microbial species such as c_Bacilli, o_Lactobacillales, f_Lachnospiraceae, s_uncultured_bacterium_g_Lactobacillus, g_Lactobacillus, f_Bacteroidaceae, g_Bacteroides, and s_uncultured_bacterium_g_Bacteroides, s_Bacteroides_acidifaciens. An increase in the proportions of three types of immune cells might associated with the above dominant bacterial species. Conclusion: Kaempferol can inhibit xenograft lung cancer models. Such inhibition effect might come from the activation of T cells, NK cells, and other immune cells which are modulated by the gut microbiota.
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Affiliation(s)
- Maoying Guan
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Weijie Xu
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Haoran Bai
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Zixiang Geng
- Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Zhihua Yu
- Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Hegen Li
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Te Liu
- Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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Sulit AK, Daigneault M, Allen-Vercoe E, Silander OK, Hock B, McKenzie J, Pearson J, Frizelle FA, Schmeier S, Purcell R. Bacterial lipopolysaccharide modulates immune response in the colorectal tumor microenvironment. NPJ Biofilms Microbiomes 2023; 9:59. [PMID: 37612266 PMCID: PMC10447454 DOI: 10.1038/s41522-023-00429-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 08/15/2023] [Indexed: 08/25/2023] Open
Abstract
Immune responses can have opposing effects in colorectal cancer (CRC), the balance of which may determine whether a cancer regresses, progresses, or potentially metastasizes. These effects are evident in CRC consensus molecular subtypes (CMS) where both CMS1 and CMS4 contain immune infiltrates yet have opposing prognoses. The microbiome has previously been associated with CRC and immune response in CRC but has largely been ignored in the CRC subtype discussion. We used CMS subtyping on surgical resections from patients and aimed to determine the contributions of the microbiome to the pleiotropic effects evident in immune-infiltrated subtypes. We integrated host gene-expression and meta-transcriptomic data to determine the link between immune characteristics and microbiome contributions in these subtypes and identified lipopolysaccharide (LPS) binding as a potential functional mechanism. We identified candidate bacteria with LPS properties that could affect immune response, and tested the effects of their LPS on cytokine production of peripheral blood mononuclear cells (PBMCs). We focused on Fusobacterium periodonticum and Bacteroides fragilis in CMS1, and Porphyromonas asaccharolytica in CMS4. Treatment of PBMCs with LPS isolated from these bacteria showed that F. periodonticum stimulates cytokine production in PBMCs while both B. fragilis and P. asaccharolytica had an inhibitory effect. Furthermore, LPS from the latter two species can inhibit the immunogenic properties of F. periodonticum LPS when co-incubated with PBMCs. We propose that different microbes in the CRC tumor microenvironment can alter the local immune activity, with important implications for prognosis and treatment response.
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Affiliation(s)
- A K Sulit
- School of Natural Sciences, Massey University, Auckland, New Zealand.
- Department of Surgery and Critical Care, University of Otago, Christchurch, New Zealand.
| | - M Daigneault
- Department of Molecular and Cellular Biology, University of Guelph, Ontario, Canada
| | - E Allen-Vercoe
- Department of Molecular and Cellular Biology, University of Guelph, Ontario, Canada
| | - O K Silander
- School of Natural Sciences, Massey University, Auckland, New Zealand
| | - B Hock
- Haematology Research Group, University of Otago, Christchurch, New Zealand
| | - J McKenzie
- Haematology Research Group, University of Otago, Christchurch, New Zealand
| | - J Pearson
- Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand
| | - F A Frizelle
- Department of Surgery and Critical Care, University of Otago, Christchurch, New Zealand
| | - S Schmeier
- School of Natural Sciences, Massey University, Auckland, New Zealand
- Evotec SE, Hamburg, Germany
| | - R Purcell
- Department of Surgery and Critical Care, University of Otago, Christchurch, New Zealand
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21
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Pang F, Yang P, Wang T, Li X, Wu X, Yue R, Bai B, Zhao Q. Comprehensive Analysis of Alternative Polyadenylation Events Associated with the Tumor Immune Microenvironment in Colon Adenocarcinoma. Curr Genomics 2023; 24:48-61. [PMID: 37920728 PMCID: PMC10334702 DOI: 10.2174/1389202924666230503122134] [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: 09/30/2022] [Revised: 03/12/2023] [Accepted: 03/21/2023] [Indexed: 11/04/2023] Open
Abstract
Objective Colon adenocarcinoma (COAD) is one of the leading causes of cancer death worldwide. Alternative polyadenylation (APA) is relevant to the variability of the 3'-UTR of mRNA. However, the posttranscriptional dysregulation of APA in COAD is poorly understood. Methods We collected APA data from The Cancer Genome Atlas (TCGA) COAD (n =7692). APA events were evaluated using PDUI values, and the prognostically significant APA events were screened by LASSO Cox regression to construct a prognostic model. Then, prognostic model functions and possible regulatory genes of characteristic APA events were analyzed. Finally, the immune regulatory network based on APA regulatory genes was analyzed and established. Results A total of 95 APA events were found to influence the COAD outcomes. Among them, 39 genes were screened as characteristic prognostic APA events by LASSO Cox regression to construct a COAD prognostic signature. The analysis results suggested that a high signature score was associated with poor prognosis and was significantly correlated with a variety of immune cells, including NK and Th1, 2 and 17 cells. Further analysis showed that APA regulators mainly served roles in the prognosis of COAD. Based on the above results, we constructed an immunoregulatory network for APA regulatory genes-APA genes-immune cells. Conclusion Our study revealed that APA events in COAD may regulate tumor progression by influencing immune cells, which provides a new direction for exploring the influencing mechanism of the tumor immune microenvironment and is expected to provide a potential new target for COAD immunotherapy.
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Affiliation(s)
- Fangning Pang
- Department of Surgery, Xi'an International Medical Center Hospital, Xi'an, China
- Institute of Health and Rehabilitation Science, School of Life Science and Technology, Xi'an Jiaotong University, Xi’an, China
| | - Peng Yang
- Institute of Health and Rehabilitation Science, School of Life Science and Technology, Xi'an Jiaotong University, Xi’an, China
| | - Tongfei Wang
- Department of Oncology, Xi’an No. 3 Hospital, Xi’an, China
| | - Xuzhao Li
- Department of Surgery, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China
| | - Xiaoyong Wu
- Department of General Surgery, Affiliated Danzhou People’s Hospital of Hainan Medical University, Danzhou, China
| | - Rong Yue
- Department of Emergency, Xi'an Daxing Hospital, Xi'an, China
| | - Bin Bai
- Department of Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
| | - Qingchuan Zhao
- Department of Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
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22
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Levy JJ, Zavras JP, Veziroglu EM, Nasir-Moin M, Kolling FW, Christensen BC, Salas LA, Barney RE, Palisoul SM, Ren B, Liu X, Kerr DA, Pointer KB, Tsongalis GJ, Vaickus LJ. Identification of Spatial Proteomic Signatures of Colon Tumor Metastasis: A Digital Spatial Profiling Approach. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:778-795. [PMID: 37037284 PMCID: PMC10284031 DOI: 10.1016/j.ajpath.2023.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 01/29/2023] [Accepted: 02/24/2023] [Indexed: 04/12/2023]
Abstract
Over 150,000 Americans are diagnosed with colorectal cancer (CRC) every year, and annually >50,000 individuals are estimated to die of CRC, necessitating improvements in screening, prognostication, disease management, and therapeutic options. CRC tumors are removed en bloc with surrounding vasculature and lymphatics. Examination of regional lymph nodes at the time of surgical resection is essential for prognostication. Developing alternative approaches to indirectly assess recurrence risk would have utility in cases where lymph node yield is incomplete or inadequate. Spatially dependent, immune cell-specific (eg, tumor-infiltrating lymphocytes), proteomic, and transcriptomic expression patterns inside and around the tumor-the tumor immune microenvironment-can predict nodal/distant metastasis and probe the coordinated immune response from the primary tumor site. The comprehensive characterization of tumor-infiltrating lymphocytes and other immune infiltrates is possible using highly multiplexed spatial omics technologies, such as the GeoMX Digital Spatial Profiler. In this study, machine learning and differential co-expression analyses helped identify biomarkers from Digital Spatial Profiler-assayed protein expression patterns inside, at the invasive margin, and away from the tumor, associated with extracellular matrix remodeling (eg, granzyme B and fibronectin), immune suppression (eg, forkhead box P3), exhaustion and cytotoxicity (eg, CD8), Programmed death ligand 1-expressing dendritic cells, and neutrophil proliferation, among other concomitant alterations. Further investigation of these biomarkers may reveal independent risk factors of CRC metastasis that can be formulated into low-cost, widely available assays.
