Identification and characterization of the human leiomyoma side population as putative tumor-initiating cells

Mas, Aymara; Cervelló, Irene; Gil-Sanchís, Claudia; Faus, Amparo; Ferro, Jaime; Pellicer, António; Simón, Carlos

doi:10.1016/j.fertnstert.2012.04.044

Cited by 101 publications

(114 citation statements)

References 51 publications

Supporting

Mentioning

109

Contrasting

Unclassified

Order By: Relevance

“…[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%

“…In contrast to the main population of myometrial cells, the side population of myometrial cells are capable of generating functional human myometrial tissues efficiently when transplanted into the uteri of severely immunodeficient mice. 145 Subsequently, the leiomyoma-derived side population, which have stem cell characteristics, were characterized and demonstrated to be responsible for cell proliferation and tumor growth 146,151 ( Figure 3). Although leiomyomas have a lower percentage of side population cells when compared to normal myometrium, 150 the wingless-type MMTV integration site family (WNT)/b-catenin pathway in leiomyoma stem cells is activated in a paracrine manner leading to the promotion of tumor growth.…”

Section: Epigenetic Regulation Of Stem Cells In Leiomyoma Future Dirmentioning

confidence: 99%

See 1 more Smart Citation

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

et al. 2016

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Epigenetic Regulation Of Stem Cells In Leiomyoma Future Dirmentioning

confidence: 99%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…The SP phenotype is thought to be a universal marker of somatic stem cells and has been used to isolate them from many adult tissues, such as the myometrium, endometrium, and mammary gland (9)(10)(11)(12). We and another group have reported that SP cells from human LM exhibit key features of the tumor-initiating cells (13,14).…”

mentioning

confidence: 99%

“…Human and mouse myometrial (MM) tissues contain multipotent somatic stem cells, a subset of tissue responsible for regeneration in an estrogen-and-progesterone (E+P)-dependent fashion (5,10,16). E+P-dependent in vivo growth of human LM tissue requires the presence of these multipotent somatic stem cells (13,14). Compared with the main, mature LM cell population or normal MM cells, however, LM stem cells express remarkably lower levels of estrogen and progesterone receptors (13,14), and their growth requires the presence of mature MM or LM cells with higher levels of the steroid receptors and their ligands.…”

mentioning

confidence: 99%

Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth

Ono

Yin²,

Navarro³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

160

135

View full text Add to dashboard Cite

Uterine leiomyomas are extremely common estrogen and progesterone-dependent tumors of the myometrium and cause irregular uterine bleeding, severe anemia, and recurrent pregnancy loss in 15-30% of reproductive-age women. Each leiomyoma is thought to arise from a single mutated myometrial smooth muscle stem cell. Leiomyoma side-population (LMSP) cells comprising 1% of all tumor cells and displaying tumor-initiating stem cell characteristics are essential for estrogen-and progesterone-dependent in vivo growth of tumors, although they have remarkably lower estrogen/progesterone receptor levels than mature myometrial or leiomyoma cells. However, how estrogen/progesterone regulates the growth of LMSP cells via mature neighboring cells is unknown. Here, we demonstrate a critical paracrine role of the wingless-type (WNT)/β-catenin pathway in estrogen/progesterone-dependent tumorigenesis, involving LMSP and differentiated myometrial or leiomyoma cells. Estrogen/progesterone treatment of mature myometrial cells induced expression of WNT11 and WNT16, which remained constitutively elevated in leiomyoma tissues. In LMSP cells cocultured with mature myometrial cells, estrogen-progesterone selectively induced nuclear translocation of β-catenin and induced transcriptional activity of its heterodimeric partner T-cell factor and their target gene AXIN2, leading to the proliferation of LMSP cells. This effect could be blocked by a WNT antagonist. Ectopic expression of inhibitor of β-catenin and T-cell factor 4 in LMSP cells, but not in mature leiomyoma cells, blocked the estrogen/ progesterone-dependent growth of human tumors in vivo. We uncovered a paracrine role of the WNT/β-catenin pathway that enables mature myometrial or leiomyoma cells to send mitogenic signals to neighboring tissue stem cells in response to estrogen and progesterone, leading to the growth of uterine leiomyomas.WNT/β-catenin signaling | paracrine signaling | tumor biology

show abstract

“…These cells also had markers of mesenchymal differentiation and developed tissues resembling human fibroids within 8week-son growing in presence of E2 and Pg in NOD-SCID mice [50] in view of samples of hysterectomy showing myometrium from uterine fibroids contained more stem cells than normal uterus [50] . Further Moravek et al reviewed that although lot of medical treatments have been demonstrated like SPRM'S, aromatase inhibitors for treatment of fibroids they utilize dependence of fibroid growth on ovarian steroids, because of which on stopping those treatment leiomyoma tend to recur.…”

Section: Role Of Stem Cellsmentioning

confidence: 99%

Medical Management of leipmyomas-emphasis for different geographical regions

KocharKaur¹

2015

JGNB

View full text Add to dashboard Cite

Leiomyomas are the common benign tumours of uterus. Surgery is the most common mode of treatment of symptomatic fibroids. With the advent of minimally invasive interventional procedures like uterine artery embolization (UAE), and focused ultrasound on MRI we got some lesser invasive techniques, although they have drawbacks regarding ovarian reserve etc for patients desiring fertility. Initially GnRH agonists like leuprolide acetate were the most effective medical agents introduced, but their drawback was bone density demineralization, hot flushes on long term use besides cost. Selective progesterone receptor modulators gradually got introduced with initial trials with mifepristone (RU486), followed by asoprisnil, ulipristalacetate. Since mifepristone had antiglucocorticoid and androgen receptor activity it was not approved by FDA for license, while four PEARL trials have got completed for UPA acetate 5&10mg regarding safety and efficacy and intermittent therapy with 5mg got FDA approval in Europe and Canada before surgery. Further trials indicated it may be the future drug of choice for patients desiring fertility for long term intermittent therapy and possibly avoiding surgery and its complications like adhesions, uterine scar and risk for rupture during pregnancy. However in countries where uripristal is not available still one is forced to use mifepristone. Detailed mechanism of all these drugs is discussed and a case report of a young unmarried girl with high BMI is reported where mifepristone intermittent was effective not only in relieving patients symptoms but effective in decreasing uterine and fibroid volume which highlights how in such young cases one can preserve future fertility without putting them at risk of surgery and sometimes myomectomy complications ending in hysterectomy.

show abstract

Identification and characterization of the human leiomyoma side population as putative tumor-initiating cells

Cited by 101 publications

References 51 publications

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth

Medical Management of leipmyomas-emphasis for different geographical regions

Contact Info

Product

Resources

About