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1.
Cancer Res ; 81(12): 3309-3318, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33863776

RESUMO

Studies have shown bacteria influence the initiation and progression of cancers arising in sites that harbor rich microbial communities, such as the colon. Little is known about the potential for the microbiome to influence tumorigenesis at sites considered sterile, including the upper female genital tract. The recent identification of distinct bacterial signatures associated with ovarian carcinomas suggests microbiota in the gut, vagina, or elsewhere might contribute to ovarian cancer pathogenesis. Here, we tested whether altering the microbiome affects tumorigenesis in a mouse model of high-grade serous carcinoma (HGSC) based on conditional oviduct-specific inactivation of the Brca1, Trp53, Rb1, and Nf1 tumor suppressor genes. Cohorts of control (n = 20) and antibiotic-treated (n = 23) mice were treated with tamoxifen to induce tumor formation and then monitored for 12 months. The antibiotic cocktail was administered for the first 5 months of the monitoring period in the treatment group. Antibiotic-treated mice had significantly fewer and less advanced tumors than control mice at study endpoint. Antibiotics induced changes in the composition of the intestinal and vaginal microbiota, which were durable in the fecal samples. Clustering analysis showed particular groups of microbiota are associated with the development of HGSC in this model. These findings demonstrate the microbiome influences HGSC pathogenesis in an in vivo model that closely recapitulates the human disease. Because the microbiome can modulate efficacy of cancer chemo- and immunotherapy, our genetically engineered mouse model system may prove useful for testing whether altering the microbiota can improve the heretofore poor response of HGSC to immunotherapies. SIGNIFICANCE: This study provides strong in vivo evidence for a role of the microbiome in ovarian cancer pathogenesis.


Assuntos
Antibacterianos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Cistadenocarcinoma Seroso/prevenção & controle , Modelos Animais de Doenças , Microbiota/efeitos dos fármacos , Neoplasias Ovarianas/prevenção & controle , Oviductos/efeitos dos fármacos , Animais , Transformação Celular Neoplásica/patologia , Cistadenocarcinoma Seroso/microbiologia , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/microbiologia , Neoplasias Ovarianas/patologia , Oviductos/microbiologia , Oviductos/patologia
2.
Nat Commun ; 10(1): 1194, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30886143

RESUMO

Chronic infections of the fallopian tubes with Chlamydia trachomatis (Ctr) cause scarring and can lead to infertility. Here we use human fallopian tube organoids and genital Ctr serovars D, K and E for long-term in vitro analysis. The epithelial monolayer responds with active expulsion of the bacteria into the lumen and with compensatory cellular proliferation-demonstrating a role of epithelial homeostasis in the defense against this pathogen. In addition, Ctr infection activates LIF signaling, which we find to be an essential regulator of stemness in the organoids. Infected organoids exhibit a less differentiated phenotype with higher stemness potential, as confirmed by increased organoid forming efficiency. Moreover, Ctr increases hypermethylation of DNA, which is an indicator of accelerated molecular aging. Thus, the chronic organoid infection model suggests that Ctr has a long-term impact on the epithelium. These heritable changes might be a contributing factor in the development of tubal pathologies, including the initiation of high grade serous ovarian cancer.


Assuntos
Infecções por Chlamydia/genética , Chlamydia trachomatis/imunologia , Ilhas de CpG/genética , Metilação de DNA/imunologia , Interações entre Hospedeiro e Microrganismos/genética , Células-Tronco/metabolismo , Fatores Etários , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/microbiologia , Chlamydia trachomatis/genética , Doença Crônica , Ilhas de CpG/imunologia , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Cistadenocarcinoma Seroso/microbiologia , Epigênese Genética/genética , Epigênese Genética/imunologia , Epitélio/imunologia , Epitélio/metabolismo , Epitélio/microbiologia , Tubas Uterinas/imunologia , Tubas Uterinas/metabolismo , Tubas Uterinas/microbiologia , Feminino , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Microscopia Intravital , Microscopia Confocal , Organoides/imunologia , Organoides/metabolismo , Organoides/microbiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/microbiologia , Sorogrupo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Análise de Célula Única , Células-Tronco/imunologia , Células-Tronco/microbiologia , Técnicas de Cultura de Tecidos
3.
Microbiome ; 5(1): 9, 2017 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-28118849

RESUMO

BACKGROUND: A variety of bacteria are known to influence carcinogenesis. Therefore, we sought to investigate if publicly available whole genome and whole transcriptome sequencing data generated by large public cancer genome efforts, like The Cancer Genome Atlas (TCGA), could be used to identify bacteria associated with cancer. The Burrows-Wheeler aligner (BWA) was used to align a subset of Illumina paired-end sequencing data from TCGA to the human reference genome and all complete bacterial genomes in the RefSeq database in an effort to identify bacterial read pairs from the microbiome. RESULTS: Through careful consideration of all of the bacterial taxa present in the cancer types investigated, their relative abundance, and batch effects, we were able to identify some read pairs from certain taxa as likely resulting from contamination. In particular, the presence of Mycobacterium tuberculosis complex in the ovarian serous cystadenocarcinoma (OV) and glioblastoma multiforme (GBM) samples was correlated with the sequencing center of the samples. Additionally, there was a correlation between the presence of Ralstonia spp. and two specific plates of acute myeloid leukemia (AML) samples. At the end, associations remained between Pseudomonas-like and Acinetobacter-like read pairs in AML, and Pseudomonas-like read pairs in stomach adenocarcinoma (STAD) that could not be explained through batch effects or systematic contamination as seen in other samples. CONCLUSIONS: This approach suggests that it is possible to identify bacteria that may be present in human tumor samples from public genome sequencing data that can be examined further experimentally. More weight should be given to this approach in the future when bacterial associations with diseases are suspected.


