Current understanding of somatic stem cells in leiomyoma formation

Mas, Aymara; Cervelló, Irene; Gil-Sanchís, Claudia; Simón, Carlos

doi:10.1016/j.fertnstert.2014.04.051

Cited by 29 publications

(34 citation statements)

References 103 publications

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“…[142][143][144] Although the cellular origin of uterine leiomyoma remains largely unknown, several lines of evidence suggests that each leiomyoma originates from the transformation of a single somatic stem cells. [145][146][147][148][149][150][151][152][153] Moreover, stem cells derived from leiomyoma carry Med12 mutations, which suggests that at least 1 genetic hit is initially required to transform myometrial stem cells. 2 The existence of putative SSCs was first identified in 2007 in mouse myometrium and nonpregnant human myometrium using 5-bromo-2'-deoxyuridine (which permits the identification of label-retaining cells), and side population technique, respectively.…”

Section: Epigenetic Regulation Of Stem Cells In Leiomyoma Future Dirmentioning

confidence: 99%

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

et al. 2016

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Uterine leiomyomas, also known as uterine fibroids, are the most common pelvic tumors, occurring in nearly 70% of all reproductive-aged women and are the leading indication for hysterectomy worldwide. The development of uterine leiomyomas involve a complex and heterogeneous constellation of hormones, growth factors, stem cells, genetic, and epigenetic abnormalities. An increasing body of evidence emphasizes the important contribution of epigenetics in the pathogenesis of leiomyomas. Genome-wide methylation analysis demonstrates that a subset of estrogen receptor (ER) response genes exhibit abnormal hypermethylation levels that are inversely correlated with their RNA expression. Several tumor suppressor genes, including Kruppel-like factor 11 (KLF11), deleted in lung and esophageal cancer 1 (DLEC1), keratin 19 (KRT19), and death-associated protein kinase 1 (DAPK1) also display higher hypermethylation levels in leiomyomas when compared to adjacent normal tissues. The important role of active DNA demethylation was recently identified with regard to the ten-eleven translocation protein 1 and teneleven translocation protein 3-mediated elevated levels of 5-hydroxymethylcytosine in leiomyoma. In addition, both histone deacetylase and histone methyltransferase are reported to be involved in the biology of leiomyomas. A number of deregulated microRNAs have been identified in leiomyomas, leading to an altered expression of their targets. More recently, the existence of side population (SP) cells with characteristics of tumor-initiating cells have been characterized in leiomyomas. These SP cells exhibit a tumorigenic capacity in immunodeficient mice when exposed to 17b-estradiol and progesterone, giving rise to fibroid-like tissue in vivo. These new findings will likely enhance our understanding of the crucial role epigenetics plays in the pathogenesis of uterine leiomyomas as well as point the way to novel therapeutic options.

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Section: Epigenetic Regulation Of Stem Cells In Leiomyoma Future Dirmentioning

confidence: 99%

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

et al. 2016

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“…Activation of the WNT/β-catenine pathway being important for mytogenic stimulation is also shared by both tumors [Mas et al 2014]. Similar molecular mechanisms underlie expansion of ECM with activation of the metalloproteinase gene family as well as many genes responsible for the growth of ECM.…”

Section: Em and Ul As Syntropic Disordersmentioning

confidence: 97%

“…Support for the existence of SCs as a side-population in human myometrium has been obtained from a series of experiments with 5-bromo-2 -deoxyuridine (BrdU) [Ono et al 2012]. Recently, it has been reported that side population cells are present in UL [Mas et al 2014]. Isolated in vitro, the undifferentiated status of side population cells from UL has been confirmed by the expression of OCT4, NANOG, DNMT3B, and GDF3 genes and by high proliferative capacity under hypoxic conditions in vitro [Ciavattini et al 2013].…”

