International Journal of Molecular Sciences

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12 pages, 2606 KiB

Open AccessArticle

Lgr5 Does Not Vary Throughout the Menstrual Cycle in Endometriotic Human Eutopic Endometrium

by Júlia Vallvé-Juanico, Cristian Barón, Elena Suárez-Salvador, Josep Castellví, Agustín Ballesteros, Antonio Gil-Moreno and Xavier Santamaria

Int. J. Mol. Sci. 2019, 20(1), 22; https://doi.org/10.3390/ijms20010022 - 21 Dec 2018

Cited by 6 | Viewed by 3526

Abstract

Endometriosis is characterized by the abnormal presence of endometrium outside of the uterus, resulting in pelvic pain and infertility. The leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) has been postulated to be a marker of stem cells in the endometrium. However, LGR5⁺ [...] Read more.

Endometriosis is characterized by the abnormal presence of endometrium outside of the uterus, resulting in pelvic pain and infertility. The leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) has been postulated to be a marker of stem cells in the endometrium. However, LGR5⁺ cells have a macrophage-like phenotype in this tissue, so it is unclear what role LGR5⁺ cells actually play in the endometrium. Macrophages serve an important function in the endometrium to maintain fertility, while LGR5⁺ cells generally have a role in tumor progression and are involved in invasion in some cancers. We sought to determine whether LGR5⁺ cells vary across the menstrual cycle in women with endometriosis and whether there are implications for LGR5 in the aggressiveness of endometriosis and reproductive outcomes. We performed immunofluorescence, flow cytometry, and primary culture in vitro experiments on eutopic and ectopic endometrium from healthy and endometriosis patients and observed that neither LGR5⁺ cells nor LGR5 expression varied throughout the cycle. Interestingly, we observed that LGR5⁺ cell percentage overexpressing CD163 (anti-inflammatory marker) was higher in healthy endometrium, suggesting that in endometriosis, endometrium presents a more pro-inflammatory phenotype that likely leads to poor obstetric outcomes. We also observed higher levels of LGR5⁺ cells in ectopic lesions compared to eutopic endometrium and specifically in deep infiltrating endometriosis, indicating that LGR5 could be involved in progression and aggressiveness of the disease. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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20 pages, 3989 KiB

Open AccessArticle

CTCF Expression is Essential for Somatic Cell Viability and Protection Against Cancer

by Charles G Bailey, Cynthia Metierre, Yue Feng, Kinsha Baidya, Galina N Filippova, Dmitri I Loukinov, Victor V Lobanenkov, Crystal Semaan and John EJ Rasko

Int. J. Mol. Sci. 2018, 19(12), 3832; https://doi.org/10.3390/ijms19123832 - 30 Nov 2018

Cited by 18 | Viewed by 5819

Abstract

CCCTC-binding factor (CTCF) is a conserved transcription factor that performs diverse roles in transcriptional regulation and chromatin architecture. Cancer genome sequencing reveals diverse acquired mutations in CTCF, which we have shown functions as a tumour suppressor gene. While CTCF is essential for [...] Read more.

CCCTC-binding factor (CTCF) is a conserved transcription factor that performs diverse roles in transcriptional regulation and chromatin architecture. Cancer genome sequencing reveals diverse acquired mutations in CTCF, which we have shown functions as a tumour suppressor gene. While CTCF is essential for embryonic development, little is known of its absolute requirement in somatic cells and the consequences of CTCF haploinsufficiency. We examined the consequences of CTCF depletion in immortalised human and mouse cells using shRNA knockdown and CRISPR/Cas9 genome editing as well as examined the growth and development of heterozygous Ctcf (Ctcf^+/−) mice. We also analysed the impact of CTCF haploinsufficiency by examining gene expression changes in CTCF-altered endometrial carcinoma. Knockdown and CRISPR/Cas9-mediated editing of CTCF reduced the cellular growth and colony-forming ability of K562 cells. CTCF knockdown also induced cell cycle arrest and a pro-survival response to apoptotic insult. However, in p53 shRNA-immortalised Ctcf^+/− MEFs we observed the opposite: increased cellular proliferation, colony formation, cell cycle progression, and decreased survival after apoptotic insult compared to wild-type MEFs. CRISPR/Cas9-mediated targeting in Ctcf^+/− MEFs revealed a predominance of in-frame microdeletions in Ctcf in surviving clones, however protein expression could not be ablated. Examination of CTCF mutations in endometrial cancers showed locus-specific alterations in gene expression due to CTCF haploinsufficiency, in concert with downregulation of tumour suppressor genes and upregulation of estrogen-responsive genes. Depletion of CTCF expression imparts a dramatic negative effect on normal cell function. However, CTCF haploinsufficiency can have growth-promoting effects consistent with known cancer hallmarks in the presence of additional genetic hits. Our results confirm the absolute requirement for CTCF expression in somatic cells and provide definitive evidence of CTCF’s role as a haploinsufficient tumour suppressor gene. CTCF genetic alterations in endometrial cancer indicate that gene dysregulation is a likely consequence of CTCF loss, contributing to, but not solely driving cancer growth. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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11 pages, 455 KiB

