Altered cervicovaginal microbiota in premenopausal ovarian cancer patients.

Nearly three hundred thousand female patients are diagnosed with ovarian cancer in the world annually, and this number shows an increasing trend. However, characteristic symptoms caused by ovarian cancer are so few that early diagnosis remains challenging, and an effective screening method has not yet been established. Here, we conducted a case-control study in Japan to analyze the association between cervicovaginal microbiome and ovarian cancer, using 16S rRNA amplicon sequencing. Analysis of DNA extracted from cervical smear samples revealed Lactobacillus-dominant and Lactobacillus-deficient, highly-diversified bacterial communities in premenopausal and postmenopausal healthy controls, respectively, as reported for vaginal microbiota previously. We found that cervicovaginal microbiota in ovarian cancer patients, regardless of their menopausal status, were frequently a diversified community and similar to those in healthy subjects at postmenopausal ages. The diverse microbiota was associated with the major histotypes of epithelial ovarian cancer, including serous ovarian cancer and ovarian clear cell cancer. The present study implies the potential of a cervicovaginal microbiome biomarker in screening ovarian cancer in premenopausal women.

Altering the Microbiome Inhibits Tumorigenesis in a Mouse Model of Oviductal High-Grade Serous Carcinoma.

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.

The role of the microbiome in ovarian cancer: mechanistic insights into oncobiosis and to bacterial metabolite signaling.

Ovarian cancer is characterized by dysbiosis, referred to as oncobiosis in neoplastic diseases. In ovarian cancer, oncobiosis was identified in numerous compartments, including the tumor tissue itself, the upper and lower female genital tract, serum, peritoneum, and the intestines. Colonization was linked to Gram-negative bacteria with high inflammatory potential. Local inflammation probably participates in the initiation and continuation of carcinogenesis. Furthermore, local bacterial colonies in the peritoneum may facilitate metastasis formation in ovarian cancer. Vaginal infections (e.g. Neisseria gonorrhoeae or Chlamydia trachomatis) increase the risk of developing ovarian cancer. Bacterial metabolites, produced by the healthy eubiome or the oncobiome, may exert autocrine, paracrine, and hormone-like effects, as was evidenced in breast cancer or pancreas adenocarcinoma. We discuss the possible involvement of lipopolysaccharides, lysophosphatides and tryptophan metabolites, as well as, short-chain fatty acids, secondary bile acids and polyamines in the carcinogenesis of ovarian cancer. We discuss the applicability of nutrients, antibiotics, and probiotics to harness the microbiome and support ovarian cancer therapy. The oncobiome and the most likely bacterial metabolites play vital roles in mediating the effectiveness of chemotherapy. Finally, we discuss the potential of oncobiotic changes as biomarkers for the diagnosis of ovarian cancer and microbial metabolites as possible adjuvant agents in therapy.

An Evaluation of the Fecal Microbiome in Lynch Syndrome.

PURPOSE: There is limited data regarding the fecal microbiome findings in patients with Lynch syndrome. We aimed to study the fecal micobiome of patients with Lynch syndrome with and without cancer. METHODS: We performed an observational study comparing the fecal microbiome of patients with Lynch syndrome (LS) with cancer with those without cancer. We included subjects older than 18 years with LS and excluded those with a history of colectomy or inflammatory bowel disease. We analyzed their fecal microbiome by 16S ribosomal subunit PCR amplification and performed comparative analyses. RESULTS: Eight patients were included: 3 of these with LS and cancer (LS-C) and 5 patients with LS and no cancer (LS-NC). We found non-significant differences at the phyla and genera level between the LS-C and LS-NC groups. At the phyla level, LS-C patients had a higher percentage of Bacteroidetes (42.2% vs. 28.5%; P = 0.068) and Verrucomicrobia (0.644% vs 0.0007%; P = 0.10), and a lower percentage of Firmicutes (48.3% vs. 65.4%; P = 0.078). At the genus level, LS-C patients had a higher rate of Akkermania (0.766% vs. 0.001%; P = 0.11). LS-C patients with endometrial cancer had a higher rate of Bacteroides (37.4% vs 17.3%; P = 0.10). LS-C patients had a lower rate of Pseudobutyrvibrio (0.74% vs. 2.71%; P = 0.10). CONCLUSIONS: The fecal microbiome of LS patients with extraintestinal cancer differs that of LS patients without cancer. Further studies are needed to explore microbiome changes in these high risk patients.