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Affiliation(s)
- Joshua J Levy
- Emerging Diagnostic and Investigative Technologies, Department of Pathology and Laboratory Medicine, Dartmouth Health, Lebanon, New Hampshire; Department of Dermatology, Dartmouth Health, Lebanon, New Hampshire; Department of Epidemiology, Dartmouth College Geisel School of Medicine, Hanover, New Hampshire; Program in Quantitative Biomedical Sciences, Dartmouth College Geisel School of Medicine, Hanover, New Hampshire.
| | | | - Eren M Veziroglu
- Dartmouth College Geisel School of Medicine, Hanover, New Hampshire
| | | | | | - Brock C Christensen
- Department of Epidemiology, Dartmouth College Geisel School of Medicine, Hanover, New Hampshire; Department of Molecular and Systems Biology, Dartmouth College Geisel School of Medicine, Hanover, New Hampshire; Department of Community and Family Medicine, Dartmouth College Geisel School of Medicine, Hanover, New Hampshire
| | - Lucas A Salas
- Department of Epidemiology, Dartmouth College Geisel School of Medicine, Hanover, New Hampshire; Department of Molecular and Systems Biology, Dartmouth College Geisel School of Medicine, Hanover, New Hampshire; Integrative Neuroscience at Dartmouth Graduate Program, Dartmouth College Geisel School of Medicine, Hanover, New Hampshire
| | - Rachael E Barney
- Emerging Diagnostic and Investigative Technologies, Department of Pathology and Laboratory Medicine, Dartmouth Health, Lebanon, New Hampshire
| | - Scott M Palisoul
- Emerging Diagnostic and Investigative Technologies, Department of Pathology and Laboratory Medicine, Dartmouth Health, Lebanon, New Hampshire
| | - Bing Ren
- Emerging Diagnostic and Investigative Technologies, Department of Pathology and Laboratory Medicine, Dartmouth Health, Lebanon, New Hampshire
| | - Xiaoying Liu
- Emerging Diagnostic and Investigative Technologies, Department of Pathology and Laboratory Medicine, Dartmouth Health, Lebanon, New Hampshire
| | - Darcy A Kerr
- Emerging Diagnostic and Investigative Technologies, Department of Pathology and Laboratory Medicine, Dartmouth Health, Lebanon, New Hampshire
| | - Kelli B Pointer
- Section of Radiation Oncology, Department of Medicine, Dartmouth College Geisel School of Medicine, Hanover, New Hampshire
| | - Gregory J Tsongalis
- Emerging Diagnostic and Investigative Technologies, Department of Pathology and Laboratory Medicine, Dartmouth Health, Lebanon, New Hampshire.
| | - Louis J Vaickus
- Emerging Diagnostic and Investigative Technologies, Department of Pathology and Laboratory Medicine, Dartmouth Health, Lebanon, New Hampshire
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23
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Novoa Díaz MB, Carriere P, Gentili C. How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells. World J Stem Cells 2023; 15:281-301. [PMID: 37342226 PMCID: PMC10277969 DOI: 10.4252/wjsc.v15.i5.281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/06/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Colorectal cancer (CRC) remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant characteristics. It is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment failure. Nevertheless, in the last decades, CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells (CCSC) with features like tumor initiation capacity, self-renewal capacity, and acquired multidrug resistance. Emerging data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic changes. These alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine signaling. It is known that in the tumor niche, different cell types, structures, and biomolecules coexist and interact with cancer cells favoring cancer growth and development. Together, these components constitute the tumor microenvironment (TME). Most recently, researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa, collectively known as gut microbiota, on CRC. Both TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of CRC. Since in the last decade, crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC, the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Pedro Carriere
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
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Sambruni G, Macandog AD, Wirbel J, Cagnina D, Catozzi C, Dallavilla T, Borgo F, Fazio N, Fumagalli-Romario U, Petz WL, Manzo T, Ravenda SP, Zeller G, Nezi L, Schaefer MH. Location and condition based reconstruction of colon cancer microbiome from human RNA sequencing data. Genome Med 2023; 15:32. [PMID: 37131219 PMCID: PMC10155404 DOI: 10.1186/s13073-023-01180-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 04/13/2023] [Indexed: 05/04/2023] Open
Abstract
BACKGROUND The association between microbes and cancer has been reported repeatedly; however, it is not clear if molecular tumour properties are connected to specific microbial colonisation patterns. This is due mainly to the current technical and analytical strategy limitations to characterise tumour-associated bacteria. METHODS Here, we propose an approach to detect bacterial signals in human RNA sequencing data and associate them with the clinical and molecular properties of the tumours. The method was tested on public datasets from The Cancer Genome Atlas, and its accuracy was assessed on a new cohort of colorectal cancer patients. RESULTS Our analysis shows that intratumoural microbiome composition is correlated with survival, anatomic location, microsatellite instability, consensus molecular subtype and immune cell infiltration in colon tumours. In particular, we find Faecalibacterium prausnitzii, Coprococcus comes, Bacteroides spp., Fusobacterium spp. and Clostridium spp. to be strongly associated with tumour properties. CONCLUSIONS We implemented an approach to concurrently analyse clinical and molecular properties of the tumour as well as the composition of the associated microbiome. Our results may improve patient stratification and pave the path for mechanistic studies on microbiota-tumour crosstalk.
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Affiliation(s)
- Gaia Sambruni
- Department of Experimental Oncology, European Institute of Oncology-IRCCS, Milano, Italy
| | - Angeli D Macandog
- Department of Experimental Oncology, European Institute of Oncology-IRCCS, Milano, Italy
| | - Jakob Wirbel
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Danilo Cagnina
- Department of Experimental Oncology, European Institute of Oncology-IRCCS, Milano, Italy
| | - Carlotta Catozzi
- Department of Experimental Oncology, European Institute of Oncology-IRCCS, Milano, Italy
| | - Tiziano Dallavilla
- Department of Experimental Oncology, European Institute of Oncology-IRCCS, Milano, Italy
| | - Francesca Borgo
- Department of Experimental Oncology, European Institute of Oncology-IRCCS, Milano, Italy
- Center for Omics Sciences, IRCCS San Raffaele Institute, Milano, Italy
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology-IRCCS, Milano, Italy
| | | | - Wanda L Petz
- Digestive Surgery, European Institute of Oncology-IRCCS, Milano, Italy
| | - Teresa Manzo
- Department of Experimental Oncology, European Institute of Oncology-IRCCS, Milano, Italy
| | - Simona P Ravenda
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology-IRCCS, Milano, Italy
| | - Georg Zeller
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Luigi Nezi
- Department of Experimental Oncology, European Institute of Oncology-IRCCS, Milano, Italy.
| | - Martin H Schaefer
- Department of Experimental Oncology, European Institute of Oncology-IRCCS, Milano, Italy.
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Bhattacharya S. An empirical review on the resistance mechanisms of epidermal growth factor receptor inhibitors and predictive molecular biomarkers in colorectal cancer. Crit Rev Oncol Hematol 2023; 183:103916. [PMID: 36717006 DOI: 10.1016/j.critrevonc.2023.103916] [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: 11/01/2022] [Revised: 12/06/2022] [Accepted: 01/20/2023] [Indexed: 01/29/2023] Open
Abstract
Despite advances in cytotoxic treatments, colorectal cancer remains a leading cause of death. Metastatic colorectal cancer (mCRC) patients have a poor prognosis despite improved treatments and more prolonged median survival. Monoclonal antibodies like cetuximab and panitumumab target the epidermal growth factor receptor (EGFR). They play an essential role in the treatment of metastatic colorectal cancer (mCRC) due to their efficacy in multiple phase III clinical trials across multiple treatment lines. It was discovered that anti-EGFR moAbs were only effective for a small number of patients. Mutations in KRAS and NRAS have been identified as biomarkers of drug resistance. New molecular predictors and prognostic markers are used clinically. The K-Ras mutation is the first molecular marker of a lack of response to EGFR-targeted therapy in K-Ras-mutant patients. Validating predictive and prognostic markers will improve cancer treatments. This article examines molecular markers that can predict colorectal cancer prognosis.
