Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA208079 | ENA |
REPOSITORIES: ENA
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Project description:Recent evidence suggests that ovarian high-grade serous carcinoma (HGSC) originates from the epithelium of the fallopian tube. However, most mouse models are based on the previous prevailing view that ovarian cancer develops from the transformation of the ovarian surface epithelium. Here, we report the extensive histological and molecular characterization of the mogp-TAg transgenic mouse, which expresses the SV40 large T-antigen (TAg) under the control of the mouse müllerian-specific Ovgp-1 promoter. Histologic analysis of the fallopian tubes of mogp-TAg mice identified a variety of neoplastic lesions analogous to those described as precursors to ovarian HGSC. We identified areas of normal appearing p53-positive epithelium that are similar to “p53 signatures” in the human fallopian tube. More advanced proliferative lesions with nuclear atypia and epithelial stratification were also identified that were morphologically and immunohistochemically reminiscent of human serous tubal intraepithelial carcinoma (STIC), a potential precursor of ovarian HGSC. Beside these noninvasive precursor lesions, we also identified invasive adenocarcinoma in the ovary of 56% of the mice. Microarray analysis revealed several genes differentially expressed between the fallopian tube of mogp-TAg and WT C57BL/6. One of these genes, Top2a, which encodes topoisomerase II-alpha, was shown by immunohistochemistry to be concurrently expressed with elevated p53 and specifically elevated in mouse STICs, but not in surrounding tissues. TOP2A protein was also found elevated in human STICs, low-grade, and high-grade serous carcinoma. The mouse model reported here displays a progression from normal tubal epithelium to invasive HGSC in the ovary, and therefore closely simulates the current emerging model of human ovarian HGSC pathogenesis. This mouse therefore has the potential to be a very useful new model for elucidating the mechanisms of serous ovarian tumorigenesis, as well as for developing novel approaches for the prevention, diagnosis, and therapy of this disease. Keywords: transgenic mouse model, ovarian cancer, fallopian tube, intraepithelial carcinoma 6 mouse fallopian tubes (FT) were analyzed with experimental repeats; 3 wildtype C57BL6 mice (FT) and 3 transgenic mogp-TAg (FT), with one set of each at 7, 8 and 9 weeks of age.
2014-04-11 | E-GEOD-52011 | biostudies-arrayexpress
Project description:Low-grade serous ovarian carcinoma is believed to arise from serous borderline ovarian tumors, yet the progression from serous borderline tumors to low-grade serous ovarian carcinoma remains poorly understood. The purpose of this study was to identify differentially expressed genes between the two groups. Expression profiles were generated from 6 human ovarian surface epithelia (HOSE), 8 serous borderline ovarian tumors (SBOT), 13 low-grade serous ovarian carcinomas (LG), and 22 high-grade serous ovarian carcinomas (HG). The anterior gradient homolog 3 (AGR3) gene was found to be highly upregulated in serous borderline ovarian tumors; this finding was validated by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. Anti-AGR3 immunohistochemistry was performed on an additional 56 LG and 103 HG tissues and the results were correlated with clinical data. Expression profiling determined that 1254 genes were differentially expressed (P < 0.005) between SBOT, LG and HG tumors. Serous borderline ovarian tumors exhibited robust positive staining for AGR3, with a lower percentage of tumor cells stained in LG and HG. Immunofluorescence staining indicated that AGR3 expression was limited to ciliated cells. Tumor samples with a high percentage (>10%) of AGR3 positively stained tumor cells were associated with improved longer median survival in both the LG (P = 0.013) and HG (P = 0.008) serous ovarian carcinoma groups. The progression of serous borderline ovarian tumors to low-grade serous ovarian carcinoma may involve the de-differentiation of ciliated cells. AGR3 could serve as a prognostic marker for survival in patients with low-grade and high-grade serous ovarian carcinomas. Total RNA were extracted from microdissected human ovarian surface epithelia (HOSE, n=6), and microdissected serous borderline ovarian tumors (LMP, n=8), low-grade serous ovarian carcinomas (LGOSC, n=13), and 22 high-grade serous ovarian carcinomas (HGOSC, n=22). Gene Expression profiles were then generated with commercial GeneChip Human Genome U133 Plus 2.0 Array. dChip was used to identify significant differentially expressed genes between LMP/LGOSC and HGOSC
2011-03-04 | E-GEOD-27651 | biostudies-arrayexpress
Project description:Many high-grade serous carcinomas (HGSCs) of the pelvis are thought to originate in the distal portion of the fallopian tube. Serous tubal intraepithelial carcinoma (STIC) lesions are the putative precursor to HGSC and identifiable in ~50% of advanced stage cases. To better understand the molecular etiology of HGSCs, we report a multi-center integrated genomic analysis of advanced stage tumors with and without STIC lesions and normal tissues. The most significant focal DNA SCNAs were shared between cases with and without STIC lesions. RNA sequence and miRNA data did not identify any clear separation between cases with and without STIC lesions. HGSCs had molecular profiles more similar to normal fallopian tube epithelium than ovarian surface epithelium or peritoneum. The data suggest that the molecular features of HGSCs with and without associated STIC lesions are mostly shared, indicating a common biologic origin, likely to be the distal fallopian tube among all cases.