Open AccessArticle

Differentially-Expressed miRNAs in Ectopic Stromal Cells Contribute to Endometriosis Development: The Plausible Role of miR-139-5p and miR-375

by Kadri Rekker, Tõnis Tasa, Merli Saare, Külli Samuel, Ülle Kadastik, Helle Karro, Martin Götte, Andres Salumets and Maire Peters

Int. J. Mol. Sci. 2018, 19(12), 3789; https://doi.org/10.3390/ijms19123789 - 28 Nov 2018

Cited by 38 | Viewed by 8334

Abstract

microRNA (miRNA) expression level alterations between endometrial tissue and endometriotic lesions indicate their involvement in endometriosis pathogenesis. However, as both endometrium and endometriotic lesions consist of different cell types in various proportions, it is not clear which cells contribute to variability in miRNA [...] Read more.

microRNA (miRNA) expression level alterations between endometrial tissue and endometriotic lesions indicate their involvement in endometriosis pathogenesis. However, as both endometrium and endometriotic lesions consist of different cell types in various proportions, it is not clear which cells contribute to variability in miRNA levels and the overall knowledge about cell-type specific miRNA expression in ectopic cells is scarce. Therefore, we utilized fluorescence-activated cell sorting to isolate endometrial stromal cells from paired endometrial and endometrioma biopsies and combined it with high-throughput sequencing to determine miRNA alterations in endometriotic stroma. The analysis revealed 149 abnormally expressed miRNAs in endometriotic lesions, including extensive upregulation of miR-139-5p and downregulation of miR-375 compared to eutopic cells. miRNA transfection experiments in the endometrial stromal cell line ST-T1b showed that the overexpression of miR-139-5p resulted in the downregulation of homeobox A9 (HOXA9) and HOXA10 expression, whereas the endothelin 1 (EDN1) gene was regulated by miR-375. The results of this study provide further insights into the complex molecular mechanisms involved in endometriosis pathogenesis and demonstrate the necessity for cell-type-specific analysis of ectopic tissues to understand the interactions between different cell populations in disease onset and progression. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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16 pages, 6358 KiB

Open AccessArticle

Development of an Image-Guided Orthotopic Xenograft Mouse Model of Endometrial Cancer with Controllable Estrogen Exposure

by Gonda FJ Konings, Niina Saarinen, Bert Delvoux, Loes Kooreman, Pasi Koskimies, Camilla Krakstad, Kristine E. Fasmer, Ingfrid S. Haldorsen, Amina Zaffagnini, Merja R. Häkkinen, Seppo Auriola, Ludwig Dubois, Natasja Lieuwes, Frank Verhaegen, Lotte EJR Schyns, Roy FPM Kruitwagen, ENITEC Consortium, Sofia Xanthoulea and Andrea Romano

Int. J. Mol. Sci. 2018, 19(9), 2547; https://doi.org/10.3390/ijms19092547 - 28 Aug 2018

Cited by 9 | Viewed by 4971

Abstract

Endometrial cancer (EC) is the most common gynaecological malignancy in Western society and the majority of cases are estrogen dependent. While endocrine drugs proved to be of insufficient therapeutic value in the past, recent clinical research shows promising results by using combinational regimens [...] Read more.

Endometrial cancer (EC) is the most common gynaecological malignancy in Western society and the majority of cases are estrogen dependent. While endocrine drugs proved to be of insufficient therapeutic value in the past, recent clinical research shows promising results by using combinational regimens and pre-clinical studies and identified potential novel endocrine targets. Relevant pre-clinical models can accelerate research in this area. In the present study we describe an orthotopic and estrogen dependent xenograft mouse model of EC. Tumours were induced in one uterine horn of female athymic nude mice using the well-differentiated human endometrial adenocarcinoma Ishikawa cell line—modified to express the luciferase gene for bioluminescence imaging (BLI). BLI and contrast-enhanced computed-tomograph (CE-CT) were used to measure non-invasive tumour growth. Controlled estrogen exposure was achieved by the use of MedRod implants releasing 1.5 μg/d of 17β-estradiol (E2) in ovariectomized mice. Stable E2 serum concentration was demonstrated by LC-MS/MS. Induced tumours were E2 responsive as increased tumour growth was observed in the presence of E2 but not placebo, assessed by BLI, CE-CT, and tumour weight at sacrifice. Metastatic spread was assessed macroscopically by BLI and histology and was seen in the peritoneal cavity, in the lymphovascular space, and in the thoracic cavity. In conclusion, we developed an orthotopic xenograft mouse model of EC that exhibits the most relevant features of human disease, regarding metastatic spread and estrogen dependency. This model offers an easy to manipulate estrogen dosage (by simply adjusting the MedRod implant length), image-guided monitoring of tumour growth, and objectively measurable endpoints (including tumour weight). This is an excellent in vivo tool to further explore endocrine drug regimens and novel endocrine drug targets for EC. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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18 pages, 1813 KiB