Neisseria macacae bacteremia: report of two cases with a literature review.

BACKGROUND: Neisseria macacae was discovered in the oral cavity of monkeys in 1983. In humans, it has been isolated from the upper respiratory tract of neutropenic patients. However, only two cases of N. macacae bacteremia have been reported in a 65-year-old man with infective endocarditis and a 5-month-old child with fever and petechiae. There are no reports of infections in cancer patients. Here, we present two cases of N. macacae bacteremia in cancer patients. CASE PRESENTATION: In the first case, a 42-year-old woman who underwent ovarian cancer surgery presented with duodenal invasion associated with multiple lymph node metastasis. N. macacae was isolated from her blood culture and identified using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS). In the second case, a 69-year-old woman with a long-standing history of esophagogastric junction cancer presented with fever. She had stage IVB cancer with lung, bone, and multiple lymph node metastasis. The last chemotherapy was administered 5 weeks before N. macacae was detected using MALDI-TOF MS and nitrate test negative. In both cases, transthoracic echography showed no vegetation. Antibiotics were administered for 14 and 13 days in the first and second cases, respectively. In both cases, fever alleviated on day 4 of antibiotic administration. Both patients were discharged after their conditions improved. CONCLUSIONS: This, to our knowledge, is the first report of N. macacae bacteremia in cancer patients. Both patients, mucosal damage was observed in the upper gastrointestinal tract. Therefore, exclusion diagnosis suggested that bacteremia invasion was caused by mucosal rupture in both cases. Both cases responded well to treatment with ß-lactam antibiotics and improved after 2 weeks. Modifying the treatment based on the source of the infection may shorten the treatment period. Therefore, further research on N. macacae bacteremia is necessary. Immunocompromised patients such as those with cancer are susceptible to mucosal damage by unusual bacterial species such as N. macacae despite not having contact with monkeys.

Association between the microbiota and women's cancers - Cause or consequences?

Breast, ovarian and uterine cancers are the most common neoplasms among women. Several mechanisms may be involved in oncogenesis and these include environmental and genetic factors. Bacteria may affect the development of some cancers, with bacterial components, their products and metabolites interacting with susceptible tissues. Commensalism and dysbiosis are important potential mechanisms involved in oncogenesis, and an effective strategy for diagnosis and treatment is required. The purpose of this review was to analyze the complex associations between these cancers in women, and the microbiota, specifically bacterial microbes. However, several cancers have an increased prevalence among individuals with HIV and HPV so the relationship between viral infections and malignancies in women is also referred to. We described how different phylum of bacteria, particularly in the gut, mammary tissue and vaginal microbiome may be involved in carcinogenesis; and we discuss the potential pathways involved: (I), that lead to cell proliferation, (II), immune system perturbation, (III), cell metabolic changes (e.g., hormonal factors), and (IV), DNA damage. Studies investigating the differences between the composition of the bacterial microbiota of healthy women compared to that present in various conditions, and the clinical trials are summarized for the few studies that have addressed the microbiota and related conditions, are also reviewed.

Assessment of peritoneal microbial features and tumor marker levels as potential diagnostic tools for ovarian cancer.

Epithelial ovarian cancer (OC) is the most deadly cancer of the female reproductive system. To date, there is no effective screening method for early detection of OC and current diagnostic armamentarium may include sonographic grading of the tumor and analyzing serum levels of tumor markers, Cancer Antigen 125 (CA-125) and Human epididymis protein 4 (HE4). Microorganisms (bacterial, archaeal, and fungal cells) residing in mucosal tissues including the gastrointestinal and urogenital tracts can be altered by different disease states, and these shifts in microbial dynamics may help to diagnose disease states. We hypothesized that the peritoneal microbial environment was altered in patients with OC and that inclusion of selected peritoneal microbial features with current clinical features into prediction analyses will improve detection accuracy of patients with OC. Blood and peritoneal fluid were collected from consented patients that had sonography confirmed adnexal masses and were being seen at SIU School of Medicine Simmons Cancer Institute. Blood was processed and serum HE4 and CA-125 were measured. Peritoneal fluid was collected at the time of surgery and processed for Next Generation Sequencing (NGS) using 16S V4 exon bacterial primers and bioinformatics analyses. We found that patients with OC had a unique peritoneal microbial profile compared to patients with a benign mass. Using ensemble modeling and machine learning pathways, we identified 18 microbial features that were highly specific to OC pathology. Prediction analyses confirmed that inclusion of microbial features with serum tumor marker levels and control features (patient age and BMI) improved diagnostic accuracy compared to currently used models. We conclude that OC pathogenesis alters the peritoneal microbial environment and that these unique microbial features are important for accurate diagnosis of OC. Our study warrants further analyses of the importance of microbial features in regards to oncological diagnostics and possible prognostic and interventional medicine.

