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Pragasam AK, Maurya S, Jain K, Pal S, Raja C, Yadav R, Kumar S, Purohit A, Pradhan D, Kajal K, Talukdar D, Singh AN, Verma J, Jana P, Rawat S, Kshetrapal P, Krishna A, Kumar S, Bansal VK, Das B, Srikanth CV, Garg PK. Invasive Salmonella Typhimurium colonizes gallbladder and contributes to gallbladder carcinogenesis through activation of host epigenetic modulator KDM6B. Cancer Lett 2025; 618:217621. [PMID: 40074067 DOI: 10.1016/j.canlet.2025.217621] [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: 12/10/2024] [Revised: 02/28/2025] [Accepted: 03/08/2025] [Indexed: 03/14/2025]
Abstract
Gallbladder stones alone do not explain the risk of gallbladder cancer (GBC) as the sole etiological factor. Chronic microbial infection, particularly Salmonella, has been implicated in GB carcinogenesis, but its causative role and the underlying mechanisms are largely unknown. We studied gut and gallbladder tissue microbiome through targeted metagenomics to identify pathogenic bacteria in GBC. Virulence and pathogenicity of identified Salmonella Typhimurium from GBC tissue were studied after culture by whole genome sequencing, phylogenetic analysis, mutational profiling, and pangenome analysis. Mechanistic studies for GBC carcinogenesis were carried out in a mouse model of gallstones and chronic Salmonella infection, a cellular model using GBC (NOZ) cell lines, and a xenograft tumor model. We found an increased abundance of Salmonella in the gut microbiome of patients with GBC and culturable S. Typhimurium from the gallbladder cancer tissue. Comparative genomics of S. Typhimurium isolated from the GBC tissue showed a high invasive index. S. Typhimurium isolates harbored horizontally acquired virulence functions in their accessory genome. Chronic S. Typhimurium infection caused chronic inflammation, pre-malignant changes, and tumor-promoting mechanisms in the mouse model with gallbladder stones with activation of the epigenetic modulator KDM6B both in the mouse model and human GBC. Inhibition of KDM6B reduced engrafted tumor size in SCID mice. Of the differentially regulated genes in human GBC tissue, ADAMTSL5, CX3CR1, and SPSB4 were also significantly dysregulated in NOZ cells infected with Salmonella. Chronic Salmonella infection contributes to gallbladder carcinogenesis through a host epigenetic mechanism involving KDM6B.
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Affiliation(s)
- Agila Kumari Pragasam
- Functional Genomics Laboratory, Centre for Microbial Research, BRIC-Translational Health Science and Technology Institute, Faridabad, 121001, India
| | - Sonalika Maurya
- Laboratory of Gut Infection and Inflammation Biology, Regional Centre for Biotechnology, Faridabad, 121001, India
| | - Kajal Jain
- Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Sujoy Pal
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Christu Raja
- Centralized Core Research Facility, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Rajni Yadav
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Shakti Kumar
- Functional Genomics Laboratory, Centre for Microbial Research, BRIC-Translational Health Science and Technology Institute, Faridabad, 121001, India
| | - Ayushi Purohit
- Functional Genomics Laboratory, Centre for Microbial Research, BRIC-Translational Health Science and Technology Institute, Faridabad, 121001, India
| | - Dibyabhaba Pradhan
- Centralized Core Research Facility, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Kirti Kajal
- Laboratory of Gut Infection and Inflammation Biology, Regional Centre for Biotechnology, Faridabad, 121001, India
| | - Daizee Talukdar
- Functional Genomics Laboratory, Centre for Microbial Research, BRIC-Translational Health Science and Technology Institute, Faridabad, 121001, India
| | - Anand Narayan Singh
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Jyoti Verma
- Functional Genomics Laboratory, Centre for Microbial Research, BRIC-Translational Health Science and Technology Institute, Faridabad, 121001, India
| | - Pradipta Jana
- Functional Genomics Laboratory, Centre for Microbial Research, BRIC-Translational Health Science and Technology Institute, Faridabad, 121001, India
| | - Shefali Rawat
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Pallavi Kshetrapal
- Pediatric Biology Center, BRIC-Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Asuri Krishna
- Centralized Core Research Facility, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Subodh Kumar
- Department of Surgery, JPN Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Virinder Kumar Bansal
- Centralized Core Research Facility, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Bhabatosh Das
- Functional Genomics Laboratory, Centre for Microbial Research, BRIC-Translational Health Science and Technology Institute, Faridabad, 121001, India.
| | - Chittur V Srikanth
- Laboratory of Gut Infection and Inflammation Biology, Regional Centre for Biotechnology, Faridabad, 121001, India.
| | - Pramod Kumar Garg
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, 110029, India.
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Xie J, Liu M, Deng X, Tang Y, Zheng S, Ou X, Tang H, Xie X, Wu M, Zou Y. Gut microbiota reshapes cancer immunotherapy efficacy: Mechanisms and therapeutic strategies. IMETA 2024; 3:e156. [PMID: 38868510 PMCID: PMC10989143 DOI: 10.1002/imt2.156] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/15/2023] [Accepted: 11/25/2023] [Indexed: 06/14/2024]
Abstract
Gut microbiota is essential for maintaining local and systemic immune homeostasis in the presence of bacterial challenges. It has been demonstrated that microbiota play contrasting roles in cancer development as well as anticancer immunity. Cancer immunotherapy, a novel anticancer therapy that relies on the stimulation of host immunity, has suffered from a low responding rate and incidence of severe immune-related adverse events (irAEs). Previous studies have demonstrated that the diversity and composition of gut microbiota were associated with the heterogeneity of therapeutic effects. Therefore, alteration in microbiota taxa can lead to improved clinical outcomes in immunotherapy. In this review, we determine whether microbiota composition or microbiota-derived metabolites are linked to responses to immunotherapy and irAEs. Moreover, we discuss various approaches to improve immunotherapy efficacy or reduce toxicities by modulating microbiota composition.
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Affiliation(s)
- Jindong Xie
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Manqing Liu
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of StomatologySun Yat‐sen UniversityGuangzhouChina
| | - Xinpei Deng
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Yuhui Tang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Shaoquan Zheng
- Department of Breast Surgery, Breast Disease Center, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Xueqi Ou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Hailin Tang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Xiaoming Xie
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Minqing Wu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Yutian Zou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
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Zhang YH, Chen XL, Wang YR, Hou YW, Zhang YD, Wang KJ. Prevention of malignant digestive system tumors should focus on the control of chronic inflammation. World J Gastrointest Oncol 2023; 15:389-404. [PMID: 37009320 PMCID: PMC10052658 DOI: 10.4251/wjgo.v15.i3.389] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 01/17/2023] [Accepted: 02/07/2023] [Indexed: 03/14/2023] Open
Abstract
Chronic inflammation, through a variety of mechanisms, plays a key role in the occurrence and development of digestive system malignant tumors (DSMTs). In this study, we feature and provide a comprehensive understanding of DSMT prevention strategies based on preventing or controlling chronic inflammation. The development and evaluation of cancer prevention strategies is a longstanding process. Cancer prevention, especially in the early stage of life, should be emphasized throughout the whole life course. Issues such as the time interval for colon cancer screening, the development of direct-acting antiviral drugs for liver cancer, and the Helicobacter pylori vaccine all need to be explored in long-term, large-scale experiments in the future.
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Affiliation(s)
- Yue-Hua Zhang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Henan International Joint Laboratory of Prevention and Treatment of Pediatric Diseases, Henan Children's Hospital Zhengzhou Children’s Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, Henan Province, China
| | - Xiao-Lin Chen
- Department of Prenatal Diagnosis Center, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yi-Ran Wang
- Henan International Joint Laboratory of Prevention and Treatment of Pediatric Diseases, Henan Children's Hospital Zhengzhou Children’s Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, Henan Province, China
| | - Yu-Wei Hou
- Henan International Joint Laboratory of Prevention and Treatment of Pediatric Diseases, Henan Children's Hospital Zhengzhou Children’s Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, Henan Province, China
| | - Yao-Dong Zhang
- Henan International Joint Laboratory of Prevention and Treatment of Pediatric Diseases, Henan Children's Hospital Zhengzhou Children’s Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, Henan Province, China
| | - Kai-Juan Wang
- Henan International Joint Laboratory of Prevention and Treatment of Pediatric Diseases, Henan Children's Hospital Zhengzhou Children’s Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, Henan Province, China
- Henan Children’s Hospital Zhengzhou Children’s Hospital, Children’s Hospital Affiliated to Zhengzhou University, Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450001, Henan Province, China
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Qin X, Zhou J, Wang Z, Feng C, Fan J, Huang J, Hu D, Baban B, Wang S, Ma D, Sun C, Zhou Z, Chen G. Metagenomic analysis of the microbiome of the upper reproductive tract: combating ovarian cancer through predictive, preventive, and personalized medicine. EPMA J 2022; 13:487-498. [PMID: 35762010 PMCID: PMC9219379 DOI: 10.1007/s13167-022-00286-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 05/12/2022] [Indexed: 11/03/2022]
Abstract
Purpose We investigated whether ovarian cancer could alter the genital microbiota in a specific way with clinical values. Furthermore, we proposed how such changes could be envisioned in a paradigm of predictive, preventive, and personalized medicine (PPPM). Methods The samples were collected using cotton swabs from the cervical, uterine cavity, fallopian tubes, and ovaries of patients subjected to the surgical procedures for the malignant/benign lesions. All samples were then analyzed by metagenomic shotgun sequencing. The distribution patterns and characteristics of the microbiota in the reproductive tract of subjects were analyzed and were interpreted in relation to the clinical outcomes of the subjects. Results While the ovarian cancer was able to alter the genital microbiota, the bacteria were the dominant microorganisms in all samples across all cohorts in the study (median 99%). The microbiota of the upper female reproductive tract were mainly from the cervical, identified by low bacterial biomass and high bacterial diversity. Ovarian cancer had a distinct microbiota signature. The tubal ligation affects its microbial distribution. There were no different species on the surface of platinum-sensitive ovarian tissues compared to samples from platinum-resistant patients. Conclusion The ovarian cancer-induced changes in microbiota magnify the potential of microbiota as a biotherapeutic modality in the treatment of ovarian cancer in this study and very likely for several malignancies and other conditions. Our findings demonstrated, for the first time, that microbiota could be dissected and applied in more specific fashion based on a predictive, preventive, and personalized medicine (PPPM) model in the treatment of ovarian cancer. Utilizing microbiota portfolio in a PPPM system in ovarian cancer would provide a unique opportunity to a clinically intelligent and novel approach in the treatment of ovarian cancer as well as several other conditions and malignancies. Supplementary Information The online version contains supplementary material available at 10.1007/s13167-022-00286-1.