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Affiliation(s)
- Sankha Bhattacharya
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra 425405, India.
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Colon Cancer Microbiome Landscaping: Differences in Right- and Left-Sided Colon Cancer and a Tumor Microbiome-Ileal Microbiome Association. Int J Mol Sci 2023; 24:ijms24043265. [PMID: 36834671 PMCID: PMC9963782 DOI: 10.3390/ijms24043265] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/01/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
In the current era of precision oncology, it is widely acknowledged that CRC is a heterogeneous disease entity. Tumor location (right- or left-sided colon cancer or rectal cancer) is a crucial factor in determining disease progression as well as prognosis and influences disease management. In the last decade, numerous works have reported that the microbiome is an important element of CRC carcinogenesis, progression and therapy response. Owing to the heterogeneous nature of microbiomes, the findings of these studies were inconsistent. The majority of the studies combined colon cancer (CC) and rectal cancer (RC) samples as CRC for analysis. Furthermore, the small intestine, as the major site for immune surveillance in the gut, is understudied compared to the colon. Thus, the CRC heterogeneity puzzle is far from being solved, and more research is necessary for prospective trials that separately investigate CC and RC. Our prospective study aimed to map the colon cancer landscape using 16S rRNA amplicon sequencing in biopsy samples from the terminal ileum, healthy colon tissue, healthy rectal tissue and tumor tissue as well as in preoperative and postoperative stool samples of 41 patients. While fecal samples provide a good approximation of the average gut microbiome composition, mucosal biopsies allow for detecting subtle variations in local microbial communities. In particular, the small bowel microbiome has remained poorly characterized, mainly because of sampling difficulties. Our analysis revealed the following: (i) right- and left-sided colon cancers harbor distinct and diverse microbiomes, (ii) the tumor microbiome leads to a more consistent cancer-defined microbiome between locations and reveals a tumor microbiome-ileal microbiome association, (iii) the stool only partly reflects the microbiome landscape in patients with CC, and (iv) mechanical bowel preparation and perioperative antibiotics together with surgery result in major changes in the stool microbiome, characterized by a significant increase in the abundance of potentially pathogenic bacteria, such as Enterococcus. Collectively, our results provide new and valuable insights into the complex microbiome landscape in patients with colon cancer.
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The Controversial Role of Intestinal Mast Cells in Colon Cancer. Cells 2023; 12:cells12030459. [PMID: 36766801 PMCID: PMC9914221 DOI: 10.3390/cells12030459] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/24/2023] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
Mast cells are tissue-resident sentinels involved in large number of physiological and pathological processes, such as infection and allergic response, thanks to the expression of a wide array of receptors. Mast cells are also frequently observed in a tumor microenvironment, suggesting their contribution in the transition from chronic inflammation to cancer. In particular, the link between inflammation and colorectal cancer development is becoming increasingly clear. It has long been recognized that patients with inflammatory bowel disease have an increased risk of developing colon cancer. Evidence from experimental animals also implicates the innate immune system in the development of sporadically occurring intestinal adenomas, the precursors to colorectal cancer. However, the exact role of mast cells in tumor initiation and growth remains controversial: mast cell-derived mediators can either exert pro-tumorigenic functions, causing the progression and spread of the tumor, or anti-tumorigenic functions, limiting the tumor's growth. Here, we review the multifaceted and often contrasting findings regarding the role of the intestinal mast cells in colon cancer progression focusing on the molecular pathways mainly involved in the regulation of mast cell plasticity/functions during tumor progression.
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Zhu A, Liu Y, Li Z, He Y, Bai L, Wu Y, Zhang Y, Huang Y, Jiang P. Diagnosis and functional prediction of microbial markers in tumor tissues of sporadic colorectal cancer patients associated with the MLH1 protein phenotype. Front Oncol 2023; 12:1116780. [PMID: 36755857 PMCID: PMC9899897 DOI: 10.3389/fonc.2022.1116780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 12/30/2022] [Indexed: 01/25/2023] Open
Abstract
Objective Most patients with sporadic colorectal cancer (SCRC) develop microsatellite instability because of defects in mismatch repair (MMR). Moreover, the gut microbiome plays a vital role in the pathogenesis of SCRC. In this study, we assessed the microbial composition and diversity of SCRC tumors with varying MutL protein homolog 1 (MLH1) status, and the effects of functional genes related to bacterial markers and clinical diagnostic prediction. Methods The tumor microbial diversity and composition were profiled using high-throughput sequencing of the 16S ribosomal RNA (rRNA) gene V4 region. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt2) software and BugBase tool were used to predict the functional roles of the microbiome. We aimed to construct a high-accuracy model to detect and evaluate the area under the receiver operating characteristic curve with candidate biomarkers. Results The study included 23 patients with negative/defective MLH1 (DM group) and 22 patients with positive/intact MLH1 (IM group). Estimation of alpha diversity indices showed that the Shannon index (p = 0.049) was significantly higher in the DM group than in the controls, while the Simpson index (p = 0.025) was significantly lower. At the genus level, we observed a significant difference in beta diversity in the DM group versus the IM group. Moreover, the abundance of Lachnoclostridium spp. and Coprococcus spp. was significantly more enriched in the DM group than in the IM group (q < 0.01 vs. q < 0.001). When predicting metagenomes, there were 18 Kyoto Encyclopedia of Genes and Genomes pathways and one BugBase function difference in both groups (all q < 0.05). On the basis of the model of diagnostic prediction, we built a simplified optimal model through stepwise selection, consisting of the top two bacterial candidate markers (area under the curve = 0.93). Conclusion In conclusion, the genera Lachnoclostridium and Coprococcus as key species may be crucial biomarkers for non-invasive diagnostic prediction of DM in patients with SCRC in the future.
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Affiliation(s)
- Anchao Zhu
- Department of Pathology, Harbin First Hospital, Harbin, China
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Yingying Liu
- Department of Pathology, Heilongjiang Provincial Hospital, Harbin, China
| | - Zongmin Li
- Department of Pathology, Harbin First Hospital, Harbin, China
| | - Ying He
- Department of Gastroenterology, Harbin First Hospital, Harbin, China
| | - Lijing Bai
- Department of Laboratory Diagnosis, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Youtian Wu
- Department of Pathology, Harbin First Hospital, Harbin, China
| | - Yuying Zhang
- Department of Pathology, Harbin First Hospital, Harbin, China
| | - Ying Huang
- Department of Pathology, Harbin First Hospital, Harbin, China
| | - Ping Jiang
- Department of Pathology, Harbin First Hospital, Harbin, China
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Denis M, Mathé D, Micoud M, Choffour PA, Grasselly C, Matera EL, Dumontet C. Impact of mouse model tumor implantation site on acquired resistance to anti-PD-1 immune checkpoint therapy. Front Immunol 2023; 13:1011943. [PMID: 36703964 PMCID: PMC9872099 DOI: 10.3389/fimmu.2022.1011943] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 12/20/2022] [Indexed: 01/12/2023] Open
Abstract
Introduction The use of tumor subcutaneous (SC) implantations rather than orthotopic sites is likely to induce a significant bias, in particular, in the field of immunotherapy. Methods In this study, we developed and characterized MC38 models, implanted subcutaneously and orthotopically, which were either sensitive or rendered resistant to anti-PD1 therapy. We characterized the tumor immune infiltrate by flow cytometry at baseline and after treatment. Results and Discussion Our results demonstrate several differences between SC and orthotopic models at basal state, which tend to become similar after therapy. These results emphasize the need to take into account tumor implantation sites when performing preclinical studies with immunotherapeutic agents.