Open AccessArticle

Functional Expression of TRP Ion Channels in Endometrial Stromal Cells of Endometriosis Patients

by Eleonora Persoons, Aurélie Hennes, Katrien De Clercq, Rita Van Bree, Goede Vriens, Dorien F. O, Daniëlle Peterse, Arne Vanhie, Christel Meuleman, Thomas Voets, Carla Tomassetti and Joris Vriens

Int. J. Mol. Sci. 2018, 19(9), 2467; https://doi.org/10.3390/ijms19092467 - 21 Aug 2018

Cited by 16 | Viewed by 5285

Abstract

Endometriosis is a common gynecological disease that is characterized by the presence of functional endometrial-like lesions in the abdominal cavity. Aside from epithelial cells, these lesions consist of stromal cells that have the capacity to migrate, adhere, proliferate, and induce neuro- and lymphangiogenesis, [...] Read more.

Endometriosis is a common gynecological disease that is characterized by the presence of functional endometrial-like lesions in the abdominal cavity. Aside from epithelial cells, these lesions consist of stromal cells that have the capacity to migrate, adhere, proliferate, and induce neuro- and lymphangiogenesis, which allows them to survive at ectopic locations. However, the exact underlying mechanisms that regulate these changes are yet to be elucidated. The common ground of these processes, however, is the second messenger, calcium. In this regard, members of the superfamily of transient receptor potential (TRP) ion channels, which are known to be calcium-permeable and expressed in the endometrium, have emerged as key regulators. Here, we assessed the molecular and functional expression of TRP channels in stromal cells isolated from the eutopic endometrium of endometriosis patients and controls. Using RT-qPCR, high mRNA levels of TRPV2, TRPV4, TRPM4, TRPM7, TRPC1, TRPC3, TRPC4, and TRPC6 were observed in the whole endometrium throughout the menstrual cycle. Additionally, and in line with previous reports of control patients, TRPV2, TRPV4, TRPC1/4, and TRPC6 were present in human endometrial stromal cells (hESC) from endometriosis patients both at the molecular and functional level. Moreover, proliferation and migration assays illustrated that these parameters were not affected in stromal cells from endometriosis patients. Furthermore, comparison between eutopic and ectopic endometrial samples revealed that the RNA expression pattern of TRP channels did not differ significantly. Collectively, although a functional expression of specific ion channels in hESCs was found, their expression did not correlate with endometriosis. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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10 pages, 1426 KiB

Open AccessArticle

Receptor Activator of Nuclear Factor Kappa B (RANK) and Clinicopathological Variables in Endometrial Cancer: A Study at Protein and Gene Level

by Raúl Gómez, Ana Castro, Jessica Martínez, Víctor Rodríguez-García, Octavio Burgués, Juan J. Tarín and Antonio Cano

Int. J. Mol. Sci. 2018, 19(7), 1848; https://doi.org/10.3390/ijms19071848 - 22 Jun 2018

Cited by 6 | Viewed by 3530

Abstract

The system integrated by the receptor activator of nuclear factor kappa B (RANK) and its ligand, RANKL, modulates the role of hormones in the genesis and progression of breast tumors. We investigated whether the expression of RANK was related with clinicopathological features of [...] Read more.