Section: Origin Of Ulmentioning

confidence: 99%

“…As the next step point mutations and chromosome aberrations may activate signal transduction pathways such as Wnt/β-catenin or Wnt/MAPK [Mas et al 2014] which stimulate SCs proliferation and transformation into self-renewed UL SCs, which divide in an uncontrolled fashion, give rise to mature fibroids. It is also important to stress that the WNT gene, acting through the frizzled family of receptors, activates the β-catenin-T-cell transcription factor (TCF) pathway, which induces overexpression of transforming growth factor β (TGF-β) and leads to excessive formation of extracellular matrix [Bulun 2013].…”

Section: Initiation Of Tumorigenicity: Ulmentioning

confidence: 99%

“…Epigenetic mechanisms including DNA methylation, histone modification, and microRNAs in UL are actively studied and provide an important clue to the origin of this tumor [Mas et al 2014]. Follow-up studies demonstrate abnormal global genomic methylation in UL compared to normal myometrium [Yamagata et al 2009], implicating possible epigenetic contributions to genetic susceptibility of UL development.…”

Section: Epigenetic Regulation Of Ulmentioning

confidence: 99%

See 2 more Smart Citations

Comparative systems genetics view of endometriosis and uterine leiomyoma: Two sides of the same coin?

Baranov

Ivaschenko

Yarmolinskaya

2016

Systems Biology in Reproductive Medicine

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Endometriosis (EM) and uterine leiomyoma (UL) are two most frequent benign tumors of monoclonal origin affecting about 30% of all women in their reproductive age. Modern molecular technologies have made a tremendous impact in understanding both disorders. Here is the first comparative analysis of molecular mechanisms underlying development of EM and UL as it looks from the platform of systems genetics. Similarities and differences of EM and UL at their incipient stages are enlightened with special emphasis on their gene networks, gene expression, and epigenetic regulation, of pathologic development. The analysis substantiates a new hypothesis postulating tumors as outgrowths of the stem cells with mesenchymal commitment lineage (mSC) which migrate from the endometrium/myometrium junctional zone of the uterus. Comparative analysis has revealed basic similarities of molecular pathogenesis of EM and UL suggesting molecular syntropy of both disorders. Peculiarities of the epigenetic landscape determining development of mSC may explain the existence of different clinical forms of EM and UL as well as their unique clinical manifestation. Some perspectives for practical and scientific application in EM and UL studies of this new hypothesis are outlined.

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Developmental Exposure to Endocrine Disruptors Expands Murine Myometrial Stem Cell Compartment as a Prerequisite to Leiomyoma Tumorigenesis

et al. 2016

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Despite the high prevalence and major negative impact of uterine fibroids (UFs) on women's health, their pathogenesis remains largely unknown. While tumor-initiating cells have been previously isolated from UFs, the cell of origin for these tumors in normal myometrium has not been identified. We isolated cells with Stro1/CD44 surface markers from normal myometrium expressing stem cell markers Oct-4/c-kit/nanog that exhibited the properties of myometrial stem/progenitor-like cells (MSCs). Using a murine model for UFs, we showed that the cervix was a hypoxic "niche" and primary site (96%) for fibroid development in these animals. The pool size of these MSCs also responded to environmental cues, contracting with age and expanding in response to developmental environmental exposures that promote fibroid development. Translating these findings to women, the number of MSCs in unaffected human myometrium correlated with risk for developing UFs. Caucasian (CC) women with fibroids had increased numbers of MSCs relative to CC women without fibroids, and African-American (AA) women at highest risk for these tumors had the highest number of MSCs: AA-with fibroids > CC-with fibroids > AA-without fibroids > CC-without fibroids. These data identify Stro1 /CD44 MSCs as MSC/progenitor cell for UFs, and a target for ethnic and environmental factors that increase UF risk. Stem Cells 2017;35:666-678.

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Current understanding of somatic stem cells in leiomyoma formation

Cited by 29 publications

References 103 publications

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

Comparative systems genetics view of endometriosis and uterine leiomyoma: Two sides of the same coin?

Developmental Exposure to Endocrine Disruptors Expands Murine Myometrial Stem Cell Compartment as a Prerequisite to Leiomyoma Tumorigenesis

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