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Affiliation(s)
- Morgane Denis
- Univ Lyon, Université Claude Bernard Lyon, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France,R&D Department, Antineo, Lyon, France
| | | | - Manon Micoud
- Univ Lyon, Université Claude Bernard Lyon, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France
| | | | - Chloé Grasselly
- Univ Lyon, Université Claude Bernard Lyon, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France
| | - Eva-Laure Matera
- Univ Lyon, Université Claude Bernard Lyon, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France
| | - Charles Dumontet
- Univ Lyon, Université Claude Bernard Lyon, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France,Hematology Department, Hospices Civils de Lyon, Lyon, France,*Correspondence: Charles Dumontet,
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Variation of Saponins in Sanguisorba officinalis L. before and after Processing ( Paozhi) and Its Effects on Colon Cancer Cells In Vitro. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27249046. [PMID: 36558181 PMCID: PMC9785891 DOI: 10.3390/molecules27249046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/13/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
The incidence of colon cancer is increasing year over year, seriously affecting human health and quality of life in recent years. However, traditional Chinese medicine (TCM) has been utilized for the treatment of colon cancer. S. officinalis Saponins (S-Saponins), the potential compound of TCM, displays multiple biological activities in colon cancer treatment. In our study, ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) combined with multivariate statistical analysis were performed to analyze and identify raw and processed saponins. Then, MTT and cell migration assays were used to preliminarily explore the effects of saponins in vitro on colon cancer cells. The results showed that 29 differential saponins compounds under Paozhi were identified by UHPLC-MS/MS. Moreover, in vitro validation showed that Sprocessed better inhibited the proliferation and migration of colon cancer cells than Sraw. This study provides a basis for the determination of the chemical fundamentals of the efficacy changes during Paozhi through inferring the changes in saponin components and its possible transformation mechanisms before and after processing S. officinalis. Meanwhile, it also provides new insights into potential bioactive ingredients for the treatment of colon cancer.
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Zhang Y, Xu T, Tian H, Wu J, Yu X, Zeng L, Liu F, Liu Q, Huang X. Coxsackievirus Group B3 Has Oncolytic Activity against Colon Cancer through Gasdermin E-Mediated Pyroptosis. Cancers (Basel) 2022; 14:cancers14246206. [PMID: 36551691 PMCID: PMC9776948 DOI: 10.3390/cancers14246206] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 12/03/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Colon cancer is the second leading cause of cancer-related death, and there are few effective therapies for colon cancer. This study explored the use of coxsackievirus group B3 (CVB3) as an oncolytic virus for the treatment of colon cancer. In this study, we verified that CVB3 induces death of colon cancer cell lines by directly observing cell morphology and Western blot results, and observed the oncolytic effects of CVB3 by constructing an immunodeficient nude mice model. Our data show that CVB3 induces pyroptosis in colon cancer cell lines. Mechanistically, we demonstrated that CVB3 causes cleavage of gasdermin E (GSDME), but not gasdermin D (GSDMD), by activating caspase-3. This leads to production of GSDME N-termini and the development of pores in the plasma membrane, inducing pyroptosis of colon cancer cell lines. We also demonstrate that CVB3-induced pyroptosis is promoted by reactive oxygen species (ROS). Finally, in vivo studies using immunodeficient nude mice revealed that intratumoral injection of CVB3 led to significant tumor regression. Our findings indicate that CVB3 has oncolytic activity in colon cancer cell lines via GSDME-mediated pyroptosis.
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Affiliation(s)
- Yejia Zhang
- Department of Medical Microbiology, School of Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Tian Xu
- Department of Medical Microbiology, School of Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Huizhen Tian
- Department of Medical Microbiology, School of Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Jianfeng Wu
- Department of Medical Microbiology, School of Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Xiaomin Yu
- Department of Medical Microbiology, School of Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Lingbing Zeng
- Department of Medical Microbiology, School of Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
- Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Fadi Liu
- The Department of Clinical Laboratory, Children’s Hospital of Jiangxi Province, Nanchang 330006, China
| | - Qiong Liu
- Department of Medical Microbiology, School of Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
- Correspondence: (Q.L.); (X.H.)
| | - Xiaotian Huang
- Department of Medical Microbiology, School of Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
- Correspondence: (Q.L.); (X.H.)
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Liang Z, Sun R, Tu P, Liang Y, Liang L, Liu F, Bian Y, Yin G, Zhao F, Jiang M, Gu J, Tang D. Immune-related gene-based prognostic index for predicting survival and immunotherapy outcomes in colorectal carcinoma. Front Immunol 2022; 13:944286. [PMID: 36591255 PMCID: PMC9795839 DOI: 10.3389/fimmu.2022.944286] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 11/25/2022] [Indexed: 12/15/2022] Open
Abstract
Introduction Colorectal cancer shows high incidence and mortality rates. Immune checkpoint blockade can be used to treat colorectal carcinoma (CRC); however, it shows limited effectiveness in most patients. Methods To identify patients who may benefit from immunotherapy using immune checkpoint inhibitors, we constructed an immune-related gene prognostic index (IRGPI) for predicting the efficacy of immunotherapy in patients with CRC. Transcriptome datasets and clinical information of patients with CRC were used to identify differential immune-related genes between tumor and para-carcinoma tissue. Using weighted correlation network analysis and Cox regression analysis, the IRGPI was constructed, and Kaplan-Meier analysis was used to evaluate its predictive ability. We also analyzed the molecular and immune characteristics between IRGPI high-and low-risk subgroups, performed sensitivity analysis of ICI treatment, and constructed overall survival-related receiver operating characteristic curves to validate the IRGPI. Finally, IRGPI genes and tumor immune cell infiltration in CRC model mice with orthotopic metastases were analyzed to verify the results. Results The IRGPI was constructed based on the following 11 hub genes: ADIPOQ, CD36, CCL24, INHBE, UCN, IL1RL2, TRIM58, RBCK1, MC1R, PPARGC1A, and LGALS2. Patients with CRC in the high-risk subgroup showed longer overall survival than those in the low-risk subgroup, which was confirmed by GEO database. Clinicopathological features associated with cancer progression significantly differed between the high- and low-risk subgroups. Furthermore, Kaplan-Meier analysis of immune infiltration showed that the increased infiltration of naïve B cells, macrophages M1, and regulatory T cells and reduced infiltration of resting dendritic cells and mast cells led to a worse overall survival in patients with CRC. The ORC curves revealed that IRGPI predicted patient survival more sensitive than the published tumor immune dysfunction and rejection and tumor inflammatory signature. Discussion Thus, the low-risk subgroup is more likely to benefit from ICIs than the high-risk subgroup. CRC model mice showed higher proportions of Tregs, M1 macrophages, M2 macrophages and lower proportions of B cells, memory B cell immune cell infiltration, which is consistent with the IRGPI results. The IRGPI can predict the prognosis of patients with CRC, reflect the CRC immune microenvironment, and distinguish patients who are likely to benefit from ICI therapy.
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Affiliation(s)
- Zhongqing Liang
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Ruolan Sun
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Pengcheng Tu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China,Laboratory of New Techniques of Restoration & Reconstruction of Orthopedics and Traumatology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yan Liang
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Li Liang
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Fuyan Liu
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yong Bian
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China,Laboratory Animal Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Gang Yin
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Fan Zhao
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Mingchen Jiang
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Junfei Gu
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China,*Correspondence: Decai Tang, ; Junfei Gu,
| | - Decai Tang
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China,*Correspondence: Decai Tang, ; Junfei Gu,
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Colorectal cancer organoid models uncover oxaliplatin-resistant mechanisms at single cell resolution. Cell Oncol (Dordr) 2022; 45:1155-1167. [PMID: 36136268 DOI: 10.1007/s13402-022-00705-5] [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: 04/21/2022] [Revised: 08/04/2022] [Accepted: 08/10/2022] [Indexed: 12/15/2022] Open
Abstract
PURPOSE Oxaliplatin-based chemotherapy is a standard treatment for advanced colorectal cancer (CRC) patients. However, chemoresistance-induced resistance is an essential cause for mortality. Therefore, it is necessary to study the mechanism of drug resistance in CRC. METHODS Here, we established two strains of patient-derived organoids (PDOs) selected from oxaliplatin-resistant and treatment-naïve CRC patients. To dissect the drug-resistant mechanisms, these CRC-PDOs were subjected to single-cell RNA sequencing (scRNA-Seq). RESULTS We found that the drug sensitivity test outcome from these organoids subjected to oxaliplatin and 5-FU exposure was consistent with the clinic readout. CRC-PDOs well recapitulated the morphology and histology of their parental biopsies based on HE and IHC staining of pathological biomarkers. The scRNA-Seq data filtered drug-resistant cell populations and related signaling pathways (e.g. oxidative phosphorylation and ATP metabolic process). The data also revealed several putative drug resistant-driven genes (STMN1, VEGFA and NDRG1) and transcription factors (E2F1, BRCA1, MYBL2, CDX2 and CDX1). CONCLUSION We generated an oxaliplatin-resistant CRC organoid model that was employed to provide potential therapeutic targets for treating CRC patients exhibiting oxaliplatin-resistance.