The system integrated by the receptor activator of nuclear factor kappa B (RANK) and its ligand, RANKL, modulates the role of hormones in the genesis and progression of breast tumors. We investigated whether the expression of RANK was related with clinicopathological features of primary endometrial tumors. Immunohistochemistry was used in an endometrial cancer tissue array containing samples from 36 tumors. The amount of RANK mRNA was examined in a tissue scan cDNA array containing cDNA from 40 tumors. Normal endometrium was examined for comparison. Immunohistochemical analyses showed that RANK expression was higher in malignant than in normal endometrium (p < 0.05). RANK expression was related to histological grade (Pearson correlation index = 0.484, p < 0.001), but not to tumor stage or to age of the women. The gene expression was similar in malignant and normal endometrium. The study of RANK isoforms confirmed that the overall relative abundance of the three clearly identified transcripts was similar in normal and pathological endometrium. RANK protein expression increased from normal to malignant endometrium, and the expression level was related with tumor grade but not with stage or the age of subjects in endometrial cancer. In contrast, similar comparisons showed no change in RANK gene expression. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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Review

Jump to: Research

17 pages, 4419 KiB

Open AccessReview

Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β Isoforms in Endometrial Cancer

by Fatemeh Mazloumi Gavgani, Victoria Smith Arnesen, Rhîan G. Jacobsen, Camilla Krakstad, Erling A. Hoivik and Aurélia E. Lewis

Int. J. Mol. Sci. 2018, 19(12), 3931; https://doi.org/10.3390/ijms19123931 - 7 Dec 2018

Cited by 28 | Viewed by 6828

Abstract

The phosphoinositide 3-kinase (PI3K) signalling pathway is highly dysregulated in cancer, leading to elevated PI3K signalling and altered cellular processes that contribute to tumour development. The pathway is normally orchestrated by class I PI3K enzymes and negatively regulated by the phosphatase and tensin [...] Read more.

The phosphoinositide 3-kinase (PI3K) signalling pathway is highly dysregulated in cancer, leading to elevated PI3K signalling and altered cellular processes that contribute to tumour development. The pathway is normally orchestrated by class I PI3K enzymes and negatively regulated by the phosphatase and tensin homologue, PTEN. Endometrial carcinomas harbour frequent alterations in components of the pathway, including changes in gene copy number and mutations, in particular in the oncogene PIK3CA, the gene encoding the PI3K catalytic subunit p110α, and the tumour suppressor PTEN. PIK3CB, encoding the other ubiquitously expressed class I isoform p110β, is less frequently altered but the few mutations identified to date are oncogenic. This isoform has received more research interest in recent years, particularly since PTEN-deficient tumours were found to be reliant on p110β activity to sustain transformation. In this review, we describe the current understanding of the common and distinct biochemical properties of the p110α and p110β isoforms, summarise their mutations and highlight how they are targeted in clinical trials in endometrial cancer. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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18 pages, 1998 KiB

Open AccessReview

Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders

by Douglas A. Gibson, Ioannis Simitsidellis, Frances Collins and Philippa T.K. Saunders

Int. J. Mol. Sci. 2018, 19(10), 3276; https://doi.org/10.3390/ijms19103276 - 22 Oct 2018

Cited by 47 | Viewed by 8620

Abstract

Peripheral tissue metabolism of steroids (intracrinology) is now accepted as a key way in which tissues, such as the endometrium, can utilise inactive steroids present in the blood to respond to local physiological demands and ‘fine-tune’ the activation or inhibition of steroid hormone [...] Read more.

Peripheral tissue metabolism of steroids (intracrinology) is now accepted as a key way in which tissues, such as the endometrium, can utilise inactive steroids present in the blood to respond to local physiological demands and ‘fine-tune’ the activation or inhibition of steroid hormone receptor-dependent processes. Expression of enzymes that play a critical role in the activation and inactivation of bioactive oestrogens (E1, E2) and androgens (A4, T, DHT), as well as expression of steroid hormone receptors, has been detected in endometrial tissues and cells recovered during the menstrual cycle. There is robust evidence that increased expression of aromatase is important for creating a local microenvironment that can support a pregnancy. Measurement of intra-tissue concentrations of steroids using liquid chromatography–tandem mass spectrometry has been important in advancing our understanding of a role for androgens in the endometrium, acting both as active ligands for the androgen receptor and as substrates for oestrogen biosynthesis. The emergence of intracrinology, associated with disordered expression of key enzymes such as aromatase, in the aetiology of common women’s health disorders such as endometriosis and endometrial cancer has prompted renewed interest in the development of drugs targeting these pathways, opening up new opportunities for targeted therapies and precision medicine. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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26 pages, 2017 KiB

Open AccessReview

Endometrial Stem Cell Markers: Current Concepts and Unresolved Questions

by Nicola Tempest, Alison Maclean and Dharani K. Hapangama

Int. J. Mol. Sci. 2018, 19(10), 3240; https://doi.org/10.3390/ijms19103240 - 19 Oct 2018

Cited by 72 | Viewed by 16707

Abstract

The human endometrium is a highly regenerative organ undergoing over 400 cycles of shedding and regeneration over a woman’s lifetime. Menstrual shedding and the subsequent repair of the functional layer of the endometrium is a process unique to humans and higher-order primates. This [...] Read more.

