Metabolomic credentialing of murine carcinogen-induced urothelial cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Afify H
PROVIDER: S-EPMC8585868 | biostudies-literature | 2021 Nov
REPOSITORIES: biostudies-literature
Publications
Metabolomic credentialing of murine carcinogen-induced urothelial cancer.
Afify Hesham H Ghoneum Alia A Almousa Sameh S Abdulfattah Ammar Yasser AY Warren Bailey B Langsten Kendall K Gonzalez Daniela D Casals Randy R Bharadwaj Manish M Kridel Steven S Said Neveen N
Scientific reports 20211111 1
Bladder cancer (BCa) is the most common malignancy of the urinary system with increasing incidence, mortality, and limited treatment options. Therefore, it is imperative to validate preclinical models that faithfully represent BCa cellular, molecular, and metabolic heterogeneity to develop new therapeutics. We performed metabolomic profiling of premalignant and non-muscle invasive bladder cancer (NMIBC) that ensued in the chemical carcinogenesis N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse ...[more]
Similar Datasets
Project description:Radiation and bacillus Calmette-Guérin (BCG) instillations are used clinically for treatment of urothelial carcinoma, but the precise mechanisms by which they activate an immune response remain elusive. The role of the cGAS-STING pathway has been implicated in both BCG and radiation-induced immune response; however, comparison of STING pathway molecules and the immune landscape following treatment in urothelial carcinoma has not been performed. We therefore comprehensively analyzed the local immune response in the bladder tumor microenvironment following radiotherapy and BCG instillations in a well-established spontaneous murine model of urothelial carcinoma to provide insight into activation of STING-mediated immune response. Mice were exposed to the oral carcinogen, BBN, for 12 weeks prior to treatment with a single 15 Gy dose of radiation or three intravesical instillations of BCG (1 × 108 CFU). At sacrifice, tumors were staged by a urologic pathologist and effects of therapy on the immune microenvironment were measured using the NanoString Myeloid Innate Immunity Panel and immunohistochemistry. Clinical relevance was established by measuring immune biomarker expression of cGAS and STING on a human tissue microarray consisting of BCG-treated non-muscle-invasive urothelial carcinomas. BCG instillations in the murine model elevated STING and downstream STING-induced interferon and pro-inflammatory molecules, intratumoral M1 macrophage and T-cell accumulation, and complete tumor eradication. In contrast, radiotherapy caused no changes in STING pathway or innate immune gene expression; rather, it induced M2 macrophage accumulation and elevated FoxP3 expression characteristic of immunosuppression. In human non-muscle-invasive bladder cancer, STING protein expression was elevated at baseline in patients who responded to BCG therapy and increased further after BCG therapy. Overall, these results show that STING pathway activation plays a key role in effective BCG-induced immune response and strongly indicate that the effects of BCG on the bladder cancer immune microenvironment are more beneficial than those induced by radiation. © 2021 The Pathological Society of Great Britain and Ireland.
| S-EPMC8738146 | biostudies-literature
Project description:Oral cancer is one of the most common cancers worldwide and ranks fourth for the mortality rate of cancers in males in Taiwan. The oral microbiota is the microbial community in the oral cavity, which is essential for maintaining oral health, but the relationship between oral tumorigenesis and the oral microbiota remains to be clarified. This study evaluated the effect of microbiome dysbiosis on oral carcinogenesis in mice, and the impact of the microbiome and its metabolic pathways on regulating oral carcinogenesis. We found that antibiotics treatment decreases carcinogen-induced oral epithelial malignant transformation. Microbiome analysis based on 16S rRNA gene sequencing revealed that the species richness of fecal specimens was significantly reduced in antibiotic-treated mice, while that in the salivary specimens was not decreased accordingly. Differences in bacterial composition, including Lactobacillus animalis abundance, in the salivary samples of cancer-bearing mice was dramatically decreased. L. animalis was the bacterial species that increased the most in the saliva of antibiotic-treated mice, suggesting that L. animalis may be negatively associated with oral carcinogenesis. In functional analysis, the microbiome in the saliva of the tumor-bearing group showed greater potential for polyamine biosynthesis. Immunochemical staining proved that spermine oxidase, an effective polyamine oxidase, was upregulated in mouse oral cancer lesions. In conclusion, oral microbiome dysbiosis may alter polyamine metabolic pathways and reduce carcinogen-induced malignant transformation of the oral epithelium.
