Molecular and Cell Biology in Endometriosis and Endometrial Cancer

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 March 2024) | Viewed by 23232

Special Issue Editor


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Guest Editor
Department Of Obstetrics And Gynaecology, Royal Women’s Hospital, University of Melbourne, Parkville, VIC 3052, Australia
Interests: uterine disease; endometriosis; endometrial cancer; molecular pathology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The endometrium has been a subject of intense research in a variety of clinical settings because of its importance in the reproductive process and its roles in women’s health. Under the exposure of different risk factors in a woman’s lifetime, normal endometrial tissue can give rise to multiple pathologic conditions, including endometriosis and endometrial cancer. Although the methods for diagnosis of endometriosis and endometrial cancer are well developed in modern gynecology, the underlying etiology and pathophysiologic changes remain largely unclear.

The focus of this Biomolecules Special Issue is on the molecular and cellular mechanisms of endometriosis and endometrial cancer. Areas to be covered in this Special Issue may include but are not limited to the molecular pathophysiology of endometriosis and endometrial cancer, genetic and epigenetic changes in endometriosis, endometrial stem/progenitor cells, the molecular basis for a specific therapeutic approach, molecular biomarkers for endometriosis and endometrial cancer.

We expect that this Special Issue will provide novel information on the abovementioned topics and be of interest to scientists and clinicians already working on or seeking to understand the molecular and cell biology of endometriosis and endometrial cancer. Therefore, contributions by experts in the field, in the form of original research papers and reviews are most welcome.

Dr. Jacqueline F. Donoghue
Guest Editor

Manuscript Submission Information

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Keywords

  • endometriosis
  • endometrial cancer
  • ovarian cancer
  • molecular basis of endometriosis and endometrial cancer

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Published Papers (11 papers)