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Affiliation(s)
- Xu Qin
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianglin Zhou
- Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Zizhuo Wang
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chenzhao Feng
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junpeng Fan
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Huang
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dianxing Hu
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Babak Baban
- Medical College of Georgia, Augusta University, Augusta, GA USA
| | - Shengqi Wang
- Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Ding Ma
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chaoyang Sun
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhe Zhou
- Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Gang Chen
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Li Z, Liu Y, Zhang L. Role of the microbiome in oral cancer occurrence, progression and therapy. Microb Pathog 2022; 169:105638. [PMID: 35718272 DOI: 10.1016/j.micpath.2022.105638] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 06/07/2022] [Accepted: 06/10/2022] [Indexed: 02/07/2023]
Abstract
The oral cavity, like other digestive or mucosal sites, contains a site-specific microbiome that plays a significant role in maintaining health and homeostasis. Strictly speaking, the gastrointestinal tract starts from the oral cavity, with special attention paid to the specific flora of the oral cavity. In healthy people, the microbiome of the oral microenvironment is governed by beneficial bacteria, that benefit the host by symbiosis. When a microecological imbalance occurs, changes in immune and metabolic signals affect the characteristics of cancer, as well as chronic inflammation, disruption of the epithelial barrier, changes in cell proliferation and cell apoptosis, genomic instability, angiogenesis, and epithelial barrier destruction and metabolic regulation. These pathophysiological changes could result in oral cancer. Rising evidence suggests that oral dysbacteriosis and particular microbes may play a positive role in the evolution, development, progression, and metastasis of oral cancer, for instance, oral squamous cell carcinoma (OSCC) through direct or indirect action.
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Affiliation(s)
- Zhengrui Li
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China.
| | - Yuan Liu
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China.
| | - Ling Zhang
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China.
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Basu A, Singh R, Gupta S. Bacterial infections in cancer: A bilateral relationship. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2022; 14:e1771. [PMID: 34994112 DOI: 10.1002/wnan.1771] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 10/09/2021] [Accepted: 11/12/2021] [Indexed: 12/15/2022]
Abstract
Bacteria share a long commensal relationship with the human body. New findings, however, continue to unravel many complexities associated with this old alliance. In the past decades, the dysbiosis of human microbiome has been linked to tumorigenesis, and more recently to spontaneous colonization of existing tumors. The topic, however, remains open for debate as the claims for causative-prevailing dual characteristics of bacteria are mostly based on epidemiological evidence rather than robust mechanistic models. There are also no reviews linking the collective impact of bacteria in tumor microenvironments to the efficacy of cancer drugs, mechanisms of pathogen-initiated cancer and bacterial colonization, personalized nanomedicine, nanotechnology, and antimicrobial resistance. In this review, we provide a holistic overview of the bilateral relationship between cancer and bacteria covering all these aspects. Our collated evidence from the literature does not merely categorize bacteria as cancer causative or prevailing agents, but also critically highlights the gaps in the literature where more detailed studies may be required to reach such a conclusion. Arguments are made in favor of dual drug therapies that can simultaneously co-target bacteria and cancer cells to overcome drug resistance. Also discussed are the opportunities for leveraging the natural colonization and remission power of bacteria for cancer treatment. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.
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Affiliation(s)
- Abhirup Basu
- Department of Chemical Engineering, Indian Institute of Technology, Delhi, India
| | - Rohini Singh
- Department of Chemical Engineering, Indian Institute of Technology, Delhi, India
| | - Shalini Gupta
- Department of Chemical Engineering, Indian Institute of Technology, Delhi, India
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Duijster JW, Franz E, Neefjes J, Mughini-Gras L. Bacterial and Parasitic Pathogens as Risk Factors for Cancers in the Gastrointestinal Tract: A Review of Current Epidemiological Knowledge. Front Microbiol 2021; 12:790256. [PMID: 34956157 PMCID: PMC8692736 DOI: 10.3389/fmicb.2021.790256] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/11/2021] [Indexed: 12/12/2022] Open
Abstract
The oncogenic potential of viral infections is well established and documented for many years already. However, the contribution of (commensal) bacteria and parasites to the development and progression of cancers has only recently gained momentum, resulting in a rapid growth of publications on the topic. Indeed, various bacteria and parasites have been suggested to play a role in the development of gastrointestinal cancer in particular. Therefore, an overview of the current epidemiological knowledge on the association between infections with bacteria and parasites and cancers of the gastrointestinal tract is needed. In this review, we summarized the methodological characteristics and main results of epidemiological studies investigating the association of 10 different bacteria (Bacteroides fragilis, Campylobacter spp., Clostridium spp., Enterococcus faecalis, Escherichia coli, Fusobacterium nucleatum, Porphyromonas gingivalis, non-typhoidal Salmonella, Salmonella Typhi, and Streptococcus spp.) and three parasites (Cryptosporidium spp., Schistosoma spp., and Strongyloides stercoralis) with gastrointestinal cancer. While the large body of studies based on microbiome sequencing provides valuable insights into the relative abundance of different bacterial taxa in cancer patients as compared to individuals with pre-malignant conditions or healthy controls, more research is needed to fulfill Koch's postulates, possibly making use of follow-up data, to assess the complex role of bacterial and parasitic infections in cancer epidemiology. Studies incorporating follow-up time between detection of the bacterium or parasite and cancer diagnosis remain valuable as these allow for estimation of cause-effect relationships.
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Affiliation(s)
- Janneke W. Duijster
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
- Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands
| | - Eelco Franz
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
| | - Jacques Neefjes
- Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands
| | - Lapo Mughini-Gras
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
- Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
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Foster N, Tang Y, Berchieri A, Geng S, Jiao X, Barrow P. Revisiting Persistent Salmonella Infection and the Carrier State: What Do We Know? Pathogens 2021; 10:1299. [PMID: 34684248 PMCID: PMC8537056 DOI: 10.3390/pathogens10101299] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/28/2021] [Accepted: 09/29/2021] [Indexed: 11/17/2022] Open
Abstract
One characteristic of the few Salmonella enterica serovars that produce typhoid-like infections is that disease-free persistent infection can occur for months or years in a small number of individuals post-convalescence. The bacteria continue to be shed intermittently which is a key component of the epidemiology of these infections. Persistent chronic infection occurs despite high levels of circulating specific IgG. We have reviewed the information on the basis for persistence in S. Typhi, S. Dublin, S. Gallinarum, S. Pullorum, S. Abortusovis and also S. Typhimurium in mice as a model of persistence. Persistence appears to occur in macrophages in the spleen and liver with shedding either from the gall bladder and gut or the reproductive tract. The involvement of host genetic background in defining persistence is clear from studies with the mouse but less so with human and poultry infections. There is increasing evidence that the organisms (i) modulate the host response away from the typical Th1-type response normally associated with immune clearance of an acute infection to Th2-type or an anti-inflammatory response, and that (ii) the bacteria modulate transformation of macrophage from M1 to M2 type. The bacterial factors involved in this are not yet fully understood. There are early indications that it might be possible to remodulate the response back towards a Th1 response by using cytokine therapy.
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Affiliation(s)
- Neil Foster
- SRUC Aberdeen Campus, Craibstone Estate, Ferguson Building, Aberdeen AB21 9YA, UK
| | - Ying Tang
- Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen 518055, China;
| | - Angelo Berchieri
- Departamento de Patologia Veterinária, Faculdade de Ciências Agrárias e Veterinárias, Univ Estadual Paulista, Via de Acesso Paulo Donato Castellane, s/n, 14884-900 Jaboticabal, SP, Brazil;
| | - Shizhong Geng
- Jiangsu Key Laboratory of Zoonosis, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China; (S.G.); (X.J.)
| | - Xinan Jiao
- Jiangsu Key Laboratory of Zoonosis, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China; (S.G.); (X.J.)
| | - Paul Barrow
- School of Veterinary Medicine, University of Surrey, Daphne Jackson Road, Guildford GU2 7AL, UK;
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Läsche M, Urban H, Gallwas J, Gründker C. HPV and Other Microbiota; Who's Good and Who's Bad: Effects of the Microbial Environment on the Development of Cervical Cancer-A Non-Systematic Review. Cells 2021; 10:cells10030714. [PMID: 33807087 PMCID: PMC8005086 DOI: 10.3390/cells10030714] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/15/2021] [Accepted: 03/22/2021] [Indexed: 02/07/2023] Open
Abstract
Cervical cancer is responsible for around 5% of all human cancers worldwide. It develops almost exclusively from an unsolved, persistent infection of the squamocolumnar transformation zone between the endo- and ecto-cervix with various high-risk (HR) human papillomaviruses (HPVs). The decisive turning point on the way to persistent HPV infection and malignant transformation is an immune system weakened by pathobionts and oxidative stress and an injury to the cervical mucosa, often caused by sexual activities. Through these injury and healing processes, HPV viruses, hijacking activated keratinocytes, move into the basal layers of the cervical epithelium and then continue their development towards the distal prickle cell layer (Stratum spinosum). The microbial microenvironment of the cervical tissue determines the tissue homeostasis and the integrity of the protective mucous layer through the maintenance of a healthy immune and metabolic signalling. Pathological microorganisms and the resulting dysbiosis disturb this signalling. Thus, pathological inflammatory reactions occur, which manifest the HPV infection. About 90% of all women contract an HPV infection in the course of their lives. In about 10% of cases, the virus persists and cervical intra-epithelial neoplasia (CIN) develops. Approximately 1% of women with a high-risk HPV infection incur a cervical carcinoma after 10 to 20 years. In this non-systematic review article, we summarise how the sexually and microbial mediated pathogenesis of the cervix proceeds through aberrant immune and metabolism signalling via CIN to cervical carcinoma. We show how both the virus and the cancer benefit from the same changes in the immune and metabolic environment.