| S-EPMC9414028 | biostudies-literature
Project description:The aim of untargeted metabolomics is to profile as many metabolites as possible, yet a major challenge is comparing experimental method performance on the basis of metabolome coverage. To date, most published approaches have compared experimental methods by counting the total number of features detected. Due to artifactual interference, however, this number is highly variable and therefore is a poor metric for comparing metabolomic methods. Here we introduce an alternative approach to benchmarking metabolome coverage which relies on mixed Escherichia coli extracts from cells cultured in regular and (13)C-enriched media. After mass spectrometry-based metabolomic analysis of these extracts, we "credential" features arising from E. coli metabolites on the basis of isotope spacing and intensity. This credentialing platform enables us to accurately compare the number of nonartifactual features yielded by different experimental approaches. We highlight the value of our platform by reoptimizing a published untargeted metabolomic method for XCMS data processing. Compared to the published parameters, the new XCMS parameters decrease the total number of features by 15% (a reduction in noise features) while increasing the number of true metabolites detected and grouped by 20%. Our credentialing platform relies on easily generated E. coli samples and a simple software algorithm that is freely available on our laboratory Web site (http://pattilab.wustl.edu/software/credential/). We have validated the credentialing platform with reversed-phase and hydrophilic interaction liquid chromatography as well as Agilent, Thermo Scientific, AB SCIEX, and LECO mass spectrometers. Thus, the credentialing platform can readily be applied by any laboratory to optimize their untargeted metabolomic pipeline for metabolite extraction, chromatographic separation, mass spectrometric detection, and bioinformatic processing.
| S-EPMC4188275 | biostudies-literature
Project description:Chemical agents can cause cancer in animals by damaging their DNA, mutating their genes, and modifying their epigenetic signatures. Carcinogen-induced preclinical cancer models are useful for understanding carcinogen-induced human cancers, as they can reproduce the diversity and complexity of tumor types, as well as the interactions with the host environment. However, these models also have some drawbacks that limit their applicability and validity. For instance, some chemicals may be more effective or toxic in animals than in humans, and the tumors may differ in their genetics and phenotypes. Some chemicals may also affect normal cells and tissues, such as by causing oxidative stress, inflammation, and cell death, which may alter the tumor behavior and response to therapy. Furthermore, some chemicals may have variable effects depending on the exposure conditions, such as dose, route, and duration, as well as the animal characteristics, such as genetics and hormones. Therefore, these models should be carefully chosen, validated, and standardized, and the results should be cautiously interpreted and compared with other models. This review covers the main features of chemically induced cancer models, such as genetic and epigenetic changes, tumor environment, angiogenesis, invasion and metastasis, and immune response. We also address the pros and cons of these models and the current and future challenges for their improvement. This review offers a comprehensive overview of the state of the art of carcinogen-induced cancer models and provides new perspectives for cancer research.
| S-EPMC10801516 | biostudies-literature
Project description:Immunization with effective cancer vaccines can offer a much needed adjuvant therapy to fill the treatment gap after liver resection to prevent relapse of hepatocellular carcinoma (HCC). However, current HCC cancer vaccines are mostly based on native shared-self/tumor antigens that are only able to induce weak immune responses. In this study we investigated whether the HCC-associated self/tumor antigen of alpha-fetoprotein (AFP) could be engineered to create an effective vaccine to break immune tolerance and potently activate CD8 T cells to prevent clinically relevant carcinogen-induced autochthonous HCC in mice. We found that the approach of computer-guided methodical epitope-optimization created a highly immunogenic AFP and that immunization with lentivector expressing the epitope-optimized AFP, but not wild-type AFP, potently activated CD8 T cells. Critically, the activated CD8 T cells not only cross-recognized short synthetic wild-type AFP peptides, but also recognized and killed tumor cells expressing wild-type AFP protein. Immunization with lentivector expressing optimized AFP, but not native AFP, completely protected mice from tumor challenge and reduced the incidence of carcinogen-induced autochthonous HCC. In addition, prime-boost immunization with the optimized AFP significantly increased the frequency of AFP-specific memory CD8 T cells in the liver that were highly effective against emerging HCC tumor cells, further enhancing the tumor prevention of carcinogen-induced autochthonous HCC.Epitope-optimization is required to break immune tolerance and potently activate AFP-specific CD8 T cells, generating effective antitumor effect to prevent clinically relevant carcinogen-induced autochthonous HCC in mice. Our study provides a practical roadmap to develop effective human HCC vaccines that may result in an improved outcome compared to the current HCC vaccines based on wild-type AFP.