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Research

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24 pages, 11094 KiB  
Article
Palmitic Acid Exerts Anti-Tumorigenic Activities by Modulating Cellular Stress and Lipid Droplet Formation in Endometrial Cancer
by Ziyi Zhao, Jiandong Wang, Weimin Kong, Meredith A. Newton, Wesley C. Burkett, Wenchuan Sun, Lindsey Buckingham, Jillian O’Donnell, Hongyan Suo, Boer Deng, Xiaochang Shen, Xin Zhang, Tianran Hao, Chunxiao Zhou and Victoria L. Bae-Jump
Biomolecules 2024, 14(5), 601; https://doi.org/10.3390/biom14050601 - 20 May 2024
Viewed by 299
Abstract
Epidemiological and clinical evidence have extensively documented the role of obesity in the development of endometrial cancer. However, the effect of fatty acids on cell growth in endometrial cancer has not been widely studied. Here, we reported that palmitic acid significantly inhibited cell [...] Read more.
Epidemiological and clinical evidence have extensively documented the role of obesity in the development of endometrial cancer. However, the effect of fatty acids on cell growth in endometrial cancer has not been widely studied. Here, we reported that palmitic acid significantly inhibited cell proliferation of endometrial cancer cells and primary cultures of endometrial cancer and reduced tumor growth in a transgenic mouse model of endometrial cancer, in parallel with increased cellular stress and apoptosis and decreased cellular adhesion and invasion. Inhibition of cellular stress by N-acetyl-L-cysteine effectively reversed the effects of palmitic acid on cell proliferation, apoptosis, and invasive capacity in endometrial cancer cells. Palmitic acid increased the intracellular formation of lipid droplets in a time- and dose-dependent manner. Depletion of lipid droplets by blocking DGAT1 and DGAT2 effectively increased the ability of palmitic acid to inhibit cell proliferation and induce cleaved caspase 3 activity. Collectively, this study provides new insight into the effect of palmitic acid on cell proliferation and invasion and the formation of lipid droplets that may have potential clinical relevance in the treatment of obesity-driven endometrial cancer. Full article
(This article belongs to the Special Issue Molecular and Cell Biology in Endometriosis and Endometrial Cancer)
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13 pages, 3334 KiB  
Article
Nerve Bundle Density and Expression of NGF and IL-1β Are Intra-Individually Heterogenous in Subtypes of Endometriosis
by Mahfuza Sreya, Dwayne R. Tucker, Jennifer Yi, Fahad T. Alotaibi, Anna F. Lee, Heather Noga and Paul J. Yong
Biomolecules 2024, 14(5), 583; https://doi.org/10.3390/biom14050583 - 15 May 2024
Viewed by 315
Abstract
Endometriosis is a gynecological disorder associated with local inflammation and neuroproliferation. Increased nerve bundle density has been attributed to increased expression of nerve growth factor (NGF) and interleukin–1β (IL-1β). Immunohistochemical analysis was carried out on 12 patients presenting with all three anatomic subtypes [...] Read more.
Endometriosis is a gynecological disorder associated with local inflammation and neuroproliferation. Increased nerve bundle density has been attributed to increased expression of nerve growth factor (NGF) and interleukin–1β (IL-1β). Immunohistochemical analysis was carried out on 12 patients presenting with all three anatomic subtypes of endometriosis (deep, superficial peritoneal, endometrioma) at surgery, with at least two surgically excised subtypes available for analysis. Immunolocalization for nerve bundle density around endometriosis using protein gene product 9.5 (PGP9.5), as well as NGF and IL-1β histoscores in endometriosis epithelium/stroma, was performed to evaluate differences in scores between lesions and anatomic subtypes per patient. Intra-individual heterogeneity in scores across lesions was assessed using the coefficient of