The differential distribution of bacteria between cancerous and noncancerous ovarian tissues in situ.

BACKGROUND: With the improvement of bacterial detection, the theory of the sterile female upper reproductive tract has been frequently challenged in recent years. However, thus far, no researchers have used ovaries as study targets. METHODS: Six women who were diagnosed with ovarian cancer were included in the cancer group, and ten women who were diagnosed with a noncancerous ovarian condition (including three patients with uterine myoma and seven patients with uterine adenomyosis) were included in the control group. Immunohistochemistry staining using an antibacterial lipopolysaccharide (LPS) antibody was used to confirm the presence of bacteria in the ovarian tissues. In addition, 16S rRNA sequencing was used to compare the differences in the bacteria between ovarian cancer tissues and noncancerous ovarian tissues. BugBase and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) were used to predict the functional composition of the bacteria. RESULTS: Bacterial LPS was present in ovarian cancer tissue and noncancerous ovarian tissue, which implied the presence of bacteria in ovarian tissue. When compared to the noncancerous ovarian bacteria at the phylum level, the cancerous ovarian bacteria were composed of increased Aquificae and Planctomycetes and decreased Crenarchaeota. When predicting metagenomes, gene functions associated with the potentially pathogenic and the oxidative stress-tolerant phenotype were enriched in the ovaries of the cancer group. Forty-six significantly different KEGG pathways existed in the ovarian bacteria of the cancer group compared to that of the control group. CONCLUSIONS: Different bacteria compositions were present in cancerous and noncancerous ovarian tissues. TRIAL REGISTRATION: Chines Clinical Trail Registry, CHiCTR1800020018, Registered 11 September 2018, http://www.chictr.org.cn/.

Multiresistent opportunistic talaromycosis in a patient with ovarian cancer.

BACKGROUND: Talaromycosis (penicillinosis) is multiresistent opportunistic mycosis. The infection can be inapparent and it can simmulate malignant tumor dissemination in some patients. CASE: We present a case of 33-years-old patient with mucinous adenocarcinoma of left ovary, initially FIGO IIC. The patient had had hysterectomy, bilateral adnexectomy, omentectomy and port-site metastasis extirpation. Six cycles of 1st chemother-apy paclitaxel and carboplatin had been administered to patient follow-ing the surgery. Positron emission tomography / computed tomography (PET/CT) scan after the treatment, had shown metabolic activity infiltrat-ing both lung apexes, supposedly with no dis-ease correlation, and hypermetabolic foci in spleen, suspicious of be-ing metastases. Pa-cient showed no clinical symp-toms, nor markers of inflammation elevation. Initially elevated serum tumor markers CA125 and CA72-4 had decreased after the treatment. Bronchoalveolar lavage cytology described presence of inflammatory infiltration with fungiform-ing hyphae - most probably an aspergillosis. Mannan and galactomannan serology was negative. In regard to splenectomy plans, treatment with voriconazol was initiated empirically. Result of fungi cultivation out of bronchoalveolar lavage was finalized later, show-ing sporadic presence o Penicillium sp. with resistance to antimycotic treatment except for amphotericin B. Liposomal amphotericin B treatment was administered in two cures, 28 days in total. Immunomodulatory treatment of secondary cellular immunodeficiency and vaccination against encapsulated bacteria was given to the patient. Splenectomy was performed 6 months after the end of chemother-apy treatment. Histopathology showed chronic granulomatous inflammation without mycotic hyphae, with no evidence of tumor cells. After the splenectomy, patient was treated by surgical incision and drainage and by klindamycin for intraabdominal abscess in left hypogastric area. CONCLUSION: Patient is under follow up by oncologist, immunologist and gynecologist 12 months after the splenectomy, she is surveilled by PET/CT and serum tumor markers. Talaromycosis can be clinically inapparent in spite of its dissemination. It can be present in diffuse, granulomatous and mixed form. Therapeutic agent is sometimes limited to amphotericin B due to its resistence. Liposomal form of amphotericin B is recommended regard-ing its pharmacokinetic properties. In case of dissemination, administration period of more than 14 days is recommended, even in inapparent form. Immunomodulatory treatment is recommended due to opportunistic infection.