| S-EPMC4151349 | biostudies-literature
Project description:Radiation and BCG instillations are used clinically for treatment of urothelial carcinoma, but the precise mechanisms by which they activate an immune response remain elusive. The role of the cGAS-STING pathway has been implicated in both BCG and radiation-induced immune response however comparison of STING-pathway molecules and immune landscape following treatment in urothelial carcinoma has not be performed. We therefore comprehensively analyzed the local immune response in the bladder tumor microenvironment following radiotherapy and BCG instillations in a well-established spontaneous murine model of urothelial carcinoma to provide insight into activation of STING-mediated immune response. Mice were exposed to the oral carcinogen, BBN, for 12 weeks prior to treatment with a single 15Gy dose of radiation or 3 intravesical instillations of BCG (1x108 CFU). At sacrifice, tumors were staged by a urologic pathologist and effects of therapy on the immune microenvironment were measured using NanoString Myeloid Innate Immunity Panel and immunohistochemistry. Clinical relevance was established by measuring immune biomarker expression of cGAS and STING on a human tissue microarray consisting of BCG-treated non-muscle invasive urothelial carcinomas. BCG instillations in the murine model elevated STING and downstream STING-induced interferon and pro-inflammatory molecules, intratumoral M1 macrophage and T-cell accumulation, and complete tumor eradication. In contrast, radiotherapy caused no changes in STING pathway or innate immune gene expression; rather, it induced M2 macrophage accumulation and elevated FoxP3 expression characteristic of immunosuppression. In human non-muscle invasive bladder cancer, STING protein expression was elevated at baseline in patients who responded to BCG therapy and increased further after BCG therapy. Overall, these results show that STING pathway activation plays a key role in effective BCG-induced immune response and strongly indicate that the effects of BCG on the bladder cancer immune microenvironment are more beneficial than those induced by radiation.
2021-10-30 | GSE186737 | GEO
Project description:Chronic exposure to carcinogens represents the major risk factor for head and neck squamous cell carcinoma (HNSCC). Beverages derived from broccoli sprout extracts (BSE) that are rich in glucoraphanin and its bioactive metabolite sulforaphane promote detoxication of airborne pollutants in humans. Herein, we investigated the potential chemopreventive activity of sulforaphane using in vitro models of normal and malignant mucosal epithelial cells and an in vivo model of murine oral cancer resulting from the carcinogen 4-nitroquinoline-1-oxide (4NQO). Sulforaphane treatment of Het-1A, a normal mucosal epithelial cell line, and 4 HNSCC cell lines led to dose- and time-dependent induction of NRF2 and the NRF2 target genes NQO1 and GCLC, known mediators of carcinogen detoxication. Sulforaphane also promoted NRF2-independent dephosphorylation/inactivation of pSTAT3, a key oncogenic factor in HNSCC. Compared with vehicle, sulforaphane significantly reduced the incidence and size of 4NQO-induced tongue tumors in mice. A pilot clinical trial in 10 healthy volunteers evaluated the bioavailability and pharmacodynamic activity of three different BSE regimens, based upon urinary sulforaphane metabolites and NQO1 transcripts in buccal scrapings, respectively. Ingestion of sulforaphane-rich BSE demonstrated the greatest, most consistent bioavailability. Mucosal bioactivity, defined as 2-fold or greater upregulation of NQO1 mRNA, was observed in 6 of 9 evaluable participants ingesting glucoraphanin-rich BSE; 3 of 6 ingesting sulforaphane-rich BSE; and 3 of 9 after topical-only exposure to sulforaphane-rich BSE. Together, our findings demonstrate preclinical chemopreventive activity of sulforaphane against carcinogen-induced oral cancer, and support further mechanistic and clinical investigation of sulforaphane as a chemopreventive agent against tobacco-related HNSCC. Cancer Prev Res; 9(7); 547-57. ©2016 AACR.
