Molecular Insights into Endometrial Cancer in Mice

Pluripotent, very small embryonic-like stem cells (VSELs) and the ‘progenitors’ endometrial stem cells (EnSCs) along with associated molecular changes in endometrial cancer, that developed seven months after neonatal exposure to estradiol in one of the sixty mice, were studied in the present study. Endocrine disruption affected both endometrium and myometrium, there was accumulation of endometrial fluid and significant hyperplasia. Disrupted endometrial-myometrial junction resulted in mobilization of myometrial cells into endometrium and epithelial and stromal cells into myometrium suggestive of adenomyosis. Markers specific for VSELs/ EnSCs (OCT-4, NANOG, SSEA-1, SCA-1, c-KIT) showed increased expression in uterine sections and marked upregulation of corresponding transcripts (Oct-4A, Oct-4, Sox-2, Nanog, Sca-1, c-Kit) was noted in RNA extracted from both uterine tissue and stem cells enriched from endometrial fluid. Hormonal receptors (ER-α, ER-β, PR, FSHR) were upregulated in both tumor sections and in endometrial fluid. ER-β and FSHR (Fshr3) expression was prominent suggesting a major role in endometrial cancer. Cancer cells showed global hypomethylation (reduced expression of 5-methyl cytosine), reduced expression of tumor suppressor gene (PTEN) and increased expression of cancer stem cells marker (CD166) which suggested dysregulation and aberrant oncogenic events. Increased expression of PCNA, Ki67, SOX-9 suggested excessive proliferation and hyperplasia which are predominant signs of endometrial cancer. Results suggest that VSELs increase in numbers and possibly transform into cancer stem cells (co-express CD166 and OCT-4) in endometrial cancer. Expression of OCT-4, CD133, ALDHA1 and CD166 in side-population cells from human endometrial cancer samples suggests a possible role of VSELs in human endometrial cancer as well. Graphical abstract Similar content being viewed by others Data availability Additional data is provided as supplement. Code availability NA. Abbreviations - VSELs: - Very small embryonic like stem cells - EnSCs: - Endometrial stem progenitor cells - OCT-4: - Octamer-binding transcription factor 4 - SOX-2: - Sex determining region Y-box 2 - SSEA-1: - Stage specific embryonic antigen-1 - SCA-1: - Stem cells antigen-1 - cKIT: - Receptor tyrosine kinase - CD166 /ALCAM: - Cluster of differentiation166 / Activated Leukocyte Cell Adhesion Molecule - ALDHA1: - Aldehyde dehydrogenases - PTEN: - Phosphatase and Tensin Homolog deleted on Chromosome 10 - 5mC: - 5-Methylcytosine - ER: - Estrogen receptors - FSHR: - Follicle stimulating hormone receptors - PCNA: - Proliferating cell nuclear antigen

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Help from Praveen, Swati and Shobha from NIRRH central facilities is acknowledged. The study was supported by Indian Council of Medical Research, Government of India, New Delhi. PS acknowledges DST-INSPIRE fellowship (IF170144). Funding The study was funded by core support provided to the corresponding author by Indian Council of Medical Research, Government of India, New Delhi. Author information Authors and Affiliations Contributions PS performed all experiments, data interpretation and manuscript preparation. DB designed the study, financial support, results interpretation, manuscript preparation. Both authors agree and approve final version of the article. Corresponding author Ethics declarations Ethics approval The study was approved by Institute Animal Ethics Committee. Consent to participate Not applicable. Consent for publication NIRRH manuscript number is RA/1116/09–2021. Conflicts of interest/Competing interests Authors declare no conflict of interest whatsoever that could be perceived as prejudicing the impartiality of the research reported. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This article belongs to the Topical Collection: Special Issue on Tissue-resident Stem/Progenitor Cells Endowed with Broader Germ Layer Specification Potential in Normal and Cancerous Tissues Supplementary Information ESM 1 (download PDF ) (PDF 879 kb) Rights and permissions About this article Cite this article Singh, P., Bhartiya, D. Molecular Insights into Endometrial Cancer in Mice. Stem Cell Rev and Rep 18, 1702–1717 (2022). https://doi.org/10.1007/s12015-022-10367-3 Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s12015-022-10367-3