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Yu I, Wu R, Tokumaru Y, Terracina KP, Takabe K. The Role of the Microbiome on the Pathogenesis and Treatment of Colorectal Cancer. Cancers (Basel) 2022; 14:5685. [PMID: 36428777 PMCID: PMC9688177 DOI: 10.3390/cancers14225685] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/13/2022] [Accepted: 11/16/2022] [Indexed: 11/22/2022] Open
Abstract
The gut microbiome has long been known to play a role in various aspects of health modulation, including the pathogenesis of colorectal cancer (CRC). With immunotherapy recently emerging as a successful treatment in microsatellite instability high (MSI-high) CRC, and with a newly demonstrated involvement of the gut microbiome in the modulation of therapeutic responses, there has been an explosion of research into the mechanisms of microbial effects on CRC. Harnessing and reprogramming the microbiome may allow for the expansion of these successes to broader categories of CRC, the prevention of CRC in high-risk patients, and the enhancement of standard treatments. In this review, we pull together both well-documented phenomena and recent discoveries that pertain to the microbiome and CRC. We explore the microbial mechanisms associated with CRC pathogenesis and progression, recent advancements in CRC systemic therapy, potential options for diagnosis and prevention, as well as directions for future research.
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Affiliation(s)
- Irene Yu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14203, USA
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | | | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14203, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
- Department of Breast Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
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Atreya I, Neurath MF. How the Tumor Micromilieu Modulates the Recruitment and Activation of Colorectal Cancer-Infiltrating Lymphocytes. Biomedicines 2022; 10:biomedicines10112940. [PMID: 36428508 PMCID: PMC9687992 DOI: 10.3390/biomedicines10112940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/17/2022] Open
Abstract
The successful treatment of advanced colorectal cancer disease still represents an insufficiently solved clinical challenge, which is further complicated by the fact that the majority of malignant colon tumors show only relatively low immunogenicity and therefore have only limited responsiveness to immunotherapeutic approaches, such as, for instance, the use of checkpoint inhibitors. As it has been well established over the past two decades that the local tumor microenvironment and, in particular, the quantity, quality, and activation status of intratumoral immune cells critically influence the clinical prognosis of patients diagnosed with colorectal cancer and their individual benefits from immunotherapy, the enhancement of the intratumoral accumulation of cytolytic effector T lymphocytes and other cellular mediators of the antitumor immune response has emerged as a targeted objective. For the future identification and clinical validation of novel therapeutic target structures, it will thus be essential to further decipher the molecular mechanisms and cellular interactions in the intestinal tumor microenvironment, which are crucially involved in immune cell recruitment and activation. In this context, our review article aims at providing an overview of the key chemokines and cytokines whose presence in the tumor micromilieu relevantly modulates the numeric composition and antitumor capacity of tumor-infiltrating lymphocytes.
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Affiliation(s)
- Imke Atreya
- Department of Medicine 1, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Correspondence: ; Tel.: +49-9131-8535204; Fax: +49-9131-8535209
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Siddiqui R, Boghossian A, Alharbi AM, Alfahemi H, Khan NA. The Pivotal Role of the Gut Microbiome in Colorectal Cancer. BIOLOGY 2022; 11:1642. [PMID: 36358343 PMCID: PMC9687647 DOI: 10.3390/biology11111642] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/16/2022] [Accepted: 10/24/2022] [Indexed: 08/06/2023]
Abstract
Colorectal cancer is the third most diagnosed cancer worldwide and the second most prevalent cause of cancer-related mortality. It is believed that alterations within the gut microbiome may impact the development and progression of cancer. Additionally, the diet an individual maintains and the amount of alcohol consumed can alter the microbiome, thus impacting the development of colorectal cancer. A diet focused on fiber intake is considered beneficial, as it contains short-chain fatty acids such as butyrate, which have antitumor properties. Furthermore, current treatment strategies, such as chemotherapy, have various side effects. In this review, we discuss the role of the gut microbiome and oral bacteria in relation to colorectal cancer. We also deliberate on the role of diet and alcohol consumption in the development of colorectal cancer. Moreover, the influence of the various metabolites within the gut and the importance of gut inflammation in the development of colorectal cancer are explained. Finally, potential therapies such as fecal microbiota transfer and post/prebiotics are elaborated on. To further comprehend risk factors in the development of colorectal cancer, future studies are warranted to determine the precise mechanisms of action between the gut microbiome and carcinogenesis in order to develop therapies that may target gut microbial dysbiosis.
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Affiliation(s)
- Ruqaiyyah Siddiqui
- College of Arts and Sciences, American University of Sharjah, Sharjah 26666, United Arab Emirates
- Department of Medical Biology, Faculty of Medicine, Istinye University, 34010 Istanbul, Turkey
| | - Anania Boghossian
- College of Arts and Sciences, American University of Sharjah, Sharjah 26666, United Arab Emirates
| | - Ahmad M. Alharbi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
| | - Hasan Alfahemi
- Department of Medical Microbiology, Faculty of Medicine, Al-Baha University, Al-Baha 65799, Saudi Arabia
| | - Naveed Ahmed Khan
- Department of Medical Biology, Faculty of Medicine, Istinye University, 34010 Istanbul, Turkey
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
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Harbiyeli IFC, Burtea DE, Ivan ET, Streață I, Nicoli ER, Uscatu D, Șerbănescu MS, Ioana M, Vilmann P, Săftoiu A. Assessing Putative Markers of Colorectal Cancer Stem Cells: From Colonoscopy to Gene Expression Profiling. Diagnostics (Basel) 2022; 12:diagnostics12102280. [PMID: 36291969 PMCID: PMC9601164 DOI: 10.3390/diagnostics12102280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer stem cells (CSCs) are proposed to be involved in colorectal cancer (CRC) initiation, growth, and metastasis. The aim of our pilot study was to assess possible correlations between the clinicopathological characteristics of CRC patients and CSCs gene expression patterns, in order to provide insight into new methods for patient stratification and targeted therapeutic strategies. Our study involved 60 CRC patients, and the following three specific CSC genes were targeted: PROM1/CD133, ALCAM/CD166 and HCAM /CD44. Data are presented as relative mRNA expression of target genes to GAPDH. The expression of total CD133 and CD166 was assessed in paired samples of CRC tumors and adjacent tissue, while CD44 was assessed in similar samples. The qRT-PCR analysis detected all three targeted genes to different extents, in both normal and tumor tissue. In nine cases (15.69%), total CD133 had a higher expression in tumor tissue, whilst in 28 cases (47.06%) the expression was higher in non-malignant peritumor tissue. The total CD166 expression was increased in tumor tissue compared with paired non-invaded peritumor samples in eight cases (13.73%), whilst in eight cases (13.73%) the expression was higher in non-malignant peritumor tissue. Total CD44 expression was higher in tumor tissue compared with paired non-invaded peritumor samples in 47 cases (78.95%). In the remaining cases the difference between paired samples was biologically insignificant. In conclusion, our study suggests that qRT-PCR is feasible in assessing the gene expression profiles of CSCs from CRC, and a promising pathway to be followed for determining how often a person needs screening by colonoscopy and at which age to start. This could improve CRC diagnosis and early patient stratification, and open the way for new oncologic treatment development.
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Affiliation(s)
- Irina Florina Cherciu Harbiyeli
- Research Center of Gastroenterology and Hepatology Craiova, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania
| | - Daniela Elena Burtea
- Research Center of Gastroenterology and Hepatology Craiova, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania
- Correspondence:
| | - Elena Tatiana Ivan
- Research Center of Gastroenterology and Hepatology Craiova, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania
| | - Ioana Streață
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Elena Raluca Nicoli
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Daniel Uscatu
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mircea-Sebastian Șerbănescu
- Department of Medical Informatics and Biostatistics, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mihai Ioana
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Peter Vilmann
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, 2730 Herlev, Denmark
| | - Adrian Săftoiu
- Research Center of Gastroenterology and Hepatology Craiova, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania
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Li W, Lin G, Xiao Z, Zhang Y, Li B, Zhou Y, Ma Y, Chai E. A review of respirable fine particulate matter (PM2.5)-induced brain damage. Front Mol Neurosci 2022; 15:967174. [PMID: 36157076 PMCID: PMC9491465 DOI: 10.3389/fnmol.2022.967174] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/09/2022] [Indexed: 11/29/2022] Open
Abstract
Respirable fine particulate matter (PM2.5) has been one of the most widely publicized indicators of pollution in recent years. Epidemiological studies have established a strong association between PM2.5, lung disease, and cardiovascular disease. Recent studies have shown that PM2.5 is also strongly associated with brain damage, mainly cerebrovascular damage (stroke) and neurological damage to the brain (changes in cognitive function, dementia, psychiatric disorders, etc.). PM2.5 can pass through the lung–gas–blood barrier and the “gut–microbial–brain” axis to cause systemic oxidative stress and inflammation, or directly enter brain tissue via the olfactory nerve, eventually damaging the cerebral blood vessels and brain nerves. It is worth mentioning that there is a time window for PM2.5-induced brain damage to repair itself. However, the exact pathophysiological mechanisms of brain injury and brain repair are not yet fully understood. This article collects and discusses the mechanisms of PM2.5-induced brain injury and self-repair after injury, which may provide new ideas for the prevention and treatment of cerebrovascular and cerebral neurological diseases.