variation (CV). The degree of score variability between subtypes was evaluated using the percentage difference between mean scores from one subtype to another subtype for each marker. PGP9.5 nerve bundle density was heterogenous across multiple subtypes of endometriosis, ranging from 50.0% to 173.2%, where most patients (8/12) showed CV ≥ 100%. The percentage difference in scores showed that PGP9.5 nerve bundle density and NGF and IL-1β expression were heterogenous between anatomic subtypes within the same patient. Based on these observations of intra-individual heterogeneity, we conclude that markers of neuroproliferation in endometriosis should be stratified by anatomic subtype in future studies of clinical correlation. Full article
(This article belongs to the Special Issue Molecular and Cell Biology in Endometriosis and Endometrial Cancer)
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17 pages, 8181 KiB  
Article
Active Estrogen–Succinate Metabolism Promotes Heme Accumulation and Increases the Proliferative and Invasive Potential of Endometrial Cancer Cells
by Jia-Jing Lu, Xing Zhang, Ayitila Abudukeyoumu, Zhen-Zhen Lai, Ding-Yu Hou, Jiang-Nan Wu, Xiang Tao, Ming-Qing Li, Xiao-Yong Zhu and Feng Xie
Biomolecules 2023, 13(7), 1097; https://doi.org/10.3390/biom13071097 - 10 Jul 2023
Cited by 2 | Viewed by 1423
Abstract
Uterine endometrial cancer (UEC) is an estrogen-related tumor. Succinate and heme metabolism play important roles in the progression of multiple tumors. However, the relationship between estrogen, succinate, and heme metabolism and related regulatory mechanisms remain largely unknown. In this study, we observed that [...] Read more.
Uterine endometrial cancer (UEC) is an estrogen-related tumor. Succinate and heme metabolism play important roles in the progression of multiple tumors. However, the relationship between estrogen, succinate, and heme metabolism and related regulatory mechanisms remain largely unknown. In this study, we observed that the expression of aminolevulinate delta synthase 1 (ALAS1) and solute carrier family member 38 (SLC25A38) in UEC tissues is significantly higher than that in normal tissues. Further analysis showed that estrogen and succinate increased the expression of ALAS1 and SLC25A38 in uterine endometrial cancer cells (UECC), and the administration of succinate upregulated the level of the estrogen receptor (ER). Silencing nuclear receptor coactivator 1 (NCOA1) reversed the effects of estrogen and succinate via downregulation of ALAS1 expression. Additionally, exposure of UECC to heme increased cell viability and invasiveness, while silencing the NCOA1 gene weakened this effect. These findings revealed that estrogen and succinate can synergistically increase the expression of ALAS1 and SLC25A38 via the ERβ/NCOA1 axis, promoting heme accumulation and increasing the proliferative and invasive potential of UECC. Full article
(This article belongs to the Special Issue Molecular and Cell Biology in Endometriosis and Endometrial Cancer)
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17 pages, 8841 KiB  
Article
The Comparative Invasiveness of Endometriotic Cell Lines to Breast and Endometrial Cancer Cell Lines
by Katherine Ellis and Rachael Wood
Biomolecules 2023, 13(6), 1003; https://doi.org/10.3390/biom13061003 - 17 Jun 2023
Cited by 1 | Viewed by 2474
Abstract
Endometriosis is an invasive condition that affects 10% of women (and people assigned as female at birth) worldwide. The purpose of this study was to characterize the relative invasiveness of three available endometriotic cell lines (EEC12Z, iEc-ESCs, tHESCs) to cancer cell lines (MDA-MB-231, [...] Read more.