Association between the cervicovaginal microbiome, BRCA1 mutation status, and risk of ovarian cancer: a case-control study.

BACKGROUND: Various factors-including age, family history, inflammation, reproductive factors, and tubal ligation-modulate the risk of ovarian cancer. In this study, our aim was to establish whether women with, or at risk of developing, ovarian cancer have an imbalanced cervicovaginal microbiome. METHODS: We did a case-control study in two sets of women aged 18-87 years in the Czech Republic, Germany, Italy, Norway, and the UK. The ovarian cancer set comprised women with epithelial ovarian cancer and controls (both healthy controls and those diagnosed with benign gynaecological conditions). The BRCA set comprised women with a BRCA1 mutation but without ovarian cancer and controls who were wild type for BRCA1 and BRCA2 (both healthy controls and those with benign gynaecological conditions). Cervicovaginal samples were gathered from all participants with the ThinPrep system and then underwent 16S rRNA gene sequencing. For each sample, we calculated the proportion of lactobacilli species (ie, Lactobacillus crispatus, Lactobacillus iners, Lactobacillus gasseri, and Lactobacillus jensenii), which are essential for the generation of a protective low vaginal pH, in the cervicovaginal microbiota. We grouped samples into those in which lactobacilli accounted for at least 50% of the species present (community type L) and those in which lactobacilli accounted for less than 50% of the species present (community type O). We assessed the adjusted association between BRCA1 status and ovarian cancer status and cervicovaginal microbiota community type, using a logistic regression model with a bias reduction method. FINDINGS: Participants were recruited between Jan 2, 2016, and July 21, 2018. The ovarian cancer set (n=360) comprised 176 women with epithelial ovarian cancer, 115 healthy controls and 69 controls with benign gynaecological conditions. The BRCA set (n=220) included 109 women with BRCA1 mutations, 97 healthy controls wild type for BRCA1 and BRCA2 and 14 controls with a benign gynaecological condition wild type for BRCA1 and BRCA2. On the basis of two-dimensional density plots, receiver-operating characteristic curve analysis, and age thresholds used previously, we divided the cohort into those younger than 50 years and those aged 50 years or older. In the ovarian cancer set, women aged 50 years or older had a higher prevalence of community type O microbiota (81 [61%] of 133 ovarian cancer cases and 84 [59%] of 142 healthy controls) than those younger than 50 years (23 [53%] of 43 cases and 12 [29%] of 42 controls). In the ovarian cancer set, women younger than 50 years with ovarian cancer had a significantly higher prevalence of community type O microbiota than did age-matched controls under a logistic regression model with bias correction (odds ratio [OR] 2·80 [95% CI 1·17-6·94]; p=0·020). In the BRCA set, women with BRCA1 mutations younger than 50 years were also more likely to have community type O microbiota than age-matched controls (OR 2·79 [95% CI 1·25-6·68]; p=0·012), after adjustment for pregnancy (ever). This risk was increased further if more than one first-degree family member was affected by any cancer (OR 5·26 [95% CI 1·83-15·30]; p=0·0022). In both sets, we noted that the younger the participants, the stronger the association between community type O microbiota and ovarian cancer or BRCA1 mutation status (eg, OR for community type O for cases aged <40 years in the ovarian cancer set 7·00 [95% CI 1·27-51·44], p=0·025; OR for community type O for BRCA1 mutation carriers aged <35 years in the BRCA set 4·40 [1·14-24·36], p=0·031). INTERPRETATION: The presence of ovarian cancer, or factors known to affect risk for the disease (ie, age and BRCA1 germline mutations), were significantly associated with having a community type O cervicovaginal microbiota. Whether re-instatement of a community type L microbiome by using, for example, vaginal suppositories containing live lactobacilli, would alter the microbiomial composition higher up in the female genital tract and in the fallopian tubes (the site of origin of high-grade serous ovarian cancer), and whether such changes could translate into a reduced incidence of ovarian cancer, needs to be investigated. FUNDING: EU Horizon 2020 Research and Innovation Programme, EU Horizon 2020 European Research Council Programme, and The Eve Appeal.