| S-EPMC4930727 | biostudies-literature
Project description:Human adenocarcinoma (AC) is the most frequently diagnosed human lung cancer, and its absolute incidence is increasing dramatically. Compared to human lung AC, the A/J mouse-urethane model exhibits similar histological appearance and molecular changes. We examined the gene expression profiles of human and murine lung tissues (normal or AC) and compared the two species' datasets after aligning approximately 7500 orthologous genes. A list of 409 gene classifiers (P value <0.0001), common to both species (joint classifiers), showed significant, positive correlation in expression levels between the two species. A number of previously reported expression changes were recapitulated in both species, such as changes in glycolytic enzymes and cell-cycle proteins. Unexpectedly, joint classifiers in angiogenesis were uniformly down-regulated in tumor tissues. The eicosanoid pathway enzymes prostacyclin synthase (PGIS) and inducible prostaglandin E(2) synthase (PGES) were joint classifiers that showed opposite effects in lung AC (PGIS down-regulated; PGES up-regulated). Finally, tissue microarrays identified the same protein expression pattern for PGIS and PGES in 108 different non-small cell lung cancer biopsies, and the detection of PGIS had statistically significant prognostic value in patient survival. Thus, the A/J mouse-urethane model reflects significant molecular details of human lung AC, and comparison of changes in orthologous gene expression may provide novel insights into lung carcinogenesis.
| S-EPMC1613183 | biostudies-literature
Project description:Inflammatory conditions elicited by extrinsic environmental factors promote malignant cell transformation, tumor growth, and metastasis. Although most attention has been focused on innate immune mechanisms of inflammatory carcinogenesis, more recently the role of T cells in cancer promotion has been examined. Although IFN-dependent Th1 responses that promote Stat1 signaling inhibit tumor growth, the role of T helper type 17 responses, and interleukin-17 (IL-17) in particular, has been controversial. Indeed, IL-17 has been reported to either enhance or inhibit the growth of transplantable tumors, depending on the system. Little is known about the role of IL-17 in de novo carcinogenesis. Using IL-17 knockout mice, we examined the role of IL-17 in the classic DMBA/TPA-induced skin carcinogenesis model. Disruption of IL-17 dramatically reduced tumorigenesis in this model in a manner correlated with diminished Stat3 activation in the tumor microenvironment. IL-17 loss reduced Stat3-associated proliferative and antiapoptotic gene expression along with epidermal cell proliferation and hyperplasia. In addition, IL-17 loss was associated with reduced expression of Stat3-regulated chemokines that attract myeloid cells and a decreased infiltration of myeloid cells into the local tumor microenvironment. Together, our findings point to a critical role of the IL-17-Stat3 pathway in supporting cancer-associated inflammation in the tumor microenvironment. Therapeutic approaches that target this pathway may therefore be effective to inhibit carcinogenesis.
| S-EPMC3059780 | biostudies-literature
Project description:Introduction Urine metabolomics has been a promising technique in the liquid biopsy of urothelial cancer (UC). The comparison of upper tract urothelial cancer (UTUC), lower tract urothelial cancer (BCa), and healthy controls (HCs) need to be performed to find related biomarkers. Methods In our investigation, urine samples from 35 UTUCs, 44 BCas, and 53 gender- and age-matched HCs were analyzed using liquid chromatography-high resolution mass spectrometry (LC-HRMS). In different groups, the differential metabolites and the disturbed metabolism pathways were explored. Transcriptomics and urine metabolomics are combined to identify the probably disturbed gene in BCa. Results With an area under the curve (AUC) of 0.815, the panel consisting of prostaglandin I2, 5-methyldeoxycytidine, 2,6-dimethylheptanoyl carnitine, and deoxyinosine was able to discriminate UC from HCs. With an AUC of 0.845, the validation group also demonstrated strong predictive ability. UTUC and BCa without hematuria could be distinguished using the panel of 5'-methylthioadenosine, L-beta-aspartyl-L-serine, dehydroepiandrosterone sulfate, and N'-formylkynurenine (AUC=0.858). The metabolite panel comprising aspartyl-methionine, 7-methylinosine, and alpha-CEHC glucuronide could discriminate UTUC from BCa with hematuria with an AUC of 0.83. Fatty acid biosynthesis, purine metabolism, tryptophan metabolism, pentose and glucuronate interconversions, and arachidonic acid metabolism were dysregulated when comparing UC with HCs. PTGIS and BCHE, the genes related to the metabolism of prostaglandin I2 and myristic acid respectively, were significantly associated with the survival of BCa. Discussion Not only could LC-HRMS urine metabolomic investigations distinguish UC from HCs, but they could also identify UTUC from BCa. Additionally, urine metabolomics combined with transcriptomics can find out the potential aberrant genes in the metabolism.
| S-EPMC10226587 | biostudies-literature