The human endometrium is a highly regenerative organ undergoing over 400 cycles of shedding and regeneration over a woman’s lifetime. Menstrual shedding and the subsequent repair of the functional layer of the endometrium is a process unique to humans and higher-order primates. This massive regenerative capacity is thought to have a stem cell basis, with human endometrial stromal stem cells having already been extensively studied. Studies on endometrial epithelial stem cells are sparse, and the current belief is that the endometrial epithelial stem cells reside in the terminal ends of the basalis glands at the endometrial/myometrial interface. Since almost all endometrial pathologies are thought to originate from aberrations in stem cells that regularly regenerate the functionalis layer, expansion of our current understanding of stem cells is necessary in order for curative treatment strategies to be developed. This review critically appraises the postulated markers in order to identify endometrial stem cells. It also examines the current evidence supporting the existence of epithelial stem cells in the human endometrium that are likely to be involved both in glandular regeneration and in the pathogenesis of endometrial proliferative diseases such as endometriosis and endometrial cancer. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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28 pages, 1313 KiB

Open AccessReview

Inside the Endometrial Cell Signaling Subway: Mind the Gap(s)

by Sofia Makieva, Elisa Giacomini, Jessica Ottolina, Ana Maria Sanchez, Enrico Papaleo and Paola Viganò

Int. J. Mol. Sci. 2018, 19(9), 2477; https://doi.org/10.3390/ijms19092477 - 21 Aug 2018

Cited by 44 | Viewed by 7704

Abstract

Endometrial cells perceive and respond to their microenvironment forming the basis of endometrial homeostasis. Errors in endometrial cell signaling are responsible for a wide spectrum of endometrial pathologies ranging from infertility to cancer. Intensive research over the years has been decoding the sophisticated [...] Read more.

Endometrial cells perceive and respond to their microenvironment forming the basis of endometrial homeostasis. Errors in endometrial cell signaling are responsible for a wide spectrum of endometrial pathologies ranging from infertility to cancer. Intensive research over the years has been decoding the sophisticated molecular means by which endometrial cells communicate to each other and with the embryo. The objective of this review is to provide the scientific community with the first overview of key endometrial cell signaling pathways operating throughout the menstrual cycle. On this basis, a comprehensive and critical assessment of the literature was performed to provide the tools for the authorship of this narrative review summarizing the pivotal components and signaling cascades operating during seven endometrial cell fate “routes”: proliferation, decidualization, implantation, migration, breakdown, regeneration, and angiogenesis. Albeit schematically presented as separate transit routes in a subway network and narrated in a distinct fashion, the majority of the time these routes overlap or occur simultaneously within endometrial cells. This review facilitates identification of novel trajectories of research in endometrial cellular communication and signaling. The meticulous study of endometrial signaling pathways potentiates both the discovery of novel therapeutic targets to tackle disease and vanguard fertility approaches. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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17 pages, 1157 KiB

Open AccessReview

Patient-Derived Xenograft Models for Endometrial Cancer Research

by Cristian P. Moiola, Carlos Lopez-Gil, Silvia Cabrera, Angel Garcia, Tom Van Nyen, Daniela Annibali, Tina Fonnes, August Vidal, Alberto Villanueva, Xavier Matias-Guiu, Camilla Krakstad, Frédéric Amant, Antonio Gil-Moreno and Eva Colas

Int. J. Mol. Sci. 2018, 19(8), 2431; https://doi.org/10.3390/ijms19082431 - 17 Aug 2018

Cited by 34 | Viewed by 5525

Abstract

Endometrial cancer (EC) is the most common malignancy of the genital tract among women in developed countries. Recently, a molecular classification of EC has been performed providing a system that, in conjunction with histological observations, reliably improves EC classification and enhances patient management. [...] Read more.

Endometrial cancer (EC) is the most common malignancy of the genital tract among women in developed countries. Recently, a molecular classification of EC has been performed providing a system that, in conjunction with histological observations, reliably improves EC classification and enhances patient management. Patient-derived xenograft models (PDX) represent nowadays a promising tool for translational research, since they closely resemble patient tumour features and retain molecular and histological features. In EC, PDX models have already been used, mainly as an individualized approach to evaluate the efficacy of novel therapies and to identify treatment-response biomarkers; however, their uses in more global or holistic approaches are still missing. As a collaborative effort within the ENITEC network, here we describe one of the most extensive EC PDX cohorts developed from primary tumour and metastasis covering all EC subtypes. Our models are histologically and molecularly characterized and represent an excellent reservoir of EC tumour samples for translational research. This review compiles the information on current methods of EC PDX generation and their utility and provides new perspectives for the exploitation of these valuable tools in order to increase the success ratio for translating results to clinical practice. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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33 pages, 1391 KiB

