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Modeling high-grade serous ovarian carcinogenesis from the fallopian tube
Open accessAbstract
High-grade serous ovarian carcinoma (HGSOC) is a lethal disease for which improved screening and treatment strategies are urgently needed. Progress in these areas is impeded by our poor understanding of HGSOC pathogenesis. Most ovarian cancer research is based on the hypothesis that HGSOC arises from ovarian surface epithelial cells. However, recent studies suggest that >50% of high-grade serous carcinomas involving the ovary likely arise from fallopian tube epithelium. Therefore, limiting HGSOC research to modeling based on ovarian surface epithelium alone is inadequate. To address the need for a fallopian tube-based model of HGSOC, we have developed a system for studying human fallopian tube secretory epithelial cell (FTSEC) transformation. Our model is based on (i) immortalization of FTSECs isolated from primary samples of normal, nondiseased human fallopian tubes, (ii) transformation of FTSECs with defined genetic elements, and (iii) xenograft-based tumorigenic assays. We use our model to show that FTSECs immortalized with human telomerase reverse transcriptase (hTERT) plus SV40 large T and small T antigens are transformed by either oncogenic Ras (H-Ras(V12)) or c-Myc expression, leading to increased proliferation, clonogenicity, and anchorage-independent growth. Additionally, we demonstrate that FTSECs remain susceptible to c-Myc-mediated transformation in the absence of viral oncoproteins, by replacing SV40 large T and small T antigens with sh-p53, mutant CDK4 (CDK4(R24C)), and sh-PP2A-B56γ. Importantly, all transformed FTSECs gave rise to high-grade Müllerian carcinomas that were grossly, histologically, immunophenotypically, and genomically similar to human HGSOC. With this model, we will now be able to assess the transformative effects of specific genetic alterations on FTSECs in order to characterize their respective roles in HGSOC development.
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“Many, perhaps most, HGSOC originate in the fallopian tube as Serous Tubal Intraepithelial Carcinomas (STICs), shedding onto the surface of the ovary and establishing a tumor (Crum et al., 2007; Karst et al., 2011; Perets and Drapkin, 2016; Zhang et al., 2019).”
From Three-dimensional modelling of ovarian cancer: from cell lines to organoids for discovery and personalized medicine (2022) · cites this paper as Karst et al., 2011
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Metadata
- Authors
- Karst, A. M., Levanon, K., & Drapkin, R.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-04-18
- Volume
- 108
- Issue
- 18
- Pages
- 7547-7552
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3088633
- OpenAlex
- W2071014344
- Cited by
- 280
- References
- 37
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 6 · 2023: 14 · 2022: 9 · 2021: 19 · 2020: 12 · 2019: 22 · 2018: 22 · 2017: 11 · 2016: 25 · 2015: 28 · 2014: 30 · 2013: 27 · 2012: 26
- FWCI
- 34.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- National Cancer Institute (P50CA105009)
- Topics
- Health Sciences › Medicine › Oncology › Ovarian cancer diagnosis and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
- Keywords
- high-grade serous ovarian cancer, fallopian tube epithelium, secretory epithelial cells, carcinogenesis, cell transformation, hTERT immortalization, oncogenic Ras, c-Myc, p53, CDK4, Müllerian carcinoma, xenograft tumorigenicity, ovarian surface epithelium
- MeSH terms
- Antigens, Polyomavirus Transforming, Carcinoma, Cell Transformation, Neoplastic, Epithelial Cells, Fallopian Tubes, Female, Humans, Immunohistochemistry, Microscopy, Fluorescence, Ovarian Neoplasms, Tumor Stem Cell Assay, Blotting, Western, Carcinogenicity Tests, Telomerase, Cell Line, Tumor, Comparative Genomic Hybridization
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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