Endometriosis is an invasive condition that affects 10% of women (and people assigned as female at birth) worldwide. The purpose of this study was to characterize the relative invasiveness of three available endometriotic cell lines (EEC12Z, iEc-ESCs, tHESCs) to cancer cell lines (MDA-MB-231, SW1353 and EM-E6/E7/TERT) and assess whether the relative invasiveness was consistent across different invasion assays. All cell lines were subjected to transwell, spheroid drop, and spheroid-gel invasion assays, and stained for vimentin, cytokeratin, E-Cadherin and N-Cadherin to assess changes in expression. In all assays, endometriotic cell lines showed comparable invasiveness to the cancer cell lines used in this study, with no significant differences in invasiveness identified. EEC12Z cells that had invaded within the assay periods showed declines in E-Cadherin expression compared to cells that had not invaded within the assay period, without significant changes in N-Cadherin expression, which may support the hypothesis that an epithelial-to-mesenchymal transition is an influence on the invasiveness shown by this peritoneal endometriosis cell line. Full article
(This article belongs to the Special Issue Molecular and Cell Biology in Endometriosis and Endometrial Cancer)
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17 pages, 6091 KiB  
Article
Using a Quantitative High-Throughput Screening Platform to Identify Molecular Targets and Compounds as Repurposing Candidates for Endometriosis
by Molly L. Churchill, Sarah J. Holdsworth-Carson, Karla J. Cowley, Jennii Luu, Kaylene J. Simpson, Martin Healey, Peter A. W. Rogers and J. F. Donoghue
Biomolecules 2023, 13(6), 965; https://doi.org/10.3390/biom13060965 - 8 Jun 2023
Viewed by 1636
Abstract
Endometriosis, defined as the growth of hormonally responsive endometrial-like tissue outside of the uterine cavity, is an estrogen-dependent, chronic, pro-inflammatory disease that affects up to 11.4% of women of reproductive age and gender-diverse people with a uterus. At present, there is no long-term [...] Read more.
Endometriosis, defined as the growth of hormonally responsive endometrial-like tissue outside of the uterine cavity, is an estrogen-dependent, chronic, pro-inflammatory disease that affects up to 11.4% of women of reproductive age and gender-diverse people with a uterus. At present, there is no long-term cure, and the identification of new therapies that provide a high level of efficacy and favourable long-term safety profiles with rapid clinical access are a priority. In this study, quantitative high-throughput compound screens of 3517 clinically approved compounds were performed on patient-derived immortalized human endometrial stromal cell lines. Following assay optimization and compound criteria selection, a high-throughput screening protocol was developed to enable the identification of compounds that interfered with estrogen-stimulated cell growth. From these screens, 23 novel compounds were identified, in addition to their molecular targets and in silico cell-signalling pathways, which included the neuroactive ligand–receptor interaction pathway, metabolic pathways, and cancer-associated pathways. This study demonstrates for the first time the feasibility of performing large compound screens for the identification of new translatable therapeutics and the improved characterization of endometriosis molecular pathophysiology. Further investigation of the molecular targets identified herein will help uncover new mechanisms involved in the establishment, symptomology, and progression of endometriosis. Full article
(This article belongs to the Special Issue Molecular and Cell Biology in Endometriosis and Endometrial Cancer)
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11 pages, 1424 KiB  
Article
Circulating Tumor Cell Detection by Liquid Biopsy during Early-Stage Endometrial Cancer Surgery: A Pilot Study
by Sarah Francini, Martha Duraes, Gauthier Rathat, Valérie Macioce, Caroline Mollevi, Laurence Pages, Catherine Ferrer, Laure Cayrefourcq and Catherine Alix-Panabières
Biomolecules 2023, 13(3), 428; https://doi.org/10.3390/biom13030428 - 24 Feb 2023
Cited by 2 | Viewed by 2004
Abstract