Open AccessReview

Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies

by Yi-Heng Lin, Ya-Hsin Chen, Heng-Yu Chang, Heng-Kien Au, Chii-Ruey Tzeng and Yen-Hua Huang

Int. J. Mol. Sci. 2018, 19(8), 2385; https://doi.org/10.3390/ijms19082385 - 13 Aug 2018

Cited by 101 | Viewed by 17469

Abstract

Endometriosis is an estrogen-dependent inflammatory disease that affects up to 10% of women of reproductive age and accounts for up to 50% of female infertility cases. It has been highly associated with poorer outcomes of assisted reproductive technology (ART), including decreased oocyte retrieval, [...] Read more.

Endometriosis is an estrogen-dependent inflammatory disease that affects up to 10% of women of reproductive age and accounts for up to 50% of female infertility cases. It has been highly associated with poorer outcomes of assisted reproductive technology (ART), including decreased oocyte retrieval, lower implantation, and pregnancy rates. A better understanding of the pathogenesis of endometriosis-associated infertility is crucial for improving infertility treatment outcomes. Current theories regarding how endometriosis reduces fertility include anatomical distortion, ovulatory dysfunction, and niche inflammation-associated peritoneal or implantation defects. This review will survey the latest evidence on the role of inflammatory niche in the peritoneal cavity, ovaries, and uterus of endometriosis patients. Nonhormone treatment strategies that target these inflammation processes are also included. Furthermore, mesenchymal stem cell-based therapies are highlighted for potential endometriosis treatment because of their immunomodulatory effects and tropism toward inflamed lesion foci. Potential applications of stem cell therapy in treatment of endometriosis-associated infertility in particular for safety and efficacy are discussed. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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22 pages, 1003 KiB

Open AccessReview

Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late

by Michiel Remmerie and Veerle Janssens

Int. J. Mol. Sci. 2018, 19(8), 2380; https://doi.org/10.3390/ijms19082380 - 13 Aug 2018

Cited by 39 | Viewed by 8341

Abstract

Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same [...] Read more.

Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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18 pages, 538 KiB

Open AccessReview

Modeling Endometrial Cancer: Past, Present, and Future

by Tom Van Nyen, Cristian P. Moiola, Eva Colas, Daniela Annibali and Frédéric Amant

Int. J. Mol. Sci. 2018, 19(8), 2348; https://doi.org/10.3390/ijms19082348 - 9 Aug 2018

Cited by 89 | Viewed by 6839

Abstract

Endometrial cancer is the most common type of cancer of the female reproductive tract. Although prognosis is generally good for patients with low-grade and early-stage diseases, the outcomes for high-grade and metastatic/recurrent cases remain poor, since traditional chemotherapy regimens based on platinum and [...] Read more.

Endometrial cancer is the most common type of cancer of the female reproductive tract. Although prognosis is generally good for patients with low-grade and early-stage diseases, the outcomes for high-grade and metastatic/recurrent cases remain poor, since traditional chemotherapy regimens based on platinum and taxanes have limited effects. No targeted agents have been approved so far, although several new drugs have been tested without striking results in clinical trials. Over the last decades, many efforts have been made towards the establishment and development of preclinical models, aiming at recapitulating the structural and molecular determinants of the disease. Here, we present an overview of the most commonly used in vitro and in vivo models and discuss their peculiar features, describing their main applications and the value in the advancement of both fundamental and translational endometrial cancer research. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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13 pages, 565 KiB

Open AccessReview

Vitamin D and Endometrium: A Systematic Review of a Neglected Area of Research

by Greta Chiara Cermisoni, Alessandra Alteri, Laura Corti, Elisa Rabellotti, Enrico Papaleo, Paola Viganò and Ana Maria Sanchez

Int. J. Mol. Sci. 2018, 19(8), 2320; https://doi.org/10.3390/ijms19082320 - 8 Aug 2018

Cited by 48 | Viewed by 6560

Abstract

Growing evidence supports a role of vitamin D (VD) in reproductive health. Vitamin D receptor (VDR) is expressed in the ovary, endometrium, and myometrium. The biological actions of VD in fertility and reproductive tissues have been investigated but mainly using animal models. Conversely, [...] Read more.