2018-05-15 | GSE114493 | GEO
Project description:Many high-grade serous carcinomas (HGSCs) of the pelvis are thought to originate in the distal portion of the fallopian tube. Serous tubal intraepithelial carcinoma (STIC) lesions are the putative precursor to HGSC and identifiable in ~50% of advanced stage cases. To better understand the molecular etiology of HGSCs, we report a multi-center integrated genomic analysis of advanced stage tumors with and without STIC lesions and normal tissues. The most significant focal DNA SCNAs were shared between cases with and without STIC lesions. RNA sequence and miRNA data did not identify any clear separation between cases with and without STIC lesions. HGSCs had molecular profiles more similar to normal fallopian tube epithelium than ovarian surface epithelium or peritoneum. The data suggest that the molecular features of HGSCs with and without associated STIC lesions are mostly shared, indicating a common biologic origin, likely to be the distal fallopian tube among all cases.
2017-07-28 | GSE101976 | GEO
Project description:Many high-grade serous carcinomas (HGSCs) of the pelvis are thought to originate in the distal portion of the fallopian tube. Serous tubal intraepithelial carcinoma (STIC) lesions are the putative precursor to HGSC and identifiable in ~50% of advanced stage cases. To better understand the molecular etiology of HGSCs, we report a multi-center integrated genomic analysis of advanced stage tumors with and without STIC lesions and normal tissues. The most significant focal DNA SCNAs were shared between cases with and without STIC lesions. RNA sequence and miRNA data did not identify any clear separation between cases with and without STIC lesions. HGSCs had molecular profiles more similar to normal fallopian tube epithelium than ovarian surface epithelium or peritoneum. The data suggest that the molecular features of HGSCs with and without associated STIC lesions are mostly shared, indicating a common biologic origin, likely to be the distal fallopian tube among all cases.
2017-08-01 | GSE102085 | GEO
Project description:Many high-grade serous carcinomas (HGSCs) of the pelvis are thought to originate in the distal portion of the fallopian tube. Serous tubal intraepithelial carcinoma (STIC) lesions are the putative precursor to HGSC and identifiable in ~50% of advanced stage cases. To better understand the molecular etiology of HGSCs, we report a multi-center integrated genomic analysis of advanced stage tumors with and without STIC lesions and normal tissues. The most significant focal DNA SCNAs were shared between cases with and without STIC lesions. RNA sequence and miRNA data did not identify any clear separation between cases with and without STIC lesions. HGSCs had molecular profiles more similar to normal fallopian tube epithelium than ovarian surface epithelium or peritoneum. The data suggest that the molecular features of HGSCs with and without associated STIC lesions are mostly shared, indicating a common biologic origin, likely to be the distal fallopian tube among all cases.
2017-08-01 | GSE102073 | GEO
Project description:Our study presents the first genetic models of de novo high-grade serous carcinomas (HGSC) that originate in fallopian tube secretory epithelial cells and recapitulate the key genetic alterations and precursor lesions characteristic of human invasive ovarian cancer. Genomic copy number analysis, using array CGH, was performed on murine tumors in order to compare the overlap of copy number alterations between HGSC models and TCGA data. Array CGH was performed on genomic DNA isolated from murine HGSC tumors. Genomic DNA from three normal mouse fallopian tubes was pooled and used as the reference.