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Affiliation(s)
- Wei Li
- The First Clinical Medical College of Gansu University of Chinese Medical, Lan Zhou, China
- Cerebrovascular Disease Center of Gansu Provincial People's Hospital, Lan Zhou, China
- Key Laboratory of Cerebrovascular Diseases in Gansu Province, Lan Zhou, China
| | - Guohui Lin
- Day Treatment Center II of Gansu Provincial Maternity and Child-Care Hospital, Lan Zhou, China
| | - Zaixing Xiao
- Cerebrovascular Disease Center of Gansu Provincial People's Hospital, Lan Zhou, China
- Key Laboratory of Cerebrovascular Diseases in Gansu Province, Lan Zhou, China
| | - Yichuan Zhang
- Cerebrovascular Disease Center of Gansu Provincial People's Hospital, Lan Zhou, China
- Key Laboratory of Cerebrovascular Diseases in Gansu Province, Lan Zhou, China
| | - Bin Li
- Cerebrovascular Disease Center of Gansu Provincial People's Hospital, Lan Zhou, China
- Key Laboratory of Cerebrovascular Diseases in Gansu Province, Lan Zhou, China
| | - Yu Zhou
- Key Laboratory of Cerebrovascular Diseases in Gansu Province, Lan Zhou, China
- The First School of Clinical Medicine of Lanzhou University, Lan Zhou, China
| | - Yong Ma
- Cerebrovascular Disease Center of Gansu Provincial People's Hospital, Lan Zhou, China
- Key Laboratory of Cerebrovascular Diseases in Gansu Province, Lan Zhou, China
| | - Erqing Chai
- Cerebrovascular Disease Center of Gansu Provincial People's Hospital, Lan Zhou, China
- Key Laboratory of Cerebrovascular Diseases in Gansu Province, Lan Zhou, China
- *Correspondence: Erqing Chai
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Texture Features of Computed Tomography Image under the Artificial Intelligence Algorithm and Its Predictive Value for Colorectal Liver Metastasis. CONTRAST MEDIA & MOLECULAR IMAGING 2022; 2022:2279018. [PMID: 35935311 PMCID: PMC9325563 DOI: 10.1155/2022/2279018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/20/2022] [Accepted: 06/27/2022] [Indexed: 11/17/2022]
Abstract
The aim of this research was to investigate the predictive role of texture features in computed tomography (CT) images based on artificial intelligence (AI) algorithms for colorectal liver metastases (CRLM). A total of 150 patients with colorectal cancer who were admitted to the hospital were selected as the research objects and randomly divided into three groups with 50 cases in each group. The patients who were found to suffer from the CRLM in the initial examination were included in group A. Patients who were found with CRLM in the follow-up were assigned to group B (B1: metastasis within 0.5 years, 16 cases; B2: metastasis within 0.5–1.0 years, 17 cases; and B3: metastasis within 1.0–2.0 years, 17 cases). Patients without liver metastases during the initial examination and subsequent follow-up were designated as group C. Image textures were analyzed for patients in each group. The prediction accuracy, sensitivity, and specificity of CRLM in patients with six classifiers were calculated, based on which the receiver operator characteristic (ROC) curves were drawn. The results showed that the logistic regression (LR) classifier had the highest prediction accuracy, sensitivity, and specificity, showing the best prediction effect, followed by the linear discriminant (LD) classifier. The prediction accuracy, sensitivity, and specificity of the LR classifier were higher in group B1 and group B3, and the prediction effect was better than that in group B2. The texture features of CT images based on the AI algorithms showed a good prediction effect on CRLM and had a guiding significance for the early diagnosis and treatment of CRLM. In addition, the LR classifier showed the best prediction effect and high clinical value and can be popularized and applied.
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NK Cells and Other Cytotoxic Innate Lymphocytes in Colorectal Cancer Progression and Metastasis. Int J Mol Sci 2022; 23:ijms23147859. [PMID: 35887206 PMCID: PMC9322916 DOI: 10.3390/ijms23147859] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/12/2022] [Accepted: 07/14/2022] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies and leading causes of cancer-related deaths worldwide. Despite its complex pathogenesis and progression, CRC represents a well-fitting example of how the immune contexture can dictate the disease outcome. The presence of cytotoxic lymphocytes, both CD8+ T cells and natural killer (NK) cells, represents a relevant prognostic factor in CRC and is associated with a better overall survival. Together with NK cells, other innate lymphocytes, namely, innate lymphoid cells (ILCs), have been found both in biopsies of CRC patients and in murine models of intestinal cancer, playing both pro- and anti-tumor activities. In particular, several type 1 innate lymphoid cells (ILC1) with cytotoxic functions have been recently described, and evidence in mice shows a role for both NK cells and ILC1 in controlling CRC metastasis. In this review, we provide an overview of the features of NK cells and the expanding spectrum of innate lymphocytes with cytotoxic functions. We also comment on both the described and the potential roles these innate lymphocytes can play during the progression of intestinal cancer leading to metastasis. Finally, we discuss recent advances in the molecular mechanisms underlying the functional regulation of cytotoxic innate lymphocytes in CRC.
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Cai M, Xiao Y, Lin Z, Lu J, Wang X, Rahman SU, Zhu S, Chen X, Gu J, Ma Y, Chen Z, Huo J. Disordered Gut Microbiota in Colorectal Tumor-Bearing Mice Altered Serum Metabolome Related to Fufangchangtai. Front Pharmacol 2022; 13:889181. [PMID: 35694271 PMCID: PMC9178095 DOI: 10.3389/fphar.2022.889181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 04/18/2022] [Indexed: 11/13/2022] Open
Abstract
Purpose: This study aimed to investigate the relationship between gut microbiota (GM) and serum metabolism using antineoplastic Fufangchangtai (FFCT) as the model prescription in the treatment of colorectal cancer (CRC).Methods: Tumor-bearing mice and normal mice were administered different doses of FFCT. The tumor volume of tumor-bearing mice was observed. The levels of CD4+ and CD8+ T cells in the blood, spleen, and tumor of mice were determined using a flow cytometer. The bacterial microbiota in stool samples from mice and the serum metabolomics of FFCT-treated mice and fecal microbiota transplantation mice were detected using 16s RNA sequencing and liquid chromatography–mass spectrometry (LC/MS), respectively.Results: The tumor volume of mice showed no significant decrease after FFCT intervention. The levels of CD4+ and CD8+T lymphocytes showed a significant increase under the intervention of FFCT. GM of colorectal tumor-bearing mice and healthy mice were determined, and the diversity and abundance of Firmicutes, Deferribacteres, Bacteroidetes, and Proteobacteria were significantly different between the two groups. Furthermore, we found that the levels of matrine, isogingerenone B, and armillaripin were significantly decreased in tumor-bearing mice after FFCT intervention, indicating that the tumor-induced dysbiosis of gut bacteria may affect the absorption and metabolism of FFCT. Under the intervention of FFCT, serum metabolism of mice transplanted with feces from CRC patients showed less metabolites related to FFCT than that from healthy people, indicating that GM could be a single factor affecting the metabolism of FFCT. Furthermore, we found that different doses of FFCT-treated mice had higher abundance of Roseburia, Turicibacter, and Flexispira than that in the non-intervention control group. Firmicutes and Bacteroidetes in FFCT-treated groups showed a similar trend compared to the healthy group, indicating that FFCT might correct the intestinal microenvironment by modulating gut microbiota in colorectal tumor-bearing mice.Conclusion: The dysbiosis of GM in tumor-bearing mice reduced the serum metabolites related to FFCT, and FFCT could correct the disordered GM of colorectal tumor-bearing mice to exert efficacy.