Growing evidence supports a role of vitamin D (VD) in reproductive health. Vitamin D receptor (VDR) is expressed in the ovary, endometrium, and myometrium. The biological actions of VD in fertility and reproductive tissues have been investigated but mainly using animal models. Conversely, the molecular data addressing the mechanisms underlying VD action in the physiologic endometrium and in endometrial pathologies are still scant. Levels of VDR expression according to the menstrual cycle are yet to be definitively clarified, possibly being lower in the proliferative compared to the secretory phase and in mid-secretory compared to early secretory phase. Endometrial tissue also expresses the enzymes involved in the metabolism of VD. The potential anti-proliferative and anti-inflammatory effects of VD for the treatment of endometriosis have been investigated in recent years. Treatment of ectopic endometrial cells with 1,25(OH)₂D₃ could significantly reduce cytokine-mediated inflammatory responses. An alteration of VD metabolism in terms of increased 24-hydroxylase mRNA and protein expression has been demonstrated in endometrial cancer, albeit not consistently. The effect of the active form of the vitamin as an anti-proliferative, pro-apoptotic, anti-inflammatory, and differentiation-inducing agent has been demonstrated in various endometrial cancer cell lines. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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12 pages, 532 KiB

Open AccessReview

Liquid Biopsy in Endometrial Cancer: New Opportunities for Personalized Oncology

by Laura Muinelo-Romay, Carlos Casas-Arozamena and Miguel Abal

Int. J. Mol. Sci. 2018, 19(8), 2311; https://doi.org/10.3390/ijms19082311 - 7 Aug 2018

Cited by 71 | Viewed by 9325

Abstract

The identification of new molecular targets and biomarkers associated with high risk of recurrence and response to therapy represents one of the main clinical challenges in the management of advanced disease in endometrial cancer. In this sense, the field of liquid biopsy has [...] Read more.

The identification of new molecular targets and biomarkers associated with high risk of recurrence and response to therapy represents one of the main clinical challenges in the management of advanced disease in endometrial cancer. In this sense, the field of liquid biopsy has emerged as a great revolution in oncology and is considered “the way” to reach personalised medicine. In this review, we discuss the promising but already relatively limited advances of liquid biopsy in endometrial cancer compared to other types of tumours like breast, colorectal or prostate cancer. We present recent data analysing circulating tumour material in minimally-invasive blood samples, but also in alternative forms of liquid biopsy like uterine aspirates. Proteomic and genomic studies focused on liquid-based uterine samples are resulting not only in optimal diagnostic tools but also in reliable approaches to address tumour heterogeneity. Likewise, circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) represent an opportunity for the correct stratification of patients, for the assessment of early recurrent disease or for the real-time monitoring of therapy responses. Appropriately designed studies and implementation in clinical trials will determine the value of liquid biopsy for precision oncology in endometrial cancer. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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22 pages, 706 KiB

Open AccessReview

Direct Cell–Cell Interactions in the Endometrium and in Endometrial Pathophysiology

by Susanne Grund and Ruth Grümmer

Int. J. Mol. Sci. 2018, 19(8), 2227; https://doi.org/10.3390/ijms19082227 - 30 Jul 2018

Cited by 27 | Viewed by 6759

Abstract

Cell contacts exhibit a considerable influence on tissue physiology and homeostasis by controlling paracellular and intercellular transport processes, as well as by affecting signaling pathways. Since they maintain cell polarity, they play an important role in cell plasticity. The knowledge about the junctional [...] Read more.

Cell contacts exhibit a considerable influence on tissue physiology and homeostasis by controlling paracellular and intercellular transport processes, as well as by affecting signaling pathways. Since they maintain cell polarity, they play an important role in cell plasticity. The knowledge about the junctional protein families and their interactions has increased considerably during recent years. In contrast to most other tissues, the endometrium undergoes extensive physiological changes and reveals an extraordinary plasticity due to its crucial role in the establishment and maintenance of pregnancy. These complex changes are accompanied by changes in direct cell–cell contacts to meet the various requirements in the respective developmental stage. Impairment of this sophisticated differentiation process may lead to failure of implantation and embryo development and may be involved in the pathogenesis of endometrial diseases. In this article, we focus on the knowledge about the distribution and regulation of the different junctional proteins in the endometrium during cycling and pregnancy, as well as in pathologic conditions such as endometriosis and cancer. Decoding these sophisticated interactions should improve our understanding of endometrial physiology as well as of the mechanisms involved in pathological conditions. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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25 pages, 1748 KiB

Open AccessReview

Non-Coding RNAs in Endometrial Physiopathology

by Alessandro La Ferlita, Rosalia Battaglia, Francesca Andronico, Salvatore Caruso, Antonio Cianci, Michele Purrello and Cinzia Di Pietro

Int. J. Mol. Sci. 2018, 19(7), 2120; https://doi.org/10.3390/ijms19072120 - 20 Jul 2018

Cited by 77 | Viewed by 9223

Abstract

The Human Genome Project led to the discovery that about 80% of our DNA is transcribed in RNA molecules. Only 2% of the human genome is translated into proteins, the rest mostly produces molecules called non-coding RNAs, which are a heterogeneous class of [...] Read more.