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10
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Choudhry H. The Microbiome and Its Implications in Cancer Immunotherapy. Molecules 2021; 26:E206. [PMID: 33401586 PMCID: PMC7795182 DOI: 10.3390/molecules26010206] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/22/2020] [Accepted: 12/30/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer is responsible for ~18 million deaths globally each year, representing a major cause of death. Several types of therapy strategies such as radiotherapy, chemotherapy and more recently immunotherapy, have been implemented in treating various types of cancer. Microbes have recently been found to be both directly and indirectly involved in cancer progression and regulation, and studies have provided novel and clear insights into the microbiome-mediated emergence of cancers. Scientists around the globe are striving hard to identify and characterize these microbes and the underlying mechanisms by which they promote or suppress various kinds of cancer. Microbes may influence immunotherapy by blocking various cell cycle checkpoints and the production of certain metabolites. Hence, there is an urgent need to better understand the role of these microbes in the promotion and suppression of cancer. The identification of microbes may help in the development of future diagnostic tools to cure cancers possibly associated with the microbiome. This review mainly focuses on various microbes and their association with different types of cancer, responses to immunotherapeutic modulation, physiological responses, and prebiotic and postbiotic effects.
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Affiliation(s)
- Hani Choudhry
- Department of Biochemistry, Faculty of Sciences, Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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11
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Irfan M, Delgado RZR, Frias-Lopez J. The Oral Microbiome and Cancer. Front Immunol 2020; 11:591088. [PMID: 33193429 PMCID: PMC7645040 DOI: 10.3389/fimmu.2020.591088] [Citation(s) in RCA: 160] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 09/29/2020] [Indexed: 12/24/2022] Open
Abstract
There is mounting evidence that members of the human microbiome are highly associated with a wide variety of cancer types. Among oral cancers, oral squamous cell carcinoma (OSCC) is the most prevalent and most commonly studied, and it is the most common malignancy of the head and neck worldwide. However, there is a void regarding the role that the oral microbiome may play in OSCC. Previous studies have not consistently found a characteristic oral microbiome composition associated with OSCC. Although a direct causality has not been proven, individual members of the oral microbiome are capable of promoting various tumorigenic functions related to cancer development. Two prominent oral pathogens, Porphyromonas gingivalis, and Fusobacterium nucleatum can promote tumor progression in mice. P. gingivalis infection has been associated with oro-digestive cancer, increased oral cancer invasion, and proliferation of oral cancer stem cells. The microbiome can influence the evolution of the disease by directly interacting with the human body and significantly altering the response and toxicity to various forms of cancer therapy. Recent studies have shown an association of certain phylogenetic groups with the immunotherapy treatment outcomes of certain tumors. On the other side of the coin, recently it has been a resurgence in interest on the potential use of bacteria to cure cancer. These kinds of treatments were used in the late nineteenth and early twentieth centuries as the first line of defense against cancer in some hospitals but later displaced by other types of treatments such as radiotherapy. Currently, organisms such as Salmonella typhimurium and Clostridium spp. have been used for targeted strategies as potential vectors to treat cancer. In this review, we briefly summarize our current knowledge of the role of the oral microbiome, focusing on its bacterial fraction, in cancer in general and in OSCC more precisely, and a brief description of the potential use of bacteria to target tumors.
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Affiliation(s)
- Muhammad Irfan
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, United States
| | | | - Jorge Frias-Lopez
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, United States
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12
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Al-Hilu SA, Al-Shujairi WH. Dual Role of Bacteria in Carcinoma: Stimulation and Inhibition. Int J Microbiol 2020; 2020:4639761. [PMID: 32908523 PMCID: PMC7463420 DOI: 10.1155/2020/4639761] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 07/10/2020] [Accepted: 07/30/2020] [Indexed: 12/11/2022] Open
Abstract
Although what unifies the carcinogenic microorganisms has not been determined by multiple studies, the role of bacteria in the development of neoplasms has not been properly elucidated. In this review, we discuss links between the bacterial species and cancer, with focus on immune responses for the stimulation of tumor cells such as induction of inflammation. Finally, we will describe the potential therapeutic strategies of bacteria on target tumors to improve treatment while mitigating adverse reactions. Cancer is a series of genetic changes that transform normal cells into tumor cells. These changes come from several reasons, including smoking, drinking alcohol, sunlight, exposure to chemical or physical factors, and finally chronic infection with microorganisms, including bacteria. In fact, bacterial infections are not carcinogenic, but recently it was discovered that the association between bacteria and cancer is through two mechanisms, the first stimulating chronic inflammation and the second producing carcinogenic metabolites. While bacteria are carcinogenic agents also, they have a dual role eliminating and removing tumor cells. However, the traditional cancer treatments that include chemotherapy, radiotherapy, surgery, and immunotherapy increase the chances of survival, and there are many side effects of these therapies, including the high toxicity of tissues and normal cells, could not penetrate the tumor cells, and resistance of these therapies by tumor cells. Therefore, the world has turned to an alternative solution, which is the use of genetically engineered microorganisms; thus, the use of living bacteria targeting cancerous cells is the unique option to overcome these challenges. Bacterial therapies, whether used alone or combination with chemotherapy, give a positive effect to treat multiple conditions of cancer. Also, bacteria can be used as vectors for drug, gene, or therapy, and this is a great step to treat cancer. Thus, we review the mechanisms underlying the interaction of the microbiota residents with cancer. Cancer-associated bacteria differ from those in healthy human and are linked with gene-expression profile. We also discuss how live bacteria interact with tumor microenvironments to induce tumor regression through colonization and spread. Finally, we provide past and ongoing clinical trials that include bacteria targeting tumors.
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Affiliation(s)
- Suad A Al-Hilu
- Department of Biology/Faculty of Sciences, University of Kufa, 54001 Najaf, Iraq
| | - Wisam H Al-Shujairi
- Department of Clinical Laboratory Sciences/College of Pharmacy, University of Babylon, 51001 Hilla, Iraq
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13
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Elsalem L, Jum'ah AA, Alfaqih MA, Aloudat O. The Bacterial Microbiota of Gastrointestinal Cancers: Role in Cancer Pathogenesis and Therapeutic Perspectives. Clin Exp Gastroenterol 2020; 13:151-185. [PMID: 32440192 PMCID: PMC7211962 DOI: 10.2147/ceg.s243337] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 04/13/2020] [Indexed: 12/24/2022] Open
Abstract
The microbiota has an essential role in the pathogenesis of many gastrointestinal diseases including cancer. This effect is mediated through different mechanisms such as damaging DNA, activation of oncogenic pathways, production of carcinogenic metabolites, stimulation of chronic inflammation, and inhibition of antitumor immunity. Recently, the concept of "pharmacomicrobiomics" has emerged as a new field concerned with exploring the interplay between drugs and microbes. Mounting evidence indicates that the microbiota and their metabolites have a major impact on the pharmacodynamics and therapeutic responses toward anticancer drugs including conventional chemotherapy and molecular-targeted therapeutics. In addition, microbiota appears as an attractive target for cancer prevention and treatment. In this review, we discuss the role of bacterial microbiota in the pathogenesis of different cancer types affecting the gastrointestinal tract system. We also scrutinize the evidence regarding the role of microbiota in anticancer drug responses. Further, we discuss the use of probiotics, fecal microbiota transplantation, and antibiotics, either alone or in combination with anticancer drugs for prevention and treatment of gastrointestinal tract cancers.
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Affiliation(s)
- Lina Elsalem
- Department of Pharmacology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Ahmad A Jum'ah
- Department of Conservative Dentistry, Faculty of Dentistry, Jordan University of Science and Technology, Irbid, Jordan
| | - Mahmoud A Alfaqih
- Department of Physiology and Biochemistry, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Osama Aloudat
- Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
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14
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Łaniewski P, Ilhan ZE, Herbst-Kralovetz MM. The microbiome and gynaecological cancer development, prevention and therapy. Nat Rev Urol 2020; 17:232-250. [PMID: 32071434 PMCID: PMC9977514 DOI: 10.1038/s41585-020-0286-z] [Citation(s) in RCA: 213] [Impact Index Per Article: 42.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/17/2020] [Indexed: 12/16/2022]
Abstract
The female reproductive tract (FRT), similar to other mucosal sites, harbours a site-specific microbiome, which has an essential role in maintaining health and homeostasis. In the majority of women of reproductive age, the microbiota of the lower FRT (vagina and cervix) microenvironment is dominated by Lactobacillus species, which benefit the host through symbiotic relationships. By contrast, the upper FRT (uterus, Fallopian tubes and ovaries) might be sterile in healthy individuals or contain a low-biomass microbiome with a diverse mixture of microorganisms. When dysbiosis occurs, altered immune and metabolic signalling can affect hallmarks of cancer, including chronic inflammation, epithelial barrier breach, changes in cellular proliferation and apoptosis, genome instability, angiogenesis and metabolic dysregulation. These pathophysiological changes might lead to gynaecological cancer. Emerging evidence shows that genital dysbiosis and/or specific bacteria might have an active role in the development and/or progression and metastasis of gynaecological malignancies, such as cervical, endometrial and ovarian cancers, through direct and indirect mechanisms, including modulation of oestrogen metabolism. Cancer therapies might also alter microbiota at sites throughout the body. Reciprocally, microbiota composition can influence the efficacy and toxic effects of cancer therapies, as well as quality of life following cancer treatment. Modulation of the microbiome via probiotics or microbiota transplant might prove useful in improving responsiveness to cancer treatment and quality of life. Elucidating these complex host-microbiome interactions, including the crosstalk between distal and local sites, will translate into interventions for prevention, therapeutic efficacy and toxic effects to enhance health outcomes for women with gynaecological cancers.