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Affiliation(s)
- Mengmeng Cai
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Laboratory of Quality and Safety Risk Assessment for Animal Products on Biohazards (Shanghai) of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Ya Xiao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Zhibing Lin
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Jiege Huo, ; Zhaoguo Chen, ; Zhibing Lin,
| | - Jinmiao Lu
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Laboratory of Quality and Safety Risk Assessment for Animal Products on Biohazards (Shanghai) of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- South China Agricultural University, Guangzhou, China
| | - Xiaoyu Wang
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China
| | - Sajid Ur Rahman
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Laboratory of Quality and Safety Risk Assessment for Animal Products on Biohazards (Shanghai) of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, China
| | - Shilan Zhu
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Laboratory of Quality and Safety Risk Assessment for Animal Products on Biohazards (Shanghai) of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- South China Agricultural University, Guangzhou, China
| | - Xiaoyu Chen
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Laboratory of Quality and Safety Risk Assessment for Animal Products on Biohazards (Shanghai) of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- South China Agricultural University, Guangzhou, China
| | - Jialin Gu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Yuzhu Ma
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Zhaoguo Chen
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Laboratory of Quality and Safety Risk Assessment for Animal Products on Biohazards (Shanghai) of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- *Correspondence: Jiege Huo, ; Zhaoguo Chen, ; Zhibing Lin,
| | - Jiege Huo
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
- *Correspondence: Jiege Huo, ; Zhaoguo Chen, ; Zhibing Lin,
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Cheng X, Wang Y, Liu L, Lv C, Liu C, Xu J. SLC7A11, a Potential Therapeutic Target Through Induced Ferroptosis in Colon Adenocarcinoma. Front Mol Biosci 2022; 9:889688. [PMID: 35517862 PMCID: PMC9065265 DOI: 10.3389/fmolb.2022.889688] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 03/23/2022] [Indexed: 01/14/2023] Open
Abstract
Background: Ferroptosis induced by SLC7A11 has an important translational value in the treatment of cancers. However, the mechanism of SLC7A11 in the pathogenesis of colon adenocarcinoma (COAD) is rarely studied in detail. Methods: SLC7A11 expression was explored with The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) databases, and Western blot assay. The correlation of SLC7A11 expression with the abundance of infiltrating immune cells was evaluated via the TIMER database. The relation of SLC7A11 expression with immune cell markers was investigated via Gene Expression Profiling Interactive Analysis (GEPIA). The co-expression genes of SLC7A11 were screened by R packages, and the PPI was constructed via the STRING database. SLC7A11 and co-expressed gene modulators were selected by NetworkAnalyst and DSigDB database. The correlations between SLC7A11 and cancer immune characteristics were analyzed via the TIMER and TISIDB databases. Results: SLC7A11 is overexpressed in most tumors, including COAD. The expression level of SLC7A11 has a significant correlation with the infiltration levels of CD8+ T cells, neutrophils, and dendritic cells in COAD. The infiltrated lymphocyte markers of Th1 cell such as TBX21, IL12RB2, IL27RA, STAT1, and IFN-γ were strongly correlated with SLC7A11 expression. Five hub genes co-expressed with SLC7A11 that induce ferroptosis were identified, and mir-335-5p, RELA, and securinine have regulatory effects on it. SLC7A11 was negatively correlated with the expression of chemokines and chemokine receptors, such as CCL17, CCL19, CCL22, CCL23, CXCL14, CCR10, CX3CR1, and CXCR3, in COAD. Conclusion: SLC7A11 may play a role in induced ferroptosis and regulating tumor immunity, which can be considered as potential therapeutic targets in COAD.
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Affiliation(s)
- Xin Cheng
- General Surgery Department, Wuhu Hospital of Traditional Chinese Medicine, Wuhu, China
| | - Yadong Wang
- General Surgery Department, Wuhu Hospital of Traditional Chinese Medicine, Wuhu, China
| | - Liangchao Liu
- General Surgery Department, Wuhu Hospital of Traditional Chinese Medicine, Wuhu, China
| | - Chenggang Lv
- General Surgery Department, Wuhu Hospital of Traditional Chinese Medicine, Wuhu, China
| | - Can Liu
- The First Affiliated Hospital of Wannan Medical College, Wuhu, China
| | - Jingyun Xu
- School of Basic Medicine, Wannan Medical College, Wuhu, China
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Kupfer SS. Broadening our Understanding of the Immune Landscape in Lynch Syndrome. Gastroenterology 2022; 162:1024-1025. [PMID: 34999096 PMCID: PMC11837409 DOI: 10.1053/j.gastro.2022.01.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 12/02/2022]
Affiliation(s)
- Sonia S Kupfer
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois.
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Seely KD, Morgan AD, Hagenstein LD, Florey GM, Small JM. Bacterial Involvement in Progression and Metastasis of Colorectal Neoplasia. Cancers (Basel) 2022; 14:1019. [PMID: 35205767 PMCID: PMC8870662 DOI: 10.3390/cancers14041019] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 02/06/2023] Open
Abstract
While the gut microbiome is composed of numerous bacteria, specific bacteria within the gut may play a significant role in carcinogenesis, progression, and metastasis of colorectal carcinoma (CRC). Certain microbial species are known to be associated with specific cancers; however, the interrelationship between bacteria and metastasis is still enigmatic. Mounting evidence suggests that bacteria participate in cancer organotropism during solid tumor metastasis. A critical review of the literature was conducted to better characterize what is known about bacteria populating a distant site and whether a tumor depends upon the same microenvironment during or after metastasis. The processes of carcinogenesis, tumor growth and metastatic spread in the setting of bacterial infection were examined in detail. The literature was scrutinized to discover the role of the lymphatic and venous systems in tumor metastasis and how microbes affect these processes. Some bacteria have a potent ability to enhance epithelial-mesenchymal transition, a critical step in the metastatic cascade. Bacteria also can modify the microenvironment and the local immune profile at a metastatic site. Early targeted antibiotic therapy should be further investigated as a measure to prevent metastatic spread in the setting of bacterial infection.
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Affiliation(s)
- Kevin D. Seely
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT 84738, USA; (A.D.M.); (L.D.H.)
| | - Amanda D. Morgan
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT 84738, USA; (A.D.M.); (L.D.H.)
| | - Lauren D. Hagenstein
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT 84738, USA; (A.D.M.); (L.D.H.)
| | - Garrett M. Florey
- College of Osteopathic Medicine, Rocky Vista University, Parker, CO 80134, USA;
| | - James M. Small
- Department of Biomedical Sciences, Rocky Vista University, Parker, CO 80134, USA;
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Immune suppressive checkpoint interactions in the tumour microenvironment of primary liver cancers. Br J Cancer 2022; 126:10-23. [PMID: 34400801 PMCID: PMC8727557 DOI: 10.1038/s41416-021-01453-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 05/05/2021] [Accepted: 05/27/2021] [Indexed: 12/24/2022] Open
Abstract
Liver cancer is one of the most prevalent cancers, and the third most common cause of cancer-related mortality worldwide. The therapeutic options for the main types of primary liver cancer-hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA)-are very limited. HCC and CCA are immunogenic cancers, but effective immune-mediated tumour control is prevented by their immunosuppressive tumour microenvironment. Despite the critical involvement of key co-inhibitory immune checkpoint interactions in immunosuppression in liver cancer, only a minority of patients with HCC respond to monotherapy using approved checkpoint inhibitor antibodies. To develop effective (combinatorial) therapeutic immune checkpoint strategies for liver cancer, in-depth knowledge of the different mechanisms that contribute to intratumoral immunosuppression is needed. Here, we review the co-inhibitory pathways that are known to suppress intratumoral T cells in HCC and CCA. We provide a detailed description of insights from preclinical studies in cellular crosstalk within the tumour microenvironment that results in interactions between co-inhibitory receptors on different T-cell subsets and their ligands on other cell types, including tumour cells. We suggest alternative immune checkpoints as promising targets, and draw attention to the possibility of combined targeting of co-inhibitory and co-stimulatory pathways to abrogate immunosuppression.