The Human Genome Project led to the discovery that about 80% of our DNA is transcribed in RNA molecules. Only 2% of the human genome is translated into proteins, the rest mostly produces molecules called non-coding RNAs, which are a heterogeneous class of RNAs involved in different steps of gene regulation. They have been classified, according to their length, into small non-coding RNAs and long non-coding RNAs, or to their function, into housekeeping non-coding RNAs and regulatory non-coding RNAs. Their involvement has been widely demonstrated in all cellular processes, as well as their dysregulation in human pathologies. In this review, we discuss the function of non-coding RNAs in endometrial physiology, analysing their involvement in embryo implantation. Moreover, we explore their role in endometrial pathologies such as endometrial cancer, endometriosis and chronic endometritis. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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14 pages, 721 KiB

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Mitochondrial Dysfunctions in Type I Endometrial Carcinoma: Exploring Their Role in Oncogenesis and Tumor Progression

by Clara Musicco, Gennaro Cormio, Vito Pesce, Vera Loizzi, Ettore Cicinelli, Leonardo Resta, Girolamo Ranieri and Antonella Cormio

Int. J. Mol. Sci. 2018, 19(7), 2076; https://doi.org/10.3390/ijms19072076 - 17 Jul 2018

Cited by 16 | Viewed by 5380

Abstract

Type I endometrial cancer (EC) is the most common form of EC, displaying less aggressive behavior than type II. The development of type I endometrial cancer is considered a multistep process, with slow progression from normal endometrium to hyperplasia, the premalignant form, and [...] Read more.

Type I endometrial cancer (EC) is the most common form of EC, displaying less aggressive behavior than type II. The development of type I endometrial cancer is considered a multistep process, with slow progression from normal endometrium to hyperplasia, the premalignant form, and endometrial cancer as a result of an unopposed estrogenic stimulation. The role of mitochondria in type I EC tumor progression and prognosis is currently emerging. This review aims to explore mitochondrial alterations in this cancer and in endometrial hyperplasia focusing on mitochondrial DNA mutations, respiratory complex I deficiency, and the activation of mitochondrial quality control systems. A deeper understanding of altered mitochondrial pathways in type I EC could provide novel opportunities to discover new diagnostic and prognostic markers as well as potential therapeutic targets. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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11 pages, 661 KiB

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Pathogenomics of Endometriosis Development

by Vladislav Baranov, Olga Malysheva and Maria Yarmolinskaya

Int. J. Mol. Sci. 2018, 19(7), 1852; https://doi.org/10.3390/ijms19071852 - 23 Jun 2018

Cited by 46 | Viewed by 9026

Abstract

For over 100 years, endometriosis, as a chronic, estrogen-dependent, inflammatory, heritable disease affecting approximately 5–10% of women in reproductive age has been the focus of clinicians and scientists. In spite of numerous environmental, genetic, epigenetic, endocrine, and immunological studies, our knowledge of endometriosis [...] Read more.

For over 100 years, endometriosis, as a chronic, estrogen-dependent, inflammatory, heritable disease affecting approximately 5–10% of women in reproductive age has been the focus of clinicians and scientists. In spite of numerous environmental, genetic, epigenetic, endocrine, and immunological studies, our knowledge of endometriosis is still fragmentary, and its precise pathophysiology and pathogenomics remain a mystery. The implementation of new technologies has provided tremendous progress in understanding the many intrinsic molecular mechanisms in the development of endometriosis, with progenitor and stem cells (SCs) of the eutopic endometrium as the starting players and endometriotic lesions as the final pathomorphological trait. Novel data on the molecular, genetic, and epigenetic mechanisms of the disease are briefly outlined. We hypothesize the existence of an endometriosis development genetic program (EMDP) that governs the origin of endometrium stem cells programmed for endometriosis (1), their transition (metaplasia) into mesenchymal SCs (2), and their invasion of the peritoneum and progression to endometriotic lesions (3). The pros and cons of the recent unifying theory of endometriosis are also discussed. Complex genomic and epigenetic interactions at different stages of the endometriosis process result in different forms of the disease, with specific features and clinical manifestations. The significance of the EMDP in elaborating a new strategy for endometriosis prediction, prevention, and treatment is discussed. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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