The recurrence of non-metastatic endometrial carcinoma (EC) (6 to 21%) might be due to disseminated tumor cells. This feasibility study investigated whether circulating tumor cells (CTCs) were detectable in blood samples from the peripheral and ovarian veins of 10 patients undergoing laparoscopic resection [...] Read more.
The recurrence of non-metastatic endometrial carcinoma (EC) (6 to 21%) might be due to disseminated tumor cells. This feasibility study investigated whether circulating tumor cells (CTCs) were detectable in blood samples from the peripheral and ovarian veins of 10 patients undergoing laparoscopic resection of stage I-II EC between July 2019 and September 2021. CTCs were detected using the CellSearch® system (i) preoperatively (T0) in peripheral blood, (ii) after ovary suspensory ligament pediculation in ovarian vein blood (T1), and (iii) before colpotomy in peripheral blood (T2). CTCs were detected only in ovarian vein samples in 8/10 patients. The CTC median number did not differ with patient age (37 (min-max: 0–91) in <70-year-old vs. 11 (0–65) in ≥70 year-old women, p = 0.59), tumor grade (15 (0–72) for grade 1 vs. 15 (0–91) for grade 2, p = 0.97), FIGO stage (72 (27–91) vs. 2 (0–65) vs. 3 (0–6]) for stage IA, B, and II, respectively; p = 0.08), and tumor size (40 (2–72) for size < 30 mm vs. 4 (0–91) for size ≥ 30 mm, p = 0.39). Estrogen receptor-positive CTCs and CTC clusters were identified. The prognostic and therapeutic values of CTCs released during EC surgery need to be determined. Full article
(This article belongs to the Special Issue Molecular and Cell Biology in Endometriosis and Endometrial Cancer)
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12 pages, 1103 KiB  
Article
Hsa-mir-135a Shows Potential as A Putative Diagnostic Biomarker in Saliva and Plasma for Endometriosis
by Alexandra Perricos, Katharina Proestling, Heinrich Husslein, Lorenz Kuessel, Quanah J. Hudson, René Wenzl and Iveta Yotova
Biomolecules 2022, 12(8), 1144; https://doi.org/10.3390/biom12081144 - 19 Aug 2022
Cited by 5 | Viewed by 1683
Abstract
Endometriosis is a chronic disease characterized by the implantation and proliferation of endometrial tissue outside of the uterine cavity. The nonspecific nature of the symptoms and the lack of sensitive, noninvasive diagnostic methods often lead to a significant delay in diagnosis, highlighting the [...] Read more.
Endometriosis is a chronic disease characterized by the implantation and proliferation of endometrial tissue outside of the uterine cavity. The nonspecific nature of the symptoms and the lack of sensitive, noninvasive diagnostic methods often lead to a significant delay in diagnosis, highlighting the need for diagnostic biomarkers. The correlation of circulating miRNAs with altered inflammatory signals seen in patients with endometriosis has raised the possibility that miRNAs can serve as biomarkers for the disease. In our study, we analyzed miRNA expression in saliva of women with and without endometriosis using a FireFly custom multiplex circulating miRNA assay. This focused panel included 28 human miRNAs, 25 of which have been previously found to be differentially expressed either in plasma, serum, and/or blood of women with endometriosis, compared to controls. We found that hsa-mir-135a was expressed significantly higher in the saliva of women with endometriosis, independent of disease stage and menstrual cycle phase. We confirmed that hsa-mir-135a also showed significantly elevated expression in the plasma of endometriosis patients. This indicates that hsa-mir-135a is a putative noninvasive biomarker of endometriosis in both saliva and plasma, but further validation studies are required to assess its clinical value as a biomarker. Full article
(This article belongs to the Special Issue Molecular and Cell Biology in Endometriosis and Endometrial Cancer)
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Review

