Molecular Insights into Endometrial Cancer in Mice
Pushpa Singh1, Deepa Bhartiya2,3
1Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive & Child Health, Jehangir Merwanji Street, Parel, Mumbai, 400012, India.
Abstract:
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.
Insights
Neonatal estradiol exposure induced endometrial cancer in mice, linked to increased very small embryonic-like stem cells (VSELs) and endometrial stem cells (EnSCs). These stem cells may transform into cancer stem cells, highlighting a potential role in endometrial cancer development.
Area of Science:
- Reproductive Biology
- Stem Cell Biology
- Oncology
Background:
- Neonatal exposure to endocrine disruptors like estradiol can lead to long-term reproductive abnormalities.
- Endometrial cancer is a complex disease influenced by hormonal factors and cellular changes.
- Very small embryonic-like stem cells (VSELs) and endometrial stem cells (EnSCs) are implicated in uterine tissue homeostasis and disease.
Purpose of the Study:
- To investigate the role of VSELs and EnSCs in endometrial cancer development following neonatal estradiol exposure.
- To analyze molecular and cellular changes in the uterus, including stem cell markers and hormonal receptors.
- To explore the potential transformation of VSELs into cancer stem cells in endometrial cancer.
Main Methods:
- Induction of endometrial cancer in mice via neonatal estradiol exposure.
- Histological analysis of uterine tissues to assess hyperplasia, fluid accumulation, and cell migration.
- Immunohistochemistry and gene expression analysis of stem cell markers (OCT-4, NANOG, etc.) and hormonal receptors (ER-α, ER-β, PR, FSHR).
- Analysis of cancer stem cell markers (CD166) and proliferation markers (PCNA, Ki67).
Main Results:
- Estradiol exposure caused endocrine disruption, endometrial hyperplasia, fluid accumulation, and adenomyosis-like changes.
- Increased expression of VSEL/EnSC markers (OCT-4, NANOG, etc.) and their transcripts was observed in uterine tissues and stem cells.
- Upregulation of hormonal receptors (ER-β, FSHR) and cancer stem cell markers (CD166) was noted in tumor sections.
- Cancer cells exhibited global hypomethylation, reduced PTEN expression, and increased proliferation markers, suggesting oncogenic dysregulation.
- VSELs showed increased numbers and potential transformation into cancer stem cells (co-expressing OCT-4 and CD166).
Conclusions:
- Neonatal estradiol exposure can induce endometrial cancer associated with VSELs and EnSCs.
- VSELs may play a crucial role in endometrial cancer development and progression by transforming into cancer stem cells.
- The findings suggest a potential link between VSELs and human endometrial cancer, warranting further investigation.