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Affiliation(s)
- Paweł Łaniewski
- Department of Basic Medical Sciences, College of Medicine – Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Zehra Esra Ilhan
- Department of Obstetrics and Gynecology, College of Medicine – Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Melissa M. Herbst-Kralovetz
- Department of Basic Medical Sciences, College of Medicine – Phoenix, University of Arizona, Phoenix, AZ, USA,Department of Obstetrics and Gynecology, College of Medicine – Phoenix, University of Arizona, Phoenix, AZ, USA,UA Cancer Center, University of Arizona, Phoenix/Tucson, AZ, USA,Correspondence:
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15
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Abstract
There is mounting evidence that members of the human microbiome are highly associated with a wide variety of cancer types. Among oral cancers, oral squamous cell carcinoma (OSCC) is the most prevalent and most commonly studied, and it is the most common malignancy of the head and neck worldwide. However, there is a void regarding the role that the oral microbiome may play in OSCC. Previous studies have not consistently found a characteristic oral microbiome composition associated with OSCC. Although a direct causality has not been proven, individual members of the oral microbiome are capable of promoting various tumorigenic functions related to cancer development. Two prominent oral pathogens, Porphyromonas gingivalis, and Fusobacterium nucleatum can promote tumor progression in mice. P. gingivalis infection has been associated with oro-digestive cancer, increased oral cancer invasion, and proliferation of oral cancer stem cells. The microbiome can influence the evolution of the disease by directly interacting with the human body and significantly altering the response and toxicity to various forms of cancer therapy. Recent studies have shown an association of certain phylogenetic groups with the immunotherapy treatment outcomes of certain tumors. On the other side of the coin, recently it has been a resurgence in interest on the potential use of bacteria to cure cancer. These kinds of treatments were used in the late nineteenth and early twentieth centuries as the first line of defense against cancer in some hospitals but later displaced by other types of treatments such as radiotherapy. Currently, organisms such as Salmonella typhimurium and Clostridium spp. have been used for targeted strategies as potential vectors to treat cancer. In this review, we briefly summarize our current knowledge of the role of the oral microbiome, focusing on its bacterial fraction, in cancer in general and in OSCC more precisely, and a brief description of the potential use of bacteria to target tumors.
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Affiliation(s)
- Muhammad Irfan
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, United States
| | | | - Jorge Frias-Lopez
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, United States
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16
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Singh R, Kumar CS, Banerjee M, Gupta S. A Dual Drug Delivery Platform for Cancer–Bacteria Cotargeting. ACS APPLIED BIO MATERIALS 2019; 2:5032-5041. [DOI: 10.1021/acsabm.9b00724] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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17
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Cogdill AP, Gaudreau PO, Arora R, Gopalakrishnan V, Wargo JA. The Impact of Intratumoral and Gastrointestinal Microbiota on Systemic Cancer Therapy. Trends Immunol 2019; 39:900-920. [PMID: 30392721 DOI: 10.1016/j.it.2018.09.007] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 09/13/2018] [Accepted: 09/14/2018] [Indexed: 01/04/2023]
Abstract
The human microbiome is a complex aggregate of microorganisms, and their genomes exert a number of influences crucial to the metabolic, immunologic, hormonal, and homeostatic function of the host. Recent work, both in preclinical mouse models and human studies, has shed light on the impact of gut and tumor microbiota on responses to systemic anticancer therapeutics. In light of this, strategies to target the microbiome to improve therapeutic responses are underway, including efforts to target gut and intratumoral microbes. Here, we discuss mechanisms by which microbiota may impact systemic and antitumor immunity, in addition to outstanding questions in the field. A deeper understanding of these is critical as we devise putative strategies to target the microbiome.
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Affiliation(s)
- Alexandria P Cogdill
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Pierre Olivier Gaudreau
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Reetakshi Arora
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Vancheswaran Gopalakrishnan
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; These authors contributed equally to this work
| | - Jennifer A Wargo
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; These authors contributed equally to this work.
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18
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Maddi A, Sabharwal A, Violante T, Manuballa S, Genco R, Patnaik S, Yendamuri S. The microbiome and lung cancer. J Thorac Dis 2019; 11:280-291. [PMID: 30863606 DOI: 10.21037/jtd.2018.12.88] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
It has become increasingly clear that we live in a symbiotic relationship with microbes within us. We are just beginning to unravel the nature and strength of this relationship and its impact on both physiology and by extension, pathology. While microorganisms have long been known to have carcinogenic potential, their role may have been underestimated. The knowledge of the role of the microbiome in carcinogenesis is rapidly evolving. This evolution has reached a tipping point with current omics technologies used for cataloguing the microbiome. The lung is an organ constantly exposed to the environment. It is now clear that the lung has a distinct microbiome and that this may influence the development of lung cancer. In addition, evidence suggests that this microbiome originates from the oral microbiome. This review summarizes current knowledge about the role of microbiome, especially the oral and lung microbiome in human lung cancer. The goal of the manuscript is to provide a summary of this rapidly evolving field while providing a context of the general role of the microbiome in carcinogenesis. In addition, a primer of the current technology used in evaluating the microbiome is provided to familiarize the practicing clinician with the experimental methods used to generate the information that will likely impact the field of lung cancer.
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Affiliation(s)
- Abhiram Maddi
- Department of Periodontics & Endodontics, School of Dental Medicine, State University of New York, Buffalo, NY, USA
| | - Amarpreet Sabharwal
- Department of Periodontics & Endodontics, School of Dental Medicine, State University of New York, Buffalo, NY, USA
| | - Timothy Violante
- Department of Periodontics & Endodontics, School of Dental Medicine, State University of New York, Buffalo, NY, USA
| | - Sunita Manuballa
- Department of Oral Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Robert Genco
- Department of Periodontics & Endodontics, School of Dental Medicine, State University of New York, Buffalo, NY, USA
| | - Santosh Patnaik
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Sai Yendamuri
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
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19
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Hiyoshi H, Tiffany CR, Bronner DN, Bäumler AJ. Typhoidal Salmonella serovars: ecological opportunity and the evolution of a new pathovar. FEMS Microbiol Rev 2018; 42:527-541. [DOI: 10.1093/femsre/fuy024] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 05/19/2018] [Indexed: 12/20/2022] Open
Affiliation(s)
- Hirotaka Hiyoshi
- Department of Medial Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616, USA
| | - Connor R Tiffany
- Department of Medial Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616, USA
| | - Denise N Bronner
- Department of Medial Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616, USA
| | - Andreas J Bäumler
- Department of Medial Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616, USA
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20
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Bacterial Infection and Associated Cancers. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1018:181-191. [DOI: 10.1007/978-981-10-5765-6_11] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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21
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Abstract
For over a century, non-virus microorganisms, notably bacteria have been implicated as causal agents of cancers, a relatively small number of researchers have provided evidence to support the so-called “cancer germ” hypothesis. With the exception of the link between Helicobacter pylori and stomach cancer, other supposed links have been ignored. A wide range of bacteria and other non-virus microbes, including fungi, have been implicated over the years in oncogenesis, as well as the ability to induce inflammation, which may cause cancer. It seems that there is no single “cancer germ,” as most bacteria can apparently induce cancer. Here, the role of bacteria and other non-virus microorganisms and oral cancers will be discussed. By ignoring bacteria as a causal agent of cancer, we set back our understanding of this crucially important disease and, as a result, have hindered the development of potential cures.
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Affiliation(s)
- Asmaa A Faden
- Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, King Saud University, Riyadh, Kingdom of Saudi Arabia. E-mail.
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22
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Murphy B, Ibrahim JE, Bugeja L, Pilgrim J, Cicuttini F. The Use of Deceased Controls in Epidemiologic Research: A Systematic Review. Am J Epidemiol 2017; 186:367-384. [PMID: 28460057 DOI: 10.1093/aje/kwx052] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 08/25/2016] [Indexed: 12/13/2022] Open
Abstract
Scholarly debate on the use of deceased controls in epidemiologic research continues. This systematic review examined published epidemiologic research using deceased persons as a control group. A systematic search of 5 major biomedical literature databases (MEDLINE, CINAHL, PsycINFO, Scopus, and EMBASE) was conducted, using variations of the search terms "deceased" and "controls" to identify relevant peer-reviewed journal articles. Information was sought on study design, rationale for using deceased controls, application of theoretical principles of control selection, and discussion of the use of deceased controls. The review identified 134 studies using deceased controls published in English between 1978 and 2015. Common health outcomes under investigation included cancer (n = 31; 23.1%), nervous system diseases (n = 26; 19.4%), and injury and other external causes (n = 22; 16.4%). The majority of studies used deceased controls for comparison with deceased cases (n = 95; 70.9%). Investigators rarely presented their rationale for control selection (n = 25/134; 18.7%); however, common reasons included comparability of information on exposures, lack of appropriate controls from other sources, and counteracting bias associated with living controls. Comparable accuracy was the most frequently observed principle of control selection (n = 92; 68.7%). This review highlights the breadth of research using deceased controls and indicates their appropriateness in studies using deceased cases.
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23
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Vyshenska D, Lam KC, Shulzhenko N, Morgun A. Interplay between viruses and bacterial microbiota in cancer development. Semin Immunol 2017; 32:14-24. [PMID: 28602713 DOI: 10.1016/j.smim.2017.05.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Revised: 05/03/2017] [Accepted: 05/30/2017] [Indexed: 12/29/2022]
Abstract
During the last few decades we have become accustomed to the idea that viruses can cause tumors. It is much less considered and discussed, however, that most people infected with oncoviruses will never develop cancer. Therefore, the genetic and environmental factors that tip the scales from clearance of viral infection to development of cancer are currently an area of active investigation. Microbiota has recently emerged as a potentially critical factor that would affect this balance by increasing or decreasing the ability of viral infection to promote carcinogenesis. In this review, we provide a model of microbiome contribution to the development of oncogenic viral infections and viral associated cancers, give examples of this process in human tumors, and describe the challenges that prevent progress in the field as well as their potential solutions.
