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Item The Endometriotic Tumor Microenvironment in Ovarian Cancer(MDPI, 2018-08) Wendel, Jillian R. Hufgard; Wang, Xiyin; Hawkins, Shannon M.; Obstetrics and Gynecology, School of MedicineWomen with endometriosis are at increased risk of developing ovarian cancer, specifically ovarian endometrioid, low-grade serous, and clear-cell adenocarcinoma. An important clinical caveat to the association of endometriosis with ovarian cancer is the improved prognosis for women with endometriosis at time of ovarian cancer staging. Whether endometriosis-associated ovarian cancers develop from the molecular transformation of endometriosis or develop because of the endometriotic tumor microenvironment remain unknown. Additionally, how the presence of endometriosis improves prognosis is also undefined, but likely relies on the endometriotic microenvironment. The unique tumor microenvironment of endometriosis is composed of epithelial, stromal, and immune cells, which adapt to survive in hypoxic conditions with high levels of iron, estrogen, and inflammatory cytokines and chemokines. Understanding the unique molecular features of the endometriotic tumor microenvironment may lead to impactful precision therapies and/or modalities for prevention. A challenge to this important study is the rarity of well-characterized clinical samples and the limited model systems. In this review, we will describe the unique molecular features of endometriosis-associated ovarian cancers, the endometriotic tumor microenvironment, and available model systems for endometriosis-associated ovarian cancers. Continued research on these unique ovarian cancers may lead to improved prevention and treatment options.Item Müllerian anomalies and endometriosis: associations and phenotypic variations(Springer Nature, 2024-12-19) Bhamidipaty-Pelosi, Surya; Kyei-Barffour, Isaac; Volpert, Marianna; O’Neill, Nora; Grimshaw, Alyssa; Eriksson, Lars; Vash-Margita, Alla; Pelosi, Emanuele; Biochemistry and Molecular Biology, School of MedicineMüllerian anomalies are congenital conditions characterized by the incomplete development of the female reproductive tract. Women affected by Müllerian anomalies often display additional malformations of the renal, skeletal, and cardiovascular system, and are at a higher risk for infertility and adverse pregnancy outcomes. Several Müllerian anomalies have been reported in association with endometriosis, but it is unclear if all classes or anatomical variations are associated with the disease. Most importantly, both Müllerian anomalies and endometriosis can manifest with a wide degree of variability, adding further complexity to their poorly defined relationship. Retrograde menstruation occurring in obstructive Müllerian anomalies is a well-accepted mechanism for the development of endometriosis. However, endometriosis can occur following surgical correction of the anomaly or in the absence of obstruction. This suggests that other mechanisms may be involved, although the specific pathogenesis remains elusive. This review provides a comprehensive summary of the current state of clinical research on endometriosis in Müllerian anomalies. This review also highlights research and knowledge gaps, informing the development of future experimental designs to address current limitations including heterogeneity of phenotypes, variable comorbidities, and lack of genetic information.Item Recreational and residential sun exposure and risk of endometriosis: a prospective cohort study(Oxford University Press, 2021) Farland, Leslie V.; Degnan, William J.; Harris, Holly R.; Han, Jiali; Cho, Eunyoung; VoPham, Trang; Kvaskoff, Marina; Missmer, Stacey A.; Epidemiology, School of Public HealthStudy question: Is recreational and residential sun exposure associated with risk of endometriosis? Summary answer: Tanning bed use in early adulthood, sunscreen use and history of sunburns were associated with a greater risk of endometriosis; however, higher residential UV exposure was associated with a lower endometriosis risk. What is known already: Previous research has reported an association between endometriosis and skin cancer, with evidence of shared risk factors between the two diseases. We investigated the potential associations between ultraviolet radiation and endometriosis risk. Study design, size, duration: The Nurses' Health Study II is a prospective cohort of 116 429 female US nurses aged 25-42 years at enrolment in 1989. Participants completed self-administered biennial questionnaires through June 2015. Participants/materials, settings, methods: We investigated self-reported measures of recreational sun-exposure and geocoded residential UV exposure in childhood and adulthood in relation to risk of laparoscopically confirmed endometriosis among premenopausal white women. We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% CIs. Main results and the role of chance: During follow-up, 4791 incident cases of laparoscopically confirmed endometriosis were reported among 1 252 248 person-years. Tanning bed use during high school/college (≥6 times per year vs. never use: HR = 1.19, 95% CI = 1.01-1.40; Ptrend = 0.04) and at ages 25-35 (HR = 1.24, 95% CI = 1.12-1.39; Ptrend ≤ 0.0001), number of sunburns during adolescence (Ptrend = 0.03) and percentage of time using sunscreen in adulthood (Ptrend = 0.002) were positively associated with risk of endometriosis. In contrast, residential UV level at birth (highest vs. lowest quintile: HR = 0.81, 95% CI = 0.72-0.92; Ptrend = 0.0001), at age 15 (HR = 0.79, 95% CI = 0.70-0.88; Ptrend ≤ 0.0001) and at age 30 (HR = 0.90, 95% CI = 0.82-0.99; Ptrend = 0.21) were associated with a decreased risk of endometriosis. Limitations, reasons for caution: Self-reported endometriosis diagnosis may be prone to misclassification; however, we restricted our definition to laparoscopically confirmed endometriosis, which has been shown to have high validity compared to medical records. Wider implications of the findings: Our results suggest that tanning bed use in early adulthood increases endometriosis risk, potentially through a harmful effect of ultraviolet A wavelengths, and that residential UV exposure reduces risk, possibly via optimal vitamin D synthesis. These findings should be investigated further to enhance our understanding of endometriosis aetiology.Item Translational Applications of Linear and Circular Long Noncoding RNAs in Endometriosis(MDPI, 2021-09-30) Wang, Xiyin; Parodi, Luca; Hawkins, Shannon M.; Obstetrics and Gynecology, School of MedicineEndometriosis is a chronic gynecologic disease that negatively affects the quality of life of many women. Unfortunately, endometriosis does not have a cure. The current medical treatments involve hormonal manipulation with unwanted side effects and high recurrence rates after stopping the medication. Sadly, a definitive diagnosis for endometriosis requires invasive surgical procedures, with the risk of complications, additional surgeries in the future, and a high rate of recurrence. Both improved therapies and noninvasive diagnostic tests are needed. The unique molecular features of endometriosis have been studied at the coding gene level. While the molecular components of endometriosis at the small RNA level have been studied extensively, other noncoding RNAs, such as long intergenic noncoding RNAs and the more recently discovered subset of long noncoding RNAs called circular RNAs, have been studied more limitedly. This review describes the molecular formation of long noncoding and the unique circumstances of the formation of circular long noncoding RNAs, their expression and function in endometriosis, and promising preclinical studies. Continued translational research on long noncoding RNAs, including the more stable circular long noncoding RNAs, may lead to improved therapeutic and diagnostic opportunities.