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Chen Y, Zheng X, Wu C. The Role of the Tumor Microenvironment and Treatment Strategies in Colorectal Cancer. Front Immunol 2021; 12:792691. [PMID: 34925375 PMCID: PMC8674693 DOI: 10.3389/fimmu.2021.792691] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/15/2021] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) has the second highest mortality rate among all cancers worldwide. Surgery, chemotherapy, radiotherapy, molecular targeting and other treatment methods have significantly prolonged the survival of patients with CRC. Recently, the emergence of tumor immunotherapy represented by immune checkpoint inhibitors (ICIs) has brought new immunotherapy options for the treatment of advanced CRC. As the efficacy of ICIs is closely related to the tumor immune microenvironment (TME), it is necessary to clarify the relationship between the immune microenvironment of CRC and the efficacy of immunotherapy to ensure that the appropriate drugs are selected. We herein review the latest research progress in the immune microenvironment and strategies related to immunotherapy for CRC. We hope that this review helps in the selection of appropriate treatment strategies for CRC patients.
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Affiliation(s)
- Yaping Chen
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiao Zheng
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Changping Wu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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Roberti MP, Rauber C, Kroemer G, Zitvogel L. Impact of the ileal microbiota on colon cancer. Semin Cancer Biol 2021; 86:955-966. [PMID: 34624451 DOI: 10.1016/j.semcancer.2021.09.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 07/20/2021] [Accepted: 09/28/2021] [Indexed: 12/17/2022]
Abstract
Besides tumor cell-intrinsic oncogenic pathways, host and environmental factors have a major impact on cancer immunosurveillance and the efficacy of immunotherapeutics. Several modalities of anticancer treatments including immunogenic chemotherapies and immune checkpoint inhibitors lose their efficacy in patients treated with broad-spectrum antibiotics, pointing to a key role for the gut microbiota. The complex interactions between intestinal microbes, gut immunity and anti-tumor responses constitute an emerging field of investigation. In this work, we revise key primary literature, with an emphasis on recent mechanistic insights, unraveling the interplay between the immunosurveillance of colon cancers and ileal factors including the local microbiota, tissue architecture and immune system.
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Affiliation(s)
- Maria Paula Roberti
- Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD), Heidelberg, Germany
| | - Conrad Rauber
- Department of Gastroenterology and Infectious Diseases, Heidelberg University Hospital (UKHD), Heidelberg, Germany
| | - Guido Kroemer
- Equipe labellisée par la Ligue contre le Cancer, INSERM U1138, Université de Paris, Sorbonne Université, Centre de Recherche des Cordeliers, Paris, France; Metabolomics Platform, Gustave Roussy Cancer Campus, Villejuif, 94805, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; Department of Women's and Children's Health, Karolinska University Hospital, 17176, Stockholm, Sweden; Gustave Roussy, 94800, Villejuif, France.
| | - Laurence Zitvogel
- Université Paris-Saclay, Gustave Roussy, Villejuif, France; Gustave Roussy, 94800, Villejuif, France; Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, France; Equipe Labellisée-Ligue Nationale contre le Cancer, 94800, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, 94800 Villejuif, France.
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The Role of Gut Microbiota in Tumor Immunotherapy. J Immunol Res 2021; 2021:5061570. [PMID: 34485534 PMCID: PMC8413023 DOI: 10.1155/2021/5061570] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 08/10/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor immunotherapy is the fourth therapy after surgery, chemotherapy, and radiotherapy. It has made great breakthroughs in the treatment of some epithelial tumors and hematological tumors. However, its adverse reactions are common or even more serious, and the response rate in some solid tumors is not satisfactory. With the maturity of genomics and metabolomics technologies, the effect of intestinal microbiota in tumor development and treatment has gradually been recognized. The microbiota may affect tumor immunity by regulating the host immune system and tumor microenvironment. Some bacteria help fight tumors by activating immunity, while some bacteria mediate immunosuppression to help cancer cells escape from the immune system. More and more studies have revealed that the effects and complications of tumor immunotherapy are related to the composition of the gut microbiota. The composition of the intestinal microbiota that is sensitive to treatment or prone to adverse reactions has certain characteristics. These characteristics may be used as biomarkers to predict the prognosis of immunotherapy and may also be developed as “immune potentiators” to assist immunotherapy. Some clinical and preclinical studies have proved that microbial intervention, including microbial transplantation, can improve the sensitivity of immunotherapy or reduce adverse reactions to a certain extent. With the development of gene editing technology and nanotechnology, the design and development of engineered bacteria that contribute to immunotherapy has become a new research hotspot. Based on the relationship between the intestinal microbiota and immunotherapy, the correct mining of microbial information and the development of reasonable and feasible microbial intervention methods are expected to optimize tumor immunotherapy to a large extent and bring new breakthroughs in tumor treatment.
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NK cell and ILC heterogeneity in colorectal cancer. New perspectives from high dimensional data. Mol Aspects Med 2021; 80:100967. [PMID: 33941383 DOI: 10.1016/j.mam.2021.100967] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/20/2021] [Accepted: 04/23/2021] [Indexed: 12/14/2022]
Abstract
Innate lymphoid cells (ILCs) and tissue-resident natural killer (NK) cells ensure immunity at environmental interfaces and help maintain barrier integrity of the intestinal tract. This wide range of innate lymphocytes is able to provide fast and potent inflammatory responses that, when deregulated, have been associated with pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC). While the presence of tumor-infiltrating NK cells is generally associated with a favorable outcome in CRC patients, emerging evidence reveals distinct roles for ILCs in regulating CRC pathogenesis and progression. Advances in next generation sequencing technology, and in particular of single-cell RNA-seq approaches, along with multidimensional flow cytometry analysis, have helped to deconvolute the complexity and heterogeneity of the ILC system both in homeostatic and pathological contexts. In this review, we discuss the protective and detrimental roles of NK cells and ILCs in the pathogenesis of CRC, focusing on the phenotypic and transcriptional modifications these cells undergo during CRC development and progression.
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Marzano M, Fosso B, Piancone E, Defazio G, Pesole G, De Robertis M. Stem Cell Impairment at the Host-Microbiota Interface in Colorectal Cancer. Cancers (Basel) 2021; 13:996. [PMID: 33673612 PMCID: PMC7957811 DOI: 10.3390/cancers13050996] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/20/2021] [Accepted: 02/23/2021] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) initiation is believed to result from the conversion of normal intestinal stem cells (ISCs) into cancer stem cells (CSCs), also known as tumor-initiating cells (TICs). Hence, CRC evolves through the multiple acquisition of well-established genetic and epigenetic alterations with an adenoma-carcinoma sequence progression. Unlike other stem cells elsewhere in the body, ISCs cohabit with the intestinal microbiota, which consists of a diverse community of microorganisms, including bacteria, fungi, and viruses. The gut microbiota communicates closely with ISCs and mounting evidence suggests that there is significant crosstalk between host and microbiota at the ISC niche level. Metagenomic analyses have demonstrated that the host-microbiota mutually beneficial symbiosis existing under physiologic conditions is lost during a state of pathological microbial imbalance due to the alteration of microbiota composition (dysbiosis) and/or the genetic susceptibility of the host. The complex interaction between CRC and microbiota is at the forefront of the current CRC research, and there is growing attention on a possible role of the gut microbiome in the pathogenesis of CRC through ISC niche impairment. Here we primarily review the most recent findings on the molecular mechanism underlying the complex interplay between gut microbiota and ISCs, revealing a possible key role of microbiota in the aberrant reprogramming of CSCs in the initiation of CRC. We also discuss recent advances in OMICS approaches and single-cell analyses to explore the relationship between gut microbiota and ISC/CSC niche biology leading to a desirable implementation of the current precision medicine approaches.
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Affiliation(s)
- Marinella Marzano
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70126 Bari, Italy; (M.M.); (B.F.); (G.P.)
| | - Bruno Fosso
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70126 Bari, Italy; (M.M.); (B.F.); (G.P.)
| | - Elisabetta Piancone
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘Aldo Moro’, 70126 Bari, Italy; (E.P.); (G.D.)
| | - Giuseppe Defazio
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘Aldo Moro’, 70126 Bari, Italy; (E.P.); (G.D.)
| | - Graziano Pesole
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70126 Bari, Italy; (M.M.); (B.F.); (G.P.)
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘Aldo Moro’, 70126 Bari, Italy; (E.P.); (G.D.)
| | - Mariangela De Robertis
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘Aldo Moro’, 70126 Bari, Italy; (E.P.); (G.D.)
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