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Affiliation(s)
- Dariia Vyshenska
- College of Pharmacy, Oregon State University, 1601 SW Jefferson Way, Corvallis, OR 97331, USA
| | - Khiem C Lam
- College of Pharmacy, Oregon State University, 1601 SW Jefferson Way, Corvallis, OR 97331, USA
| | - Natalia Shulzhenko
- College of Veterinary Medicine, Oregon State University, 208 Dryden Hall, Corvallis, OR 97331, USA.
| | - Andrey Morgun
- College of Pharmacy, Oregon State University, 1601 SW Jefferson Way, Corvallis, OR 97331, USA.
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24
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Koshiol J, Wozniak A, Cook P, Adaniel C, Acevedo J, Azócar L, Hsing AW, Roa JC, Pasetti MF, Miquel JF, Levine MM, Ferreccio C. Salmonella enterica serovar Typhi and gallbladder cancer: a case-control study and meta-analysis. Cancer Med 2016; 5:3310-3235. [PMID: 27726295 PMCID: PMC5119987 DOI: 10.1002/cam4.915] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 07/21/2016] [Accepted: 08/22/2016] [Indexed: 01/10/2023] Open
Abstract
In Chile, where gallbladder cancer (GBC) rates are high and typhoid fever was endemic until the 1990s, we evaluated the association between Salmonella enterica serovar Typhi (S. Typhi) antibodies and GBC. We tested 39 GBC cases, 40 gallstone controls, and 39 population-based controls for S. Typhi Vi antibodies and performed culture and quantitative polymerase chain reaction for the subset with bile, gallstone, tissue, and stool samples available. We calculated gender and education-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association with GBC. We also conducted a meta-analysis of >1000 GBC cases by combining our results with previous studies. GBC cases were more likely to have high Vi antibody titer levels than combined controls (OR: 4.0, 95% CI: 0.9-18.3), although S. Typhi was not recovered from bile, gallstone, tissue, or stool samples. In our meta-analysis, the summary relative risk was 4.6 (95% CI: 3.1-6.8, Pheterogeneity =0.6) for anti-Vi and 5.0 (95% CI: 2.7-9.3, Pheterogeneity = 0.2) for bile or stool culture. Our results are consistent with the meta-analysis. Despite differences in study methods (e.g., S. Typhi detection assay), most studies found a positive association between S. Typhi and GBC. However, the mechanism underlying this association requires further investigation.
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Affiliation(s)
- Jill Koshiol
- Infections and Immunoepidemiology BranchDivision of Cancer Epidemiology and GeneticsNational Cancer InstituteMD
| | - Aniela Wozniak
- Laboratory of MicrobiologyPontificia Universidad Católica de ChileSantiagoChile
| | - Paz Cook
- Escuela de MedicinaAdvanced Center for Chronic DiseasesACCDiSPontificia Universidad Católica de ChileSantiagoChile
| | - Christina Adaniel
- Laboratory of MicrobiologyPontificia Universidad Católica de ChileSantiagoChile
| | - Johanna Acevedo
- Escuela de MedicinaAdvanced Center for Chronic DiseasesACCDiSPontificia Universidad Católica de ChileSantiagoChile
| | - Lorena Azócar
- Department of GastroenterologySchool of MedicinePontificia Universidad Católica de ChileSantiagoChile
| | - Ann W. Hsing
- Stanford Cancer InstitutePalo AltoCA
- Department of Health Research and PolicyStanford School of MedicinePalo AltoCA
| | - Juan C. Roa
- Department of PathologySchool of MedicinePontificia Universidad Católica de ChileSantiagoChile
| | - Marcela F. Pasetti
- Center for Vaccine DevelopmentUniversity of Maryland School of MedicineBaltimoreMD
| | - Juan F. Miquel
- Department of GastroenterologySchool of MedicinePontificia Universidad Católica de ChileSantiagoChile
| | - Myron M. Levine
- Center for Vaccine DevelopmentUniversity of Maryland School of MedicineBaltimoreMD
| | - Catterina Ferreccio
- Escuela de MedicinaAdvanced Center for Chronic DiseasesACCDiSPontificia Universidad Católica de ChileSantiagoChile
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25
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Russo E, Taddei A, Ringressi MN, Ricci F, Amedei A. The interplay between the microbiome and the adaptive immune response in cancer development. Therap Adv Gastroenterol 2016; 9:594-605. [PMID: 27366226 PMCID: PMC4913328 DOI: 10.1177/1756283x16635082] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The data from different studies suggest a bacterial role in cancer genesis/progression, often modulating the local immune response. This is particularly so at the mucosal level where the bacterial presence is strong and the immune system is highly reactive. The epithelial surfaces of the body, such as the skin and mucosa, are colonized by a vast number of microorganisms, which represent the so-called normal microbiome. Normally the microbiome does not cause a proinflammatory response because the immune system has developed different strategies for the tolerance of commensal bacteria, but when these mechanisms are impaired or new pathogenic bacteria are introduced into this balanced system, the immune system reacts to the microbiome and can trigger tumor growth in the intestine. In this review, we discuss the potential role of the bacterial microbiome in carcinogenesis, focusing on the direct and indirect immune adaptive mechanisms, that the bacteria can modulate in different ways.
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Affiliation(s)
- Edda Russo
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Antonio Taddei
- Department of Surgery and Translational Medicine (DCMT), University of Florence, Florence, Italy
| | - Maria Novella Ringressi
- Department of Surgery and Translational Medicine (DCMT), University of Florence, Florence, Italy
| | - Federica Ricci
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine – Section of Internal Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
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26
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Espinoza JA, Bizama C, García P, Ferreccio C, Javle M, Miquel JF, Koshiol J, Roa JC. The inflammatory inception of gallbladder cancer. Biochim Biophys Acta Rev Cancer 2016; 1865:245-54. [PMID: 26980625 DOI: 10.1016/j.bbcan.2016.03.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 03/09/2016] [Accepted: 03/10/2016] [Indexed: 02/06/2023]
Abstract
Gallbladder cancer is a lethal disease with notable geographical variations worldwide and a predilection towards women. Its main risk factor is prolonged exposure to gallstones, although bacterial infections and other inflammatory conditions are also associated. The recurrent cycles of gallbladder epithelium damage and repair enable a chronic inflammatory environment that promotes progressive morphological impairment through a metaplasia-dysplasia-carcinoma, along with cumulative genome instability. Inactivation of TP53, which is mutated in over 50% of GBC cases, seems to be the earliest and one of the most important carcinogenic pathways involved. Increased cell turnover and oxidative stress promote early alteration of TP53, cell cycle deregulation, apoptosis and replicative senescence. In this review, we will discuss evidence for the role of inflammation in gallbladder carcinogenesis obtained through epidemiological studies, genome-wide association studies, experimental carcinogenesis, morphogenetic studies and comparative studies with other inflammation-driven malignancies. The evidence strongly supports chronic, unresolved inflammation as the main carcinogenic mechanism of gallbladder cancer, regardless of the initial etiologic trigger. Given this central role of inflammation, evaluation of the potential for GBC prevention removing causes of inflammation or using anti-inflammatory drugs in high-risk populations may be warranted.
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Affiliation(s)
- Jaime A Espinoza
- SciLifeLab, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Stockholm SE171 76, Sweden
| | - Carolina Bizama
- Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), UC-Center for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Patricia García
- Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), UC-Center for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Catterina Ferreccio
- Department of Public Health, Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Milind Javle
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Juan F Miquel
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Jill Koshiol
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda 20850, MD, USA
| | - Juan C Roa
- Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), UC-Center for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
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Crump JA, Sjölund-Karlsson M, Gordon MA, Parry CM. Epidemiology, Clinical Presentation, Laboratory Diagnosis, Antimicrobial Resistance, and Antimicrobial Management of Invasive Salmonella Infections. Clin Microbiol Rev 2015; 28:901-37. [PMID: 26180063 PMCID: PMC4503790 DOI: 10.1128/cmr.00002-15] [Citation(s) in RCA: 688] [Impact Index Per Article: 68.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Salmonella enterica infections are common causes of bloodstream infection in low-resource areas, where they may be difficult to distinguish from other febrile illnesses and may be associated with a high case fatality ratio. Microbiologic culture of blood or bone marrow remains the mainstay of laboratory diagnosis. Antimicrobial resistance has emerged in Salmonella enterica, initially to the traditional first-line drugs chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole. Decreased fluoroquinolone susceptibility and then fluoroquinolone resistance have developed in association with chromosomal mutations in the quinolone resistance-determining region of genes encoding DNA gyrase and topoisomerase IV and also by plasmid-mediated resistance mechanisms. Resistance to extended-spectrum cephalosporins has occurred more often in nontyphoidal than in typhoidal Salmonella strains. Azithromycin is effective for the management of uncomplicated typhoid fever and may serve as an alternative oral drug in areas where fluoroquinolone resistance is common. In 2013, CLSI lowered the ciprofloxacin susceptibility breakpoints to account for accumulating clinical, microbiologic, and pharmacokinetic-pharmacodynamic data suggesting that revision was needed for contemporary invasive Salmonella infections. Newly established CLSI guidelines for azithromycin and Salmonella enterica serovar Typhi were published in CLSI document M100 in 2015.