Assuntos
Carcinoma/genética , Carcinoma/microbiologia , Bases de Dados Genéticas , Genoma Bacteriano , Genoma Humano , Leucemia Mieloide Aguda/microbiologia , Microbiota , Acinetobacter/genética , Bactérias/genética , Bactérias/isolamento & purificação , Sequência de Bases , Carcinoma/classificação , Carcinoma Epitelial do Ovário , Mapeamento Cromossômico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/microbiologia , Glioblastoma/genética , Glioblastoma/microbiologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/genética , Mycobacterium tuberculosis/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/microbiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/microbiologia , Pseudomonas/genética
4.
Eur J Gynaecol Oncol ; 28(2): 117-20, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17479672

RESUMO

PURPOSE OF INVESTIGATION: Epithelial ovarian cancer (EOC) is the leading cause of death from gynaecological malignancy in the UK. The pathogenesis of this disease is poorly understood. Our hypothesis was that chlamydial infection might play a role in the pathogenesis of EOC. METHODS: 122 serum samples of patients undergoing surgery for benign or malignant gynaecological conditions were analysed. There was a total of 41 patients with EOC (33.6%), 27 with benign cystadenomas (22.1%) and 54 with normal ovaries (44.3%). RESULTS: There was a higher incidence of IgA seropositivity and lower incidence of IgG seropositivity in the EOC group compared with the other groups; however, this was not statistically significant. There was no statistical difference in the serum IgM antibodies to chlamydia in the three different groups. CONCLUSION: Although chronic infection and persistent inflammation may contribute to the pathogenesis of EOC, and chlamydia is a common genital tract pathogen, our study did not find an association between chlamydia and EOC.


Assuntos
Infecções por Chlamydia/imunologia , Cistadenocarcinoma Seroso/imunologia , Cistadenocarcinoma Seroso/microbiologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/microbiologia , Idoso , Distribuição de Qui-Quadrado , Infecções por Chlamydia/microbiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Pessoa de Meia-Idade , Fatores de Risco , Reino Unido
5.
Gynecol Oncol ; 100(1): 216-7, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16169576

RESUMO

BACKGROUND: Invasive aspergillus is a rarely reported infection in patients with solid tumors. CASE: A 59-year-old woman developed invasive pulmonary aspergillus after surgical debulking of an advanced ovarian adenocarcinoma and initiation of adjuvant combination chemotherapy. CONCLUSION: Invasive pulmonary aspergillus is rarely diagnosed in patients with solid tumors such as ovarian cancer. Risk factors for development of the disease can include neutropenia, immunosuppression and chronic steroid use. Successful treatment of the infection relies upon prompt diagnosis and utilization of effective antifungal medications for a prolonged period of time.


Assuntos
Aspergilose/etiologia , Cistadenocarcinoma Seroso/microbiologia , Pneumopatias Fúngicas/etiologia , Neoplasias Ovarianas/microbiologia , Aspergilose/diagnóstico , Aspergillus , Biópsia por Agulha Fina , Cistadenocarcinoma Seroso/cirurgia , Feminino , Humanos , Pneumopatias Fúngicas/diagnóstico , Pessoa de Meia-Idade , Neoplasias Ovarianas/cirurgia , Polimialgia Reumática/microbiologia
6.
APMIS ; 111(10): 951-4, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14616547

RESUMO

Serous papillary adenocarcinomas of the ovary are often associated with microcalcifications, namely psammoma bodies. Archebacteria such as nanobacteria are, for example, involved in kidney stone formation. Nanobacteria deserve close scrutiny as their cytotoxicity and ability to cross the placenta present a potential clinical risk. In this study we investigated whether nanobacteria are associated with psammoma bodies in ovarian cancer. We identified in all seven carcinomas with multiple psammoma body nanobacterial antigens in histological specimens and in the ascitic fluid. Control cases of adenocarcinomas without such calcifications did not present nanobacterial antigens. This finding indicates that apart from non-malignant conditions, nanobacteria could also be found in cancer. Hence, nanobacterial infection may be of clinical importance as these bacteria are related to microcalifications in ovarian cancer.


Assuntos
Bactérias/isolamento & purificação , Calcinose/microbiologia , Cistadenocarcinoma Papilar/microbiologia , Cistadenocarcinoma Seroso/microbiologia , Neoplasias Ovarianas/microbiologia , Adulto , Idoso , Antígenos de Bactérias/metabolismo , Líquido Ascítico/microbiologia , Bactérias/patogenicidade , Calcinose/metabolismo , Calcinose/patologia , Estudos de Casos e Controles , Cristalização , Cistadenocarcinoma Papilar/metabolismo , Cistadenocarcinoma Papilar/patologia , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Durapatita/metabolismo , Feminino , Humanos , Corpos de Inclusão/metabolismo , Corpos de Inclusão/microbiologia , Corpos de Inclusão/patologia , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Espectrofotometria Infravermelho
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