Chronic Chlamydia infection in human organoids increases stemness and promotes age-dependent CpG methylation.

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.

The biodiversity Composition of Microbiome in Ovarian Carcinoma Patients.

Ovarian carcinoma is caused by multiple factors, but its etiology associated with microbes and infection is unknown. Using 16S rRNA high-throughput sequencing methods, the diversity and composition of the microbiota from ovarian cancer tissues (25 samples) and normal distal fallopian tube tissues (25 samples) were analyzed. High-throughput sequencing showed that the diversity and richness indexes were significantly decreased in ovarian cancer tissues compared to tissues from normal distal fallopian tubes. The ratio of the two phyla for Proteobacteria/Firmicutes was notably increased in ovarian cancer, which revealed that microbial composition change might be associated with the process of ovarian cancer development. In addition, transcriptome-sequencing (RNA-seq) analyses suggested that the transcriptional profiles were statistically different between ovarian carcinoma and normal distal fallopian tubes. Moreover, a set of genes including 84 different inflammation-associated or immune-associated genes, which had been named as the human antibacterial-response genes were also modulated expression. Therefore, we hypothesize that the microbial composition change, as a novel risk factor, may be involving the initiation and progression of ovarian cancer via influencing and regulating the local immune microenvironment of fallopian tubes except for regular pathways.

Mycobacterium mucogenicum bacteremia: major role of clinical microbiologists.

INTRODUCTION: Mycobacterium mucogenicum is a rare but emerging cause of infections, especially in immunocompromised patients. CASE PRESENTATION: We describe a new case of M. mucogenicum catheter-related bloodstream infection in a 34-year-old woman with ovarian cancer. M. mucogenicum was at first considered as a contaminant, and susceptibility testing was not performed. Usual susceptibility of M. mucogenicum motivated prescription of clarithromycin and moxifloxacin. Finally, our isolate was confirmed susceptible to both drugs. Clinical outcome was favorable with no relapse of infection after antibiotics discontinuation despite concomitant chemotherapy. CONCLUSION: Our case illustrates the need for a clinician-microbiologist dialogue in case of suspected M. mucogenicum infection to avoid delaying appropriate management.

Rare cause of ovarian mass.

Pelvic actinomycosis is a rare entity that occurs almost exclusively in women, the presentation of which is usually non-specific and variable. Pelvic actinomycosis is almost always associated with the use of an intrauterine contraceptive device (IUD). Pelvic actinomycosis unrelated to IUD use is almost always associated with previous surgical procedures. The symptoms, clinical signs and radiological findings are usually non-specific, mimicking an ovarian malignancy. So an awareness of this rare condition and a proper diagnosis can avoid unnecessary surgeries because these cases can be treated with a prolonged course of antibiotics. We present a case of pelvic actinomycosis which masqueraded as an ovarian malignancy.

Frontline Science: Microbiota reconstitution restores intestinal integrity after cisplatin therapy.

Due to their cytotoxic activities, many anticancer drugs cause extensive damage to the intestinal mucosa and have antibiotic activities. Here, we show that cisplatin induces significant changes in the repertoire of intestinal commensal bacteria that exacerbate mucosal damage. Restoration of the microbiota through fecal-pellet gavage drives healing of cisplatin-induced intestinal damage. Bacterial translocation to the blood stream is correspondingly abrogated, resulting in a significant reduction in systemic inflammation, as evidenced by decreased serum IL-6 and reduced mobilization of granulocytes. Mechanistically, reversal of dysbiosis in response to fecal gavage results in the production of protective mucins and mobilization of CD11b+ myeloid cells to the intestinal mucosa, which promotes angiogenesis. Administration of Ruminococcus gnavus, a bacterial strain selectively depleted by cisplatin treatment, could only partially restore the integrity of the intestinal mucosa and reduce systemic inflammation, without measurable increases in the accumulation of mucin proteins. Together, our results indicate that reconstitution of the full repertoire of intestinal bacteria altered by cisplatin treatment accelerates healing of the intestinal epithelium and ameliorates systemic inflammation. Therefore, fecal microbiota transplant could paradoxically prevent life-threatening bacteremia in cancer patients treated with chemotherapy.