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Affiliation(s)
- John A Crump
- Centre for International Health, University of Otago, Dunedin, Otago, New Zealand Division of Foodborne, Waterborne, and Environmental Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Maria Sjölund-Karlsson
- Division of Foodborne, Waterborne, and Environmental Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Melita A Gordon
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi
| | - Christopher M Parry
- School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
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Nagaraja V, Eslick GD. Systematic review with meta-analysis: the relationship between chronic Salmonella typhi carrier status and gall-bladder cancer. Aliment Pharmacol Ther 2014; 39:745-50. [PMID: 24612190 DOI: 10.1111/apt.12655] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Revised: 12/23/2013] [Accepted: 01/23/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND Carcinoma of the gall-bladder is the fifth commonest gastrointestinal tract cancer and is endemic in several countries. An association of chronic typhoid carriage and carcinoma of the gall-bladder has been reported. AIM To clarify whether chronic Salmonella typhi carrier state is associated with carcinoma of the gall-bladder. METHODS A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents, Cochrane library, Google Scholar, Science Direct and Web of Science. Original data were abstracted from each study and used to calculate a pooled odds ratio (OR) and 95% confidence interval (95% CI). RESULTS Of the articles selected, only 17 studies met full criteria for analysis. The overall OR for chronic S. typhi carrier state was 4.28(95% CI: 1.84-9.96). Most of the studies were from South Asia especially India and China. When a subgroup analysis was performed according to region, a significant association was observed in South-East Asia (OR: 4.13, 95% CI: 2.87-5.94, P value <0.01). Chronic S. typhi carrier state was associated with carcinoma of the gall-bladder based on detection methods of S. typhi antibody levels (OR: 3.52, 95% CI: 2.48-5.00, P value <0.01) and even more so on culture (OR: 4.14, 95% CI: 2.41-7.12, P value <0.01). The association was prominent in controls without gallstones (OR: 5.86, 95% CI: 3.84-8.95, P value <0.01) when compared with controls with gallstones (OR: 2.71, 95% CI: 1.92-3.83, P value <0.01). CONCLUSIONS Chronic S. typhi carrier state is an important risk factor among patients with carcinoma of the gall-bladder. Given the high risk associated with this carrier state, management options should include either elective cholecystectomy or careful monitoring using ultrasound.
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Affiliation(s)
- V Nagaraja
- The Whiteley-Martin Research Centre, Discipline of Surgery, The Sydney Medical School Nepean, Penrith, NSW, Australia
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Kovalchuk O, Walz P, Kovalchuk I. Does bacterial infection cause genome instability and cancer in the host cell? Mutat Res 2014; 761:1-14. [PMID: 24472301 DOI: 10.1016/j.mrfmmm.2014.01.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Revised: 12/08/2013] [Accepted: 01/16/2014] [Indexed: 06/03/2023]
Abstract
Research of the past several decades suggests that bacterial infection can lead to genome instability of the host cell often resulting in cancer development. However, there is still a substantial lack of knowledge regarding possible mechanisms involved in the development of genomic instability. Several questions remain unanswered, namely: Why has the causative relationship between the bacterial infection and cancer been established only for a small number of cancers? What is the mechanism responsible for the induction of genome instability and cancer? Is the infection process required to cause genome instability and cancer? In this review, we present a hypothesis that the bacterial infection, exposure to heat-killed bacteria or even some bacterial determinants may trigger genome instability of exposed and distal cells, and thus may cause cancer. We will discuss the mechanisms of host responses to the bacterial infection and present the possible pathways leading to genome instability and cancer through exposure to bacteria.
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Affiliation(s)
- Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge T1K 3M4, Alberta, Canada.
| | - Paul Walz
- Department of Biological Sciences, University of Lethbridge, Lethbridge T1K 3M4, Alberta, Canada.
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge T1K 3M4, Alberta, Canada.
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Epidemiology of Cholangiocarcinoma and Gallbladder Carcinoma. BILIARY TRACT AND GALLBLADDER CANCER 2014. [DOI: 10.1007/978-3-642-40558-7_1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Gonzalez-Escobedo G, La Perle KMD, Gunn JS. Histopathological analysis of Salmonella chronic carriage in the mouse hepatopancreatobiliary system. PLoS One 2013; 8:e84058. [PMID: 24349565 PMCID: PMC3861519 DOI: 10.1371/journal.pone.0084058] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 11/18/2013] [Indexed: 12/13/2022] Open
Abstract
Salmonella Typhi asymptomatic chronic carriage represents a challenge for the diagnosis and prevention of typhoid fever in endemic areas. Such carriers are thought to be reservoirs for further spread of the disease. Gallbladder carriage has been demonstrated to be mediated by biofilm formation on gallstones and by intracellular persistence in the gallbladder epithelium of mice. In addition, both gallstones and chronic carriage have been associated with chronic inflammation and the development of gallbladder carcinoma. However, the pathogenic relationship between typhoid carriage and the development of pre-malignant and/or malignant lesions in the hepatopancreatobiliary system as well as the host-pathogen interactions occurring during chronic carriage remains unclear. In this study, we monitored the histopathological features of chronic carriage up to 1 year post-infection. Chronic cholecystitis and hepatitis ranging from mild to severe were present in infected mice regardless of the presence of gallstones. Biliary epithelial hyperplasia was observed more commonly in the gallbladder of mice with gallstones (uninfected or infected). However, pre-malignant lesions, atypical hyperplasia and metaplasia of the gallbladder and exocrine pancreas, respectively, were only associated with chronic Salmonella carriage. This study has implications regarding the role of Salmonella chronic infection and inflammation in the development of pre-malignant lesions in the epithelium of the gallbladder and pancreas that could lead to oncogenesis.
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Affiliation(s)
- Geoffrey Gonzalez-Escobedo
- Departments of Microbiology and Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, United States of America
| | - Krista M. D. La Perle
- Department of Veterinary Biosciences, Comparative Pathology and Mouse Phenotyping Shared Resource, The Ohio State University, Columbus, Ohio, United States of America
| | - John S. Gunn
- Departments of Microbiology and Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, United States of America
- * E-mail:
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Abstract
Microbiota and host form a complex 'super-organism' in which symbiotic relationships confer benefits to the host in many key aspects of life. However, defects in the regulatory circuits of the host that control bacterial sensing and homeostasis, or alterations of the microbiome, through environmental changes (infection, diet or lifestyle), may disturb this symbiotic relationship and promote disease. Increasing evidence indicates a key role for the bacterial microbiota in carcinogenesis. In this Opinion article, we discuss links between the bacterial microbiota and cancer, with a particular focus on immune responses, dysbiosis, genotoxicity, metabolism and strategies to target the microbiome for cancer prevention.
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Affiliation(s)
- Robert F. Schwabe
- Department of Medicine, and Institute of Human Nutrition, Columbia University, College of Physicians and Surgeons, New York 10032, USA
| | - Christian Jobin
- Department of Medicine and Department of Infectious Diseases & Pathology, University of Florida, Gainesville, Florida 32611, USA
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33
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Chronic inflammation and gallbladder cancer. Cancer Lett 2013; 345:242-8. [PMID: 23981574 DOI: 10.1016/j.canlet.2013.08.034] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Revised: 08/13/2013] [Accepted: 08/18/2013] [Indexed: 12/15/2022]
Abstract
Gallbladder cancer (GBC) is the most common biliary tract malignancy with an extremely poor prognosis. Epidemiological data have demonstrated that chronic inflammation resulting from infection of gallbladder or gallstones predispose individuals to GBC. Recent studies have begun to elucidate molecular mechanisms underlying the development of GBC in the setting of chronic inflammation. It is possible that persistently local inflammatory reactions may contribute to the development and progression of GBC through inducing genetic alterations, and subsequent promoting survival and proliferation of mutated sells, inhibiting apoptosis, stimulating angiogenesis and metastasis. This article reviews the current understanding of the involvement of chronic inflammation in gallbladder tumorigenesis.
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Identification of Salmonella enterica serovar Typhimurium genes regulated during biofilm formation on cholesterol gallstone surfaces. Infect Immun 2013; 81:3770-80. [PMID: 23897604 DOI: 10.1128/iai.00647-13] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Salmonella spp. are able to form biofilms on abiotic and biotic surfaces. In vivo studies in our laboratory have shown that Salmonella can form biofilms on the surfaces of cholesterol gallstones in the gallbladders of mice and human carriers. Biofilm formation on gallstones has been demonstrated to be a mechanism of persistence. The purpose of this work was to identify and evaluate Salmonella sp. cholesterol-dependent biofilm factors. Differential gene expression analysis between biofilms on glass or cholesterol-coated surfaces and subsequent quantitative real-time PCR (qRT-PCR) revealed that type 1 fimbria structural genes and a gene encoding a putative outer membrane protein (ycfR) were specifically upregulated in Salmonella enterica serovar Typhimurium biofilms grown on cholesterol-coated surfaces. Spatiotemporal expression of ycfR and FimA verified their regulation during biofilm development on cholesterol-coated surfaces. Surprisingly, confocal and scanning electron microscopy demonstrated that a mutant of type 1 fimbria structural genes (ΔfimAICDHF) and a ycfR mutant showed increased biofilm formation on cholesterol-coated surfaces. In vivo experiments using Nramp1(+/+) mice harboring gallstones showed that only the ΔycfR mutant formed extensive biofilms on mouse gallstones at 7 and 21 days postinfection; ΔfimAICDHF was not observed on gallstone surfaces after the 7-day-postinfection time point. These data suggest that in Salmonella spp., wild-type type 1 fimbriae are important for attachment to and/or persistence on gallstones at later points of chronic infection, whereas YcfR may represent a specific potential natural inhibitor of initial biofilm formation on gallstones.
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The Role of Bacteria in Cancer Development. Infect Agent Cancer 2013. [DOI: 10.1007/978-94-007-5955-8_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Feasey NA, Dougan G, Kingsley RA, Heyderman RS, Gordon MA. Invasive non-typhoidal salmonella disease: an emerging and neglected tropical disease in Africa. Lancet 2012; 379:2489-2499. [PMID: 22587967 PMCID: PMC3402672 DOI: 10.1016/s0140-6736(11)61752-2] [Citation(s) in RCA: 670] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Invasive strains of non-typhoidal salmonellae have emerged as a prominent cause of bloodstream infection in African adults and children, with an associated case fatality of 20-25%. The clinical presentation of invasive non-typhoidal salmonella disease in Africa is diverse: fever, hepatosplenomegaly, and respiratory symptoms are common, and features of enterocolitis are often absent. The most important risk factors are HIV infection in adults, and malaria, HIV, and malnutrition in children. A distinct genotype of Salmonella enterica var Typhimurium, ST313, has emerged as a new pathogenic clade in sub-Saharan Africa, and might have adapted to cause invasive disease in human beings. Multidrug-resistant ST313 has caused epidemics in several African countries, and has driven the use of expensive antimicrobial drugs in the poorest health services in the world. Studies of systemic cellular and humoral immune responses in adults infected with HIV have revealed key host immune defects contributing to invasive non-typhoidal salmonella disease. This emerging pathogen might therefore have adapted to occupy an ecological and immunological niche provided by HIV, malaria, and malnutrition in Africa. A good understanding of the epidemiology of this neglected disease will open new avenues for development and implementation of vaccine and public health strategies to prevent infections and interrupt transmission.
