Contents of Endometriotic Cysts, Especially the High Concentration of Free Iron, Are a Possible Cause of Carcinogenesis in the Cysts through the Iron-Induced Persistent Oxidative Stress
Open accessAbstract
PURPOSE: Endometriotic cysts are known to transform into ovarian cancers, such as clear cell and endometrioid carcinomas. We hypothesized that an iron-rich environment produced by the repetition of hemorrhage in the endometriotic cysts during the reproductive period may play a crucial role in carcinogenesis in the cysts through the iron-induced persistent oxidative stress. EXPERIMENTAL DESIGN: Contents of human ovarian cysts, including 21 endometriotic cysts, 4 clear cell carcinomas, and 11 nonendometriotic cysts, were analyzed for the concentrations of free "catalytic" iron, lactose dehydrogenase, potential antioxidant, lipid peroxide, and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Iron deposition and 8-OHdG levels were also analyzed histologically. Reactive oxygen species and the mutagenicity of the contents in endometriotic cyst were determined in vitro. RESULTS: The concentration of free iron in endometriotic cysts (100.9 mmol/L) was significantly higher than that in nonendometriotic cysts (0.075 mmol/L; P < 0.01). The average concentrations of lactose dehydrogenase, potential antioxidant, lipid peroxide, and 8-OHdG were also significantly higher in endometriotic cysts (P < 0.01). There was a correlation between the concentration of free iron and that of 8-OHdG (P < 0.01). Histologically, we could observe iron deposits more abundantly in endometriotic cysts than in nonendometriotic cysts (P < 0.01). The level of 8-OHdG in carcinoma associated with endometriosis was higher than that of carcinoma without endometriosis (P < 0.05). In vitro analyses showed that the contents of endometriotic cyst could produce more reactive oxygen species and could induce gene mutations more frequently than the contents in the other cysts. CONCLUSIONS: Abundant free iron in the contents of endometriotic cysts was strongly associated with greater oxidative stress and frequent DNA mutations. A long-standing history of the RBCs accumulated in the ovarian endometriotic cysts during the reproductive period produces oxidative stress that is a possible cause for the malignant change of the endometriotic cyst.
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The inflammatory tumor microenvironment and its main components play an impact on endometriosis and tumor and malignancy development.
“The inflammatory tumor microenvironment and its main components, non-tumoral cells (different immune cell types, fibroblasts tumor-associated), soluble factors secreted by both tumoral and non-tumoral cells, such as VEGF, FGF, EGF, IL-6, TNFα and immune checkpoint molecules, play an impact on endometriosis and tumor and malignancy development [45,46].”
From Malignancy in Abdominal Wall Endometriosis: Is There a Way to Avoid It? A Systematic Review (2024) · cites this paper as [46]
The Discussion (page not provided) suggests that iron-rich endometriotic cyst contents cause oxidative stress and DNA damage that may contribute to carcinogenesis. The paper also mentions increased VEGF in endometriosis-associated ovarian cancer, but it does not establish the claimed role of immune cells, fibroblasts, the other listed soluble factors, or immune checkpoint molecules in an inflammatory tumor microenvironment. (LLM, conf=0.82)
Experimental — accuracy not yet measuredYamaguchi et al. demonstrated that endometriotic cysts have an abundance of free iron that is strongly associated with frequent DNA mutations and may play a crucial role in the malignant transformation to ovarian cancers.
“Yamaguchi et al. demonstrated that endometriotic cysts have an abundance of free iron that is strongly associated with frequent DNA mutations and may play a crucial role in the malignant transformation to ovarian cancers [46].”
From Malignancy in Abdominal Wall Endometriosis: Is There a Way to Avoid It? A Systematic Review (2024) · cites this paper as [46]
When cystic lesions occur in the ovaries, old blood in the cysts produces iron oxide in the cysts.
“In addition to these changes in the surrounding environment that can promote carcinogenesis, when cystic lesions occur in the ovaries, old blood in the cysts produces iron oxide in the cysts, which promotes carcinogenesis through genomic DNA mutations [105].”
From Malignancies Associated with Extraovarian Endometriosis: A Literature Review (2021) · cites this paper as [105]
Iron oxide in ovarian endometriotic cysts promotes carcinogenesis through genomic DNA mutations.
“In addition to these changes in the surrounding environment that can promote carcinogenesis, when cystic lesions occur in the ovaries, old blood in the cysts produces iron oxide in the cysts, which promotes carcinogenesis through genomic DNA mutations [105].”
From Malignancies Associated with Extraovarian Endometriosis: A Literature Review (2021) · cites this paper as [105]
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References 51 · Cited by 324
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- Authors
- Yamaguchi, K., Mandai, M., Toyokuni, S., Hamanishi, J., Higuchi, T., Takakura, K., & Fujii, S.
- Affiliations
- 1Gynecology and Obstetrics and Departments of
- Kyoto University (JP)
- Kyoto Medical Center (JP)
- Venue
- Clinical Cancer Research
- Published
- 2008-01-01
- Volume
- 14
- Issue
- 1
- Pages
- 32-40
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2127488625
- Cited by
- 324
- References
- 51
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 22 · 2023: 19 · 2022: 14 · 2021: 17 · 2020: 21 · 2019: 18 · 2018: 25 · 2017: 18 · 2016: 17 · 2015: 34 · 2014: 19 · 2013: 21 · 2012: 23
- Type
- paratext
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- endometriotic cysts, free iron, oxidative stress, carcinogenesis, ovarian cancer, clear cell carcinoma, endometrioid carcinoma, 8-hydroxy-2'-deoxyguanosine, DNA damage, reactive oxygen species, mutagenicity, iron accumulation, lactate dehydrogenase, lipid hydroperoxides, endometriosis-associated cancer
- MeSH terms
- 8-Hydroxy-2'-Deoxyguanosine, Cell Transformation, Neoplastic, Deoxyguanosine, DNA Damage, Endometriosis, Female, Humans, Immunohistochemistry, Iron, L-Lactate Dehydrogenase, Ovarian Cysts, Precancerous Conditions, Endometrial Neoplasms, Reactive Oxygen Species, Oxidative Stress, Cyst Fluid
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