Acoustic reporter genes for noninvasive imaging of microorganisms in mammalian hosts.

The mammalian microbiome has many important roles in health and disease, and genetic engineering is enabling the development of microbial therapeutics and diagnostics. A key determinant of the activity of both natural and engineered microorganisms in vivo is their location within the host organism. However, existing methods for imaging cellular location and function, primarily based on optical reporter genes, have limited deep tissue performance owing to light scattering or require radioactive tracers. Here we introduce acoustic reporter genes, which are genetic constructs that allow bacterial gene expression to be visualized in vivo using ultrasound, a widely available inexpensive technique with deep tissue penetration and high spatial resolution. These constructs are based on gas vesicles, a unique class of gas-filled protein nanostructures that are expressed primarily in water-dwelling photosynthetic organisms as a means to regulate buoyancy. Heterologous expression of engineered gene clusters encoding gas vesicles allows Escherichia coli and Salmonella typhimurium to be imaged noninvasively at volumetric densities below 0.01% with a resolution of less than 100 µm. We demonstrate the imaging of engineered cells in vivo in proof-of-concept models of gastrointestinal and tumour localization, and develop acoustically distinct reporters that enable multiplexed imaging of cellular populations. This technology equips microbial cells with a means to be visualized deep inside mammalian hosts, facilitating the study of the mammalian microbiome and the development of diagnostic and therapeutic cellular agents.

The ovarian cancer oncobiome.

Humans and other mammals are colonized by microbial agents across the kingdom which can represent a unique microbiome pattern. Dysbiosis of the microbiome has been associated with pathology including cancer. We have identified a microbiome signature unique to ovarian cancers, one of the most lethal malignancies of the female reproductive system, primarily because of its asymptomatic nature during the early stages in development. We screened ovarian cancer samples along with matched, and non-matched control samples using our pan-pathogen array (PathoChip), combined with capture-next generation sequencing. The results show a distinct group of viral, bacterial, fungal and parasitic signatures of high significance in ovarian cases. Further analysis shows specific viral integration sites within the host genome of tumor samples, which may contribute to the carcinogenic process. The ovarian cancer microbiome signature provides insights for the development of targeted therapeutics against ovarian cancers.

Iron overload and altered iron metabolism in ovarian cancer.

Iron is an essential element required for many processes within the cell. Dysregulation in iron homeostasis due to iron overload is detrimental. This nutrient is postulated to contribute to the initiation of cancer; however, the mechanisms by which this occurs remain unclear. Defining how iron promotes the development of ovarian cancers from precursor lesions is essential for developing novel therapeutic strategies. In this review, we discuss (1) how iron overload conditions may initiate ovarian cancer development, (2) dysregulated iron metabolism in cancers, (3) the interplay between bacteria, iron, and cancer, and (4) chemotherapeutic strategies targeting iron metabolism in cancer patients.

Distinguishing potential bacteria-tumor associations from contamination in a secondary data analysis of public cancer genome sequence data.

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.

Intraperitoneal administration of tumor-targeting Salmonella typhimurium A1-R inhibits disseminated human ovarian cancer and extends survival in nude mice.

UNLABELLED: Peritoneal disseminated cancer is highly treatment resistant. We here report the efficacy of intraperitoneal (i.p.) administration of tumor-targeting Salmonella typhimurium A1-R in a nude mouse model of disseminated human ovarian cancer. The mouse model was established by intraperitoneal injection of the human ovarian cancer cell line SKOV3-GFP. Seven days after implantation, mice were treated with S. typhimurium A1-R via intravenous (i.v.) or i.p. administration at the same dose, 5 × 10(7) CFU, once per week. Both i.v. and i.p. treatments effected prolonged survival compared with the untreated control group (P=0.025 and P<0.001, respectively). However, i.p. treatment was less toxic than i.v. TREATMENT: Tumor-specific targeting of S. typhimurium A1-R was confirmed with bacterial culture from tumors and various organs and tumor or organ colony formation after i.v. or i.p. injection. Selective tumor targeting was most effective with i.p. administration. The results of the present study show S. typhimurium A1-R has promising clinical potential for disseminated ovarian cancer, especially via i.p. administration.