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Affiliation(s)
- Nicholas A Feasey
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | | | | | - Robert S Heyderman
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Liverpool School of Tropical Medicine, Liverpool, UK
| | - Melita A Gordon
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
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Kaiser P, Diard M, Stecher B, Hardt WD. The streptomycin mouse model for Salmonella diarrhea: functional analysis of the microbiota, the pathogen's virulence factors, and the host's mucosal immune response. Immunol Rev 2012; 245:56-83. [PMID: 22168414 DOI: 10.1111/j.1600-065x.2011.01070.x] [Citation(s) in RCA: 137] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The mammalian intestine is colonized by a dense microbial community, the microbiota. Homeostatic and symbiotic interactions facilitate the peaceful co-existence between the microbiota and the host, and inhibit colonization by most incoming pathogens ('colonization resistance'). However, if pathogenic intruders overcome colonization resistance, a fierce, innate inflammatory defense can be mounted within hours, the adaptive arm of the immune system is initiated, and the pathogen is fought back. The molecular nature of the homeostatic interactions, the pathogen's ability to overcome colonization resistance, and the triggering of native and adaptive mucosal immune responses are still poorly understood. To study these mechanisms, the streptomycin mouse model for Salmonella diarrhea is of great value. Here, we review how S. Typhimurium triggers mucosal immune responses by active (virulence factor elicited) and passive (MyD88-dependent) mechanisms and introduce the S. Typhimurium mutants available for focusing on either response. Interestingly, mucosal defense turns out to be a double-edged sword, limiting pathogen burdens in the gut tissue but enhancing pathogen growth in the gut lumen. This model allows not only studying the molecular pathogenesis of Salmonella diarrhea but also is ideally suited for analyzing innate defenses, microbe handling by mucosal phagocytes, adaptive secretory immunoglobulin A responses, probing microbiota function, and homeostatic microbiota-host interactions. Finally, we discuss the general need for defined assay conditions when using animal models for enteric infections and the central importance of littermate controls.
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Affiliation(s)
- Patrick Kaiser
- Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland
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Ruby T, McLaughlin L, Gopinath S, Monack D. Salmonella's long-term relationship with its host. FEMS Microbiol Rev 2012; 36:600-15. [PMID: 22335190 DOI: 10.1111/j.1574-6976.2012.00332.x] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Revised: 01/30/2012] [Accepted: 02/07/2012] [Indexed: 12/23/2022] Open
Abstract
Host-adapted strains of Salmonella enterica cause systemic infections and have the ability to persist systemically for long periods of time and pose significant public-health problems. Multidrug-resistant S. enterica serovar Typhi (S. Typhi) and nontyphoidal Salmonella (NTS) are on the increase and are often associated with HIV infection. Chronically infected hosts are often asymptomatic and transmit disease to naïve hosts via fecal shedding of bacteria, thereby serving as a critical reservoir for disease. Salmonella utilizes multiple ways to evade and modulate host innate and adaptive immune responses in order to persist in the presence of a robust immune response. Survival in macrophages and modulation of immune cells migration allow Salmonella to evade various immune responses. The ability of Salmonella to persist depends on a balance between immune responses that lead to the clearance of the pathogen and avoidance of damage to host tissues.
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Affiliation(s)
- Thomas Ruby
- Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA
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Lax A. The Pasteurella multocida toxin: a new paradigm for the link between bacterial infection and cancer. Curr Top Microbiol Immunol 2012; 361:131-44. [PMID: 22695919 DOI: 10.1007/82_2012_236] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
The concept that bacterial infection could cause cancer has only recently become accepted because of the strong epidemiological and molecular evidence for a major carcinogenic role played by Helicobacter pylori. However, information on other potential bacterial carcinogens is very limited and thereby unconvincing. A different approach is to assess bacteria for potentially pro-carcinogenic properties. The Pasteurella multocida toxin (PMT) has many properties that mark it out as a potential carcinogen. PMT is a highly potent mitogen and has been demonstrated to block apoptosis. PMT modifies and activates members of three of the four families of heterotrimeric G-proteins, all of which have potential roles in carcinogenesis. Many signalling components downstream of these G-proteins are known proto-oncogenes and have been shown to be activated by PMT. These include, amongst others, the Rho GTPase, focal adhesion kinase, cyclooxygenase-2, β-catenin signalling and calcium signalling. PMT action potentially influences many of the acquired Hanahan/Weinberg capabilities necessary for oncogenic transformation. Although there is little evidence that PMT might have a role in human cancer, it serves as an important and novel paradigm for a bacterial link to cancer.
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Affiliation(s)
- Alistair Lax
- Department of Microbiology, King's College London Dental Institute, London, UK.
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40
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Puneet, Nath G, Shukla VK. Possible Strategies of Bacterial Involvement in Cancer Development. BACTERIA AND CANCER 2012:165-184. [DOI: 10.1007/978-94-007-2585-0_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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41
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Caygill CPJ, Gatenby PAC. Epidemiology of the Association Between Bacterial Infections and Cancer. BACTERIA AND CANCER 2012:1-24. [DOI: 10.1007/978-94-007-2585-0_1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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The Vi conjugate typhoid vaccine is safe, elicits protective levels of IgG anti-Vi, and is compatible with routine infant vaccines. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2011; 18:730-5. [PMID: 21411598 DOI: 10.1128/cvi.00532-10] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Typhoid fever remains a serious problem in developing countries. Current vaccines are licensed for individuals who are 5 years old or older. A conjugate of the capsular polysaccharide (CP) of Salmonella enterica serovar Typhi (Vi) bound to recombinant exoprotein A of Pseudomonas aeruginosa (Vi-rEPA) enhanced Vi immunogenicity and protected 2- to 5-year-olds in Vietnam. In this study, Vi-rEPA was evaluated for use in infants. A total of 301 full-term Vietnamese infants received Expanded Program on Immunization (EPI) vaccines alone or with Vi-rEPA or Haemophilus influenzae type b-tetanus toxoid conjugate (Hib-TT) at 2, 4, and 6 months and Vi-rEPA or Hib-TT alone at 12 months. Infants were visited 6, 24, and 48 h after each injection to monitor adverse reactions. Maternal, cord, and infant sera were assayed for IgG anti-Vi and for IgG antibodies to Hib CP and the diphtheria, tetanus, and pertussis toxins at 7, 12, and 13 months. No vaccine-related serious adverse reactions occurred. In the Vi-rEPA group, the IgG anti-Vi geometric mean (GM) increased from the cord level of 0.66 to 17.4 enzyme-linked immunosorbent assay units (EU) at 7 months, declined to 4.76 EU at 12 months, and increased to 50.1 EU 1 month after the 4th dose (95% of infants had levels of ≥ 3.5 EU, the estimated protective level). Controls had no increase of the IgG anti-Vi GM. Infants with cord anti-Vi levels of <3.5 EU responded with significantly higher IgG anti-Vi levels than those with levels of ≥ 3.5 EU. Anti-diphtheria, -tetanus, and -pertussis toxin levels were similar in all groups. Vi-rEPA was safe, induced protective anti-Vi levels, and was compatible with EPI vaccines, and it can be used in infants. High cord IgG anti-Vi levels partially suppressed infant responses to Vi-rEPA.
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Abstract
Recently, an unprecedented effort has been directed at understanding the interplay between chronic inflammation and development of cancer, with the case of inflammatory bowel disease (IBD)-associated colorectal cancer at the forefront of this research endeavor. The last decade has been particularly fertile, with the discovery of numerous innovative paradigms linking various inflammatory, proliferative, and innate and adaptive immune signaling pathways to the development of colorectal cancer. Because of the preponderant role of the intestinal microbiota in the initiation and progression of IBD, recent efforts have been directed at understanding the relationship between bacteria and colorectal cancer. The microbiota and its collective genome, the microbiome, form a diverse and complex ecological community that profoundly impacts intestinal homeostasis and disease states. This review will discuss the differential influence of the microbiota on the development of IBD-associated colorectal cancer and highlight the role of innate immune sensor-dependent as well as -independent mechanisms in this pathology.
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Affiliation(s)
- Janelle C Arthur
- Department of Medicine and the Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina 27599-7080, USA
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44
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Nath G, Gulati AK, Shukla VK. Role of bacteria in carcinogenesis, with special reference to carcinoma of the gallbladder. World J Gastroenterol 2010; 16:5395-404. [PMID: 21086555 PMCID: PMC2988230 DOI: 10.3748/wjg.v16.i43.5395] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Carcinoma of the gallbladder (CaGB) is the fifth commonest gastrointestinal tract cancer and is endemic in several countries. The interplay of genetic susceptibility, infections, and life style factors has been proposed to be responsible for carcinogenesis of gallbladder. Persistence of infection leading to chronic inflammation, and production of certain toxins and metabolites with carcinogenic potentials, by certain bacteria has been speculated to be involved in the transformation of the gallbladder epithelium. Therefore, any bacteria that have evolved to acquire both of the above carcinogenic mechanisms can cause cancer. Salmonella typhi has been found to be prominently associated with CaGB. Chronic typhoid carriage (persistence) and production of mediators of chronic inflammation and a genotoxic toxin (cytotoxic distending toxin, CdtB) are also known for this bacterium. Furthermore, the natural concentrating function of the gallbladder might amplify the carcinogenic effect of the mediators of carcinogenesis. In addition to S. typhi, certain species of Helicobacter (H. bilis and H. hepaticus) and Escherichia coli have also been implicated in carcinogenesis. As the isolation rate is very poor with the presently available culture techniques, the existence of bacteria in a viable but non-cultivable state is quite likely; therefore, sensitive and specific molecular techniques might reveal the etiological role of bacterial infection in gallbladder carcinogenesis. If bacteria are found to be causing cancers, then eradication of such infections might help in reducing the incidence of some cancers.