2013-12-17 | E-GEOD-49827 | biostudies-arrayexpress
Project description:Objective: Ovarian tumors of low-malignant potential (LMP) and low-grade serous ovarian carcinomas are thought to represent different stages on a tumorigenic continuum and to develop along pathways distinct from that of high-grade serous ovarian carcinoma. Past studies have utilized gene expression profiles to support this theory. The objective of the current study was to identify new genes whose expression profiles in LMP ovarian tumors and low-grade ovarian carcinomas differ from that in high-grade ovarian carcinomas. Methods: We used RNA from 3 normal human ovarian surface epithelia (HOSE) and from 10 low-grade and 10 high-grade serous ovarian carcinoma samples to perform gene expression profiling. Using real-time reverse-transcription polymerase chain reaction (RT-PCR), we evaluated changes in PAX2 mRNA expression in cDNA created from RNA extracted from an independent set of ovarian tissue samples (7 LMP tumors and 17 low-grade and 23 high-grade serous carcinomas). We also examined PAX2 expression using Western blot analysis of protein extracted from a set of ovarian LMP and low- and high-grade carcinoma tissue samples. Additionally, we used immunohistochemistry (IHC) to validate PAX2 overexpression in a third independent set of paraffin ovarian tissue sections from 17 LMP tumors and 16 low- and 257 high-grade carcinomas. Results: Gene profiling revealed higher expression of PAX2 in low-grade than in high-grade ovarian carcinomas. Real-time RT-PCR demonstrated a statistically significant difference in median PAX2 mRNA expression, expressed as fold change, among ovarian LMP tumor (1837.38), low-grade (183.12), and high-grade (3.72) carcinoma samples (p=0.015). Western blot analysis revealed strong PAX2 expression in ovarian LMP and low-grade carcinoma samples but no PAX2 protein expression in high-grade carcinomas. On IHC, more LMP tumor and low-grade carcinoma samples expressed moderate to high levels of PAX2 than did high-grade ovarian carcinoma samples. The numbers of samples with strong nuclear staining was significantly higher for ovarian LMP tumors (10 of 17, p<0.001) and low-grade serous carcinomas (10 of 16, p<0.001) than for high-grade carcinomas (27 of 257). Discussion: Our identification and validation of higher PAX2 expression in ovarian LMP tumors and low-grade serous carcinomas than in high-grade carcinomas supports the two-tiered hypothesis that the first two are on a continuum and are distinct from high-grade ovarian carcinomas. PAX2 may represent a potential biomarker and future therapeutic target for individualizing chemotherapy for ovarian LMP tumors and low-grade carcinomas in the future. Experiment Overall Design: We used RNA from 3 normal human ovarian surface epithelia (HOSE) and from 10 low-grade and 10 high-grade serous ovarian carcinoma samples to perform gene expression profiling. Using real-time reverse-transcription polymerase chain reaction (RT-PCR), we evaluated changes in PAX2 mRNA expression in cDNA created from RNA extracted from an independent set of ovarian tissue samples (7 LMP tumors and 17 low-grade and 23 high-grade serous carcinomas). We also examined PAX2 expression using Western blot analysis of protein extracted from a set of ovarian LMP and low- and high-grade carcinoma tissue samples. Additionally, we used immunohistochemistry (IHC) to validate PAX2 overexpression in a third independent set of paraffin ovarian tissue sections from 17 LMP tumors and 16 low- and 257 high-grade carcinomas.
2009-06-08 | E-GEOD-14001 | biostudies-arrayexpress
Project description:Precision medicine approaches in ovarian cancer require the accurate diagnosis of histotypes. In particular, there is a critical need to distinguish endometroid (EC) from high grade serous (HGSC) carcinomas, which differ greatly in outcomes, genetic predisposition and optimal treatment approaches. Herein, we performed label-free quantitative proteomics on freshly frozen tumour tissues to discover biomarkers that may distinguish EC from HGSC, and then used IHC to validate these using a contemporarily classified cohort of EC and HGSC samples.
2019-03-13 | PXD012998 | Pride
Project description:Our study presents the first genetic models of de novo high-grade serous carcinomas (HGSC) that originate in fallopian tube secretory epithelial cells and recapitulate the key genetic alterations and precursor lesions characteristic of human invasive ovarian cancer. Genomic copy number analysis, using array CGH, was performed on murine tumors in order to compare the overlap of copy number alterations between HGSC models and TCGA data.
2013-12-17 | GSE49827 | GEO