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16 pages, 1101 KiB  
Review
Endometriosis-Associated Ovarian Carcinomas: How PI3K/AKT/mTOR Pathway Affects Their Pathogenesis
by Tatiana S. Driva, Christoph Schatz and Johannes Haybaeck
Biomolecules 2023, 13(8), 1253; https://doi.org/10.3390/biom13081253 - 16 Aug 2023
Cited by 7 | Viewed by 2277
Abstract
Ovarian clear cell (OCCC) and endometrioid (EnOC) carcinomas are often subsumed under the umbrella term “endometriosis-associated ovarian cancer” (EAOC), since they frequently arise from ectopic endometrium settled in the ovaries. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is [...] Read more.
Ovarian clear cell (OCCC) and endometrioid (EnOC) carcinomas are often subsumed under the umbrella term “endometriosis-associated ovarian cancer” (EAOC), since they frequently arise from ectopic endometrium settled in the ovaries. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is known to be aberrantly activated both in endometriosis and EAOC; however, its role in the progression of endometriosis to ovarian cancer remains unclear. In fact, cancer-associated alterations in the mTOR pathway may be found in normal uterine epithelium, likely acting as a first step towards ovarian cancer, through the intermediary stage of endometriosis. This review aims to summarize the current knowledge regarding mTOR signaling dysregulation in the uterine endometrium, endometriosis, and EAOC while focusing on the interconnections between the PI3K/AKT/mTOR pathway and other signaling molecules that give rise to synergistic molecular mechanisms triggering ovarian cancer development in the presence of endometriosis. Full article
(This article belongs to the Special Issue Molecular and Cell Biology in Endometriosis and Endometrial Cancer)
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17 pages, 293 KiB  
Review
Endometriosis-Associated Ovarian Cancer: What Are the Implications for Women with Intact Endometrioma Planning for a Future Pregnancy? A Reproductive Clinical Outlook
by Johnny S. Younis
Biomolecules 2022, 12(11), 1721; https://doi.org/10.3390/biom12111721 - 21 Nov 2022
Cited by 7 | Viewed by 2773
Abstract
Endometriosis is a chronic, universal, and prevalent disease estimated to affect up to 1:10 women of reproductive age. Endometriosis-associated ovarian cancer (EAOC) developing at reproductive age is challenging and of concern for women and practitioners alike. This outlook review focuses on the occurrence [...] Read more.
Endometriosis is a chronic, universal, and prevalent disease estimated to affect up to 1:10 women of reproductive age. Endometriosis-associated ovarian cancer (EAOC) developing at reproductive age is challenging and of concern for women and practitioners alike. This outlook review focuses on the occurrence of EAOC, especially in infertile women or those planning for a future pregnancy, from the perspective of a reproductive endocrinologist, based on recent evidence. Contemporary pathogenesis, genetic profiles, evidence of causality, clinical diagnosis, prognosis, and up-to-date management are discussed. EAOC seems to be merely associated with endometrioma and includes clear-cell and endometrioid ovarian carcinoma. Although endometrioma is frequently found in women of reproductive age (up to 1:18 of women), EAOC appears to be a rare occurrence. These women are of more advanced reproductive age, nulliparous, and hyperestrogenic, with a large-sized unilateral endometrioma (>9 cm) containing solid components and papillary projections. Each case suspected to have EAOC has specific characteristics, and a multidisciplinary discussion and appropriate patient counseling should be conducted to reach an optimal therapeutic plan. Since most of these cases are diagnosed at an early stage with a favorable prognosis, fertility-sparing surgery may be feasible. The pros and cons of fertility preservation techniques should be discussed. Full article
(This article belongs to the Special Issue Molecular and Cell Biology in Endometriosis and Endometrial Cancer)
14 pages, 816 KiB  
Review
Emerging Drug Targets for Endometriosis
by Marie-Madeleine Dolmans and Jacques Donnez
Biomolecules 2022, 12(11), 1654; https://doi.org/10.3390/biom12111654 - 8 Nov 2022
Cited by 10 | Viewed by 3052
Abstract
Endometriosis is a chronic inflammatory disease causing distressing symptoms and requiring a life-long management strategy. The objective of this review is to evaluate endometriosis-related pathways and identify novel therapies to treat it. We focused on the crucial role of inflammation and inflammatory molecules [...] Read more.
Endometriosis is a chronic inflammatory disease causing distressing symptoms and requiring a life-long management strategy. The objective of this review is to evaluate endometriosis-related pathways and identify novel therapies to treat it. We focused on the crucial role of inflammation and inflammatory molecules in order to define new perspectives for non-hormonal treatment of the disease by targeting inflammation, nuclear factor kappa B and cytokines, or reactive oxygen species, apoptotic and autophagic pathways, regulators of epithelial-mesenchymal transition, and angiogenesis and neuroangiogenesis. Novel non-steroidal therapies targeting these pathways for endometriosis were explored, but multiple challenges remain. While numerous agents have been investigated in preclinical trials, few have reached the clinical testing stage because of use of inappropriate animal models, with no proper study design or reporting of preclinical strategies. Targeting estrogens is still the best way to control endometriosis progression and inflammation. Full article
(This article belongs to the Special Issue Molecular and Cell Biology in Endometriosis and Endometrial Cancer)
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15 pages, 1543 KiB  
Review
Interferon Signaling in the Endometrium and in Endometriosis
by Yuri Park and Sang Jun Han
Biomolecules 2022, 12(11), 1554; https://doi.org/10.3390/biom12111554 - 25 Oct 2022
Cited by 2 | Viewed by 3874
Abstract
Endometriosis is an estrogen-dependent inflammatory disease that develops in reproductive-aged women who experience pelvic pain and infertility. Even though endometriosis is not a new disease, its molecular etiology has not been clearly elucidated. Defects in the immune system might be one of the [...] Read more.
Endometriosis is an estrogen-dependent inflammatory disease that develops in reproductive-aged women who experience pelvic pain and infertility. Even though endometriosis is not a new disease, its molecular etiology has not been clearly elucidated. Defects in the immune system might be one of the factors that promote endometriosis progression. For example, elevated levels of proinflammatory cytokines are associated with endometriosis. Interferon is one of the cytokines that is elevated in endometriotic tissues compared with normal endometrium. Therefore, high interferon levels play a crucial role in endometriosis progression. In addition to endometriosis, however, interferon has a critical role in endometrial function, particularly in the initiation and maintenance of pregnancy. Therefore, this review describes the double-edged sword of interferon signaling in normal endometrial function versus endometriosis progression and also discusses interferon targeting as a new nonhormonal therapy for endometriosis. This approach may increase the efficacy of endometriosis treatment and reduce the adverse effects associated with current hormonal therapy for this disease. Full article
(This article belongs to the Special Issue Molecular and Cell Biology in Endometriosis and Endometrial Cancer)
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