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Andrews-Polymenis HL, Bäumler AJ, McCormick BA, Fang FC. Taming the elephant: Salmonella biology, pathogenesis, and prevention. Infect Immun 2010; 78:2356-69. [PMID: 20385760 PMCID: PMC2876576 DOI: 10.1128/iai.00096-10] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Salmonella infections continue to cause substantial morbidity and mortality throughout the world. However, recent discoveries and new paradigms promise to lead to novel strategies to diagnose, treat, and prevent Salmonella infections. This review provides an update of the Salmonella field based on oral presentations given at the recent 3rd ASM Conference on Salmonella: Biology, Pathogenesis and Prevention.
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Affiliation(s)
- Helene L. Andrews-Polymenis
- Department of Microbiology and Molecular Pathogenesis, Texas A&M University System Health Science Center, College Station, Texas, Department of Medical Microbiology and Immunology, University of California at Davis, Davis, California, Department of Molecular Genetics and Microbiology, University of Massachusetts Medical Center, Worcester, Massachusetts, Departments of Microbiology and Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington
| | - Andreas J. Bäumler
- Department of Microbiology and Molecular Pathogenesis, Texas A&M University System Health Science Center, College Station, Texas, Department of Medical Microbiology and Immunology, University of California at Davis, Davis, California, Department of Molecular Genetics and Microbiology, University of Massachusetts Medical Center, Worcester, Massachusetts, Departments of Microbiology and Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington
| | - Beth A. McCormick
- Department of Microbiology and Molecular Pathogenesis, Texas A&M University System Health Science Center, College Station, Texas, Department of Medical Microbiology and Immunology, University of California at Davis, Davis, California, Department of Molecular Genetics and Microbiology, University of Massachusetts Medical Center, Worcester, Massachusetts, Departments of Microbiology and Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington
| | - Ferric C. Fang
- Department of Microbiology and Molecular Pathogenesis, Texas A&M University System Health Science Center, College Station, Texas, Department of Medical Microbiology and Immunology, University of California at Davis, Davis, California, Department of Molecular Genetics and Microbiology, University of Massachusetts Medical Center, Worcester, Massachusetts, Departments of Microbiology and Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington
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Bacteriemia por Salmonella typhi tras colocación de stent biliar. Enferm Infecc Microbiol Clin 2010; 28:327-9. [DOI: 10.1016/j.eimc.2009.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2009] [Revised: 06/03/2009] [Accepted: 06/09/2009] [Indexed: 11/18/2022]
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Kosaka T, Tajima Y, Kuroki T, Mishima T, Adachi T, Tsuneoka N, Fukuda K, Kanematsu T. Helicobacter bilis colonization of the biliary system in patients with pancreaticobiliary maljunction. Br J Surg 2010; 97:544-9. [PMID: 20155791 DOI: 10.1002/bjs.6907] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Helicobacter bilis is considered to be a causative factor in the pathogenesis of biliary cancer. This study investigated the prevalence of H. bilis colonization of the biliary system of patients with pancreaticobiliary maljunction (PBM). METHODS Bile juice and biliary tissue samples were collected from 17 patients with PBM and 27 controls who had benign biliary disease without PBM. DNA extracted from each biliary sample was subjected to polymerase chain reaction (PCR) analysis for H. bilis and Helicobacter pylori. RESULTS PCR assays revealed that 12 of the 17 patients with PBM were positive for H. bilis DNA, compared with eight of 27 patients without PBM (P = 0.009). Among patients with PBM, H. bilis DNA was identified in six of eight children, including a 2-month-old infant, and in six of nine adults. The high prevalence of H. bilis DNA in the biliary system of patients with PBM was independent of age, sex, common bile duct dilatation, configuration of the pancreatic and bile ducts, and amylase activity in bile. CONCLUSION H. bilis colonization of the biliary system is extremely common in patients with PBM. This may point to a role in the pathogenesis of biliary cancer.
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Affiliation(s)
- T Kosaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan.
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Pandey D. Surgical management of gallbladder cancer. Indian J Surg 2010; 71:363-7. [PMID: 23133192 DOI: 10.1007/s12262-009-0095-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2009] [Accepted: 11/23/2009] [Indexed: 01/28/2023] Open
Abstract
Gallbladder cancer is a very common malignancy in the northern part of India. Surgery is the only potentially curative modality of treatment for this disease. Radical cholecystectomy is the optimal surgical standard for resectable gallbladder cancer. This includes cholecystectomy, liver resection (wedge, segments 4b and 5, or extended right hepatectomy), and regional lymphadenectomy along the hepatoduodenal ligament, behind the duodenum and pancreatic head, common hepatic artery and celiac axis. Controversies regarding extent of liver resection, lymphadenectomy and role of multiorgan resection have been discussed. Incidental gallbladder cancer is often detected on histopathologic examination of the simple cholecystectomy specimen removed for a presumed gallstone disease. Revision surgery should be performed for incidental cancers that invade muscularis propria or beyond (T1b or more). Advanced gallbladder cancer should be treated non-operatively with a palliative intent. Obstructive jaundice in the setting of an advanced gallbladder cancer can be palliated with biliary stenting by endoscopic or transhepatic means. Occasionally, a surgical biliary bypass may be indicated to relieve intractable pruritus in a jaundiced patient with gallbladder cancer. There is no role of a planned R2 resection of advanced gallbladder cancer for the purpose of cytoreduction. Further improvement in the management of gallbladder cancer will need integration of systemic chemotherapy with radical surgery.
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Affiliation(s)
- Durgatosh Pandey
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005 U.P. India
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Travaglione S, Fabbri A, Fiorentini C. The Rho-activating CNF1 toxin from pathogenic E. coli: a risk factor for human cancer development? Infect Agent Cancer 2008; 3:4. [PMID: 18336718 PMCID: PMC2323363 DOI: 10.1186/1750-9378-3-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2007] [Accepted: 03/12/2008] [Indexed: 12/12/2022] Open
Abstract
Nowadays, there is increasing evidence that some pathogenic bacteria can contribute to specific stages of cancer development. The concept that bacterial infection could be involved in carcinogenesis acquired a widespread interest with the discovery that H. pylori is able to establish chronic infections in the stomach and that this infection is associated with an increased risk of gastric adenocarcinoma and mucosa associated lymphoid tissue lymphoma. Chronic infections triggered by bacteria can facilitate tumor initiation or progression since, during the course of infection, normal cell functions can come under the control of pathogen factors that directly manipulate the host regulatory pathways and the inflammatory reactions.Renowned publications have recently corroborated the molecular mechanisms that link bacterial infections, inflammation and cancer, indicating certain strains of Escherichia coli as a risk factor for patients with colon cancer. E. coli is a normal inhabitant of the human intestine that becomes highly pathogenic following the acquisition of virulence factors, including a protein toxin named cytotoxic necrotizing factor 1 (CNF1). This toxin permanently activates the small GTP-binding proteins belonging to the Rho family, thus promoting a prominent polymerization of the actin cytoskeleton as well as a number of cellular responses, including changes in protein expression and functional modification of the cell physiology. CNF1 is receiving an increasing attention as a putative factor involved in transformation because of its ability to: (i) induce COX2 expression, an immediate-early gene over-expressed in some type of cancers; (ii) induce a long-lasting activation of the transcription factor NF-kB, a largely accepted marker of tumor cells; (iii) protect epithelial cells from apoptosis; (iv) ensue the release of pro-inflammatory cytokines in epithelial and endothelial cells; and (v) promote cellular motility. As cancer may arise through dysfunction of the same regulatory systems, it seems likely that CNF1-producing E. coli infections can contribute to tumor development.This review focuses on the aspects of CNF1 activity linked to cell transformation with the aim of contributing to the identification of a possible carcinogenic agent from the microbial world.
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Affiliation(s)
- Sara Travaglione
- Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, viale Regina Elena 299, 00161-Rome, Italy.
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Kiguchi K, Ruffino L, Kawamoto T, Franco E, Kurakata SI, Fujiwara K, Hanai M, Rumi M, DiGiovanni J. Therapeutic effect of CS-706, a specific cyclooxygenase-2 inhibitor, on gallbladder carcinoma in BK5.ErbB-2 mice. Mol Cancer Ther 2007; 6:1709-17. [PMID: 17575102 DOI: 10.1158/1535-7163.mct-07-0015] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Biliary tract cancer is still challenging to treat and manage due to its poor sensitivity to conventional therapies and the inability to prevent or detect the early tumor formation. The most well known risk factor for gallbladder cancer is the presence of chronic inflammation, usually related to gallstones. It has been suggested that cyclooxygenase-2 (COX-2) plays a variety of roles in the gastrointestinal tract, including pathogenic processes such as neoplasia. Recently, we have generated transgenic mice that overexpress rat ErbB-2 under the control of bovine keratin 5 promoter (BK5.ErbB-2 mice). Homozygous BK5.ErbB-2 mice develop adenocarcinoma of gallbladder with an approximately 90% incidence. In addition to the activation of ErbB-2 and epidermal growth factor receptor, mRNA and protein levels of COX-2 were up-regulated in the gallbladder carcinomas that developed in these transgenic mice. The aim of this study was to examine the effects of a COX-2 inhibitor, CS-706, on the development of gallbladder carcinomas using the BK5.ErbB-2 mouse model. Ultrasound image analysis as well as histologic evaluation revealed a significant therapeutic effect of CS-706 on the gallbladder tumors, either as reversion to a milder phenotype or inhibition of tumor progression. The antitumor effect was associated with inhibition of prostaglandin E(2) synthesis. CS-706 treatment also down-regulated the activation of ErbB-2 and epidermal growth factor receptor, resulting in decreased levels of phosphorylated Akt and COX-2 in gallbladder cancers of BK5.ErbB-2 mice. Based on our results, targeting COX-2 could provide a potentially new and effective therapy alone or in combination with other therapeutic agents for patients with biliary tract cancer.
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Affiliation(s)
- Kaoru Kiguchi
- Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA
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