Human endometrial epithelial telomerase is important for epithelial proliferation and glandular formation with potential implications in endometriosis

Valentijn, Anthony; Saretzki, Gabriele; Tempest, Nicola; Critchley, Hilary O. D.; Hapangama, D

doi:10.1093/humrep/dev267

Cited by 39 publications

(91 citation statements)

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“…( B ) Endometrial TA increases steadily under the influence of estrogen in the proliferative phase, whereas the levels plummet in the progesterone-dominant secretory phase of the cycle ( Kyo et al ., 1997 ; Saito et al ., 1997 ; Williams et al ., 2001 ; Hapangama, Turner, Drury, Quenby, et al ., 2008 ; Hapangama et al ., 2009 ). ( C ) Our recent work further demonstrates similar dynamic changes in the mean endometrial TL across the menstrual cycle ( Valentijn et al ., 2015 ). ( D ) In full thickness endometrial tissue sections, hTERT protein expression studied with immunohistochemistry employing a monoclonal mouse anti-human telomerase antibody (ab27573, Abcam, Cambridge UK), detection with ImmPRESS anti-mouse/rabbit polymer and visualization with ImmPACT DAB (Vector Laboratories, Peterborough, UK).…”

Section: The Endometriumsupporting

confidence: 75%

Implications of telomeres and telomerase in endometrial pathology

Hapangama

Kamal

Saretzki

2016

Hum. Reprod. Update

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BACKGROUNDEukaryotic chromosomal ends are linear and are protected by nucleoprotein complexes known as telomeres. The complex structural anatomy and the diverse functions of telomeres as well as the unique reverse transcriptase enzyme, telomerase that maintains telomeres are under intensive scientific scrutiny. Both are involved in many human diseases including cancer, but also in ageing and chronic disease such as diabetes. Their intricate involvement in many cellular processes and pathways is being dynamically deciphered in many organs including the endometrium. This review summarizes our current knowledge on the topic of telomeres and telomerase and their potential role in providing plausible explanations for endometrial aberrations related to common gynaecological pathologies.OBJECTIVE AND RATIONALEThis review outlines the recent major findings in telomere and telomerase functions in the context of endometrial biology. It highlights the contemporary discoveries in hormonal regulation, normal endometrial regeneration, stem cells and common gynaecological diseases such as endometriosis, infertility, recurrent reproductive failure and endometrial cancer (EC).SEARCH METHODSThe authors carried out systematic PubMed (Medline) and Ovid searches using the key words: telomerase, telomeres, telomere length, human telomerase reverse transcriptase, telomeric RNA component, with endometrium, hormonal regulation, endometrial stem/progenitor cells, endometrial regeneration, endometriosis, recurrent miscarriage, infertility, endometrial hyperplasia, EC and uterine cancer. Publications used in this review date from 1995 until 31st June 2016.OUTCOMESThe human endometrium is a unique somatic organ, which displays dynamic telomerase activity (TA) related to the menstrual cycle. Telomerase is implicated in almost all endometrial pathologies and appears to be crucial to endometrial stem cells. In particular, it is vital for normal endometrial regeneration, providing a distinct route to formulate possible curative, non-hormonal therapies to treat chronic endometrial conditions. Furthermore, our current understanding of telomere maintenance in EC is incomplete. Data derived from other malignancies on the role of telomerase in carcinogenesis cannot be extrapolated to EC because unlike in other cancers, TA is already present in proliferating healthy endometrial cells.WIDER IMPLICATIONSSince telomerase is pivotal to endometrial regeneration, further studies elucidating the role of telomeres, telomerase, their associated proteins and their regulation in normal endometrial regeneration as well as their role in endometrial pathologies are essential. This approach may allow future development of novel treatment strategies that are not only non-hormonal but also potentially curative.

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Section: The Endometriumsupporting

confidence: 75%

Implications of telomeres and telomerase in endometrial pathology

Hapangama

Kamal

Saretzki

2016

Hum. Reprod. Update

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“…The study, however, did not assess the functional ASC activity of mTERT + endometrial cells. Adequate telomerase activity is a prerequisite of proliferating endometrial epithelial cells [ 140 ]; therefore, although there is evidence for telomerase activity in the proposed ASC compartment in the human endometrium, further work is needed to clarify if telomerase is a specific phenotypical ASC marker or is merely marking the activation status/proliferation of the ASCs.…”

Section: Examining Endometrium For the Expression Of Putative Stemmentioning

confidence: 99%

Endometrial Stem Cell Markers: Current Concepts and Unresolved Questions

Tempest

Maclean

Hapangama

2018

IJMS

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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.

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“…Consistent with the potential role of TP53 in fibrogenesis in endometriosis, endometriotic cells are reported to have longer telomeres and higher telomerase expression. [111][112][113] In addition, miR-125b is found to be critical for FMT and fibrosis, and to promote fibroblast proliferation through suppression of TP53. 114 Remarkably, miR-125b upregulation has been reported in endometriosis.…”

Section: Tp53mentioning

confidence: 99%

Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

Guo

2018

Reprod Medicine & Biology

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BackgroundOne recent study reports cancer driver mutations in deep endometriosis, but its biological/clinical significance remains unclear. Since the natural history of endometriosis is essentially gradual progression toward fibrosis, it is thus hypothesized that the six driver genes reported to be mutated in endometriosis (the RP set) may play important roles in fibrogenesis but not necessarily malignant transformation.MethodsExtensive PubMed search to see whether RP and another set of driver genes not yet reported (NR) to be mutated in endometriosis have any roles in fibrogenesis. All studies reporting on the role of fibrogenesis of the genes in both RP and NR sets were retrieved and evaluated in this review.ResultsAll six RP genes were involved in various aspects of fibrogenesis as compared with only three NR genes. These nine genes can be anchored in networks linking with their upstream and downstream genes that are known to be aberrantly expressed in endometriosis, piecing together seemingly unrelated findings.ConclusionsGiven that somatic driver mutations can and do occur frequently in physiologically normal tissues, it is argued that these mutations in endometriosis are not necessarily synonymous with malignancy or premalignancy, but the result of enormous pressure for fibrogenesis.

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Human endometrial epithelial telomerase is important for epithelial proliferation and glandular formation with potential implications in endometriosis

Abstract: The observed effects of telomerase inhibition in vitro on epithelial cell proliferation, suggest that telomerase might be an attractive target in developing new therapies for proliferative disorders of the endometrium, such as endometriosis.

Cited by 39 publications

References 49 publications

Implications of telomeres and telomerase in endometrial pathology

Implications of telomeres and telomerase in endometrial pathology

Endometrial Stem Cell Markers: Current Concepts and Unresolved Questions

Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

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