From Elegance to Complexity: The Intricate Dance of Myometrial Stem Cells Transforming into Leiomyoma Stem Cells: Unraveling the Symphony of Genetic and Epigenetic Refinement
DOI:
https://doi.org/10.17140/CSMMOJ-8-136Keywords:
Genetic, Epigenetic, Leiomyomas, Stem cellAbstract
Uterine leiomyomas (LM), commonly referred to as uterine fibroids (UFs), pelvic tumor in women of reproductive age globally
and are main indicators of hysterectomies if become symptomatic. The progression of uterine LM involves a complex interplay
of hormones, stem cells, growth factors, and genetic/epigenetic irregularities. Both endometrial and myometrial stem/progenitor
cells play pivotal roles in the uterus’ response to hormonal stimuli and return to its basal state. LM, arising from a single stem cell
of smooth muscle cells with acquired mutations, exhibit diverse cellular transcriptomic patterns influenced by genotype. Affecting
over 70% of women at some point in their lives, with significant clinical symptoms, such as pelvic pain, infertility, and heavy
uterine bleeding. Recent literature underscores the potential importance of LM stem cells and their paracrine interactions with
specialized cells, connecting the gap between medications targeting leiomyoma expansion and potential eradication strategies.
Keeping these points in view, this review discusses the current understanding of the involvement of myometrial stem/progenitor
cells and the genetic and epigenetic changes occurring in these cells during the pathogenesis of uterine LM.
References
Kjerulff KH, Langenberg P, Seidman JD, Stolley PD, Guzinski GM. Uterine leiomyomas. Racial differences in severity, symp-toms and age at diagnosis. J Reprod Med. 1996; 41(7): 483-490.
Huyck KL, Panhuysen CIM, Cuenco KT, et al. The impact of race as a risk factor for symptom severity and age at diagnosis of uterine leiomyomata among affected sisters. Am J Obstet Gynecol. 2008; 198(2): 168.e1-168.e9. doi: 10.1016/j.ajog.2007.05.038
Rezk A, Kahn J, Singh M. Fertility sparing management. In: Uterine Fibroids. Treasure Island (FL), USA: StatPearls Publishing; 2022. https://www.ncbi.nlm.nih.gov/books/NBK574504/. Ac-cessed November 11, 2023.
Yang Q, Mas A, Diamond MP, Al-Hendy A. The mechanism and function of epigenetics in uterine leiomyoma Development. Reprod Sci. 2016; 23(2): 163-175. doi: 10.1177/1933719115584449
Jamaluddin MFB, Nahar P, Tanwar PS. Proteomic characteriza-tion of the extracellular matrix of human uterine fibroids. En-docrinology. 2018; 159(7): 2656-2669. doi: 10.1210/en.2018-00151
Ratajczak MZ, Bujko K, Mack A, Kucia M, Ratajczak J. Cancer from the perspective of stem cells and misappropriated tissue re-generation mechanisms. Leukemia. 2018; 32(12): 2519-2526. doi: 10.1038/s41375-018-0294-7
Chaudhry SR, Liman MNP; Peterson DC. Anatomy, Abdomen and Pelvis: Stomach. Treasure Island (FL), USA: StatPearls Pub-lishing. 2021. Webstie. https://www.ncbi.nlm.nih.gov/books/ NBK482334/. Accessed November 11, 2023.
Brakta S, Mas A, Al-Hendy A. The ontogeny of myometrial stem cells in OCT4-GFP transgenic mouse model. Stem Cell Res Ther. 2018; 9(1): 333. doi: 10.1186/s13287-018-1079-7
Bozorgmehr M, Gurung S, Darzi S, et al. Endometrial and menstrual blood mesenchymal stem/stromal cells: Biological properties and clinical application. Front Cell Dev Biol. 2020; 8: 497. doi: 10.3389/fcell.2020.00497
Ono M, Bulun SE, Maruyama T. Tissue-specific stem cells in the myometrium and tumor-initiating cells in leiomyoma. Bio Reprod. 2014; 91(6): 149. doi: 10.1095/biolreprod.114.123794 15 Vafaei S
Mas A, Cervello I, Gil-Sanchis C, Simón C. Current under-standing of somatic stem cells in leiomyoma formation. Fertil Ster-il. 2014; 102(3): 613-620. doi: 10.1016/j.fertnstert.2014.04.051
Al-Hendy A, Myers ER, Stewart E. Uterine fibroids: Burden and unmet medical need. Semin Reprod Med. 2017; 35(6): 473-480. doi: 10.1055/s-0037-1607264
Sheaffer KL, Kim R, Aoki R, et al. DNA methylation is required for the control of stem cell differentiation in the small intestine. Genes Dev. 2014; 28(6): 652-664. doi: 10.1101/gad.230318.113
Mazloumi Z, Farahzadi R, Rafat A, et al. Effect of aberrant DNA methylation on cancer stem cell properties. Exp Mol Pathol. 2022; 125: 104757. doi: 10.1016/j.yexmp.2022.104757
Wang Y, Cardenas H, Fang F, et al. Epigenetic targeting of ovarian cancer stem cells. Cancer Res. 2014; 74(17): 4922-4936. doi: 10.1158/0008-5472.CAN-14-1022
Liu S, Yin P, Xu J, et al. Targeting DNA methylation depletes uterine leiomyoma stem cell-enriched population by stimulating their differentiation. Endocrinology. 2020; 161(10): bqaa143. doi: 10.1210/endocr/bqaa143
Mas A, Cervelló I, Gil-Sanchis C, et al. Identification and characterization of the human leiomyoma side population as pu-tative tumor-initiating cells. Fertil Steril. 2012; 98(3): 741-751.e6. doi: 10.1016/j.fertnstert.2012.04.044
Moravek MB, Yin P, Ono M, et al. Ovarian steroids, stem cells and uterine leiomyoma: Therapeutic implications. Hum Reprod Update. 2015; 21(1): 1-12. doi: 10.1093/humupd/dmu048
Mas A, Stone L, O’Connor PM, et al. Developmental expo-sure to endocrine disruptors expands murine myometrial stem cell compartment as a prerequisite to leiomyoma tumorigenesis. Stem Cells. 2017; 35(3): 666-678. doi: 10.1002/stem.2519
Ono M, Qiang W, Serna VA, et al. Role of stem cells in hu-man uterine leiomyoma growth. PLoS One. 2012; 7(5): e36935. doi: 10.1371/journal.pone.0036935
Mas A, Cervelló I, Fernández-Álvarez A, et al. Overexpres-sion of the truncated form of High Mobility Group A proteins (HMGA2) in human myometrial cells induces leiomyoma-like tissue formation. Mol Hum Reprod. 2015; 21(4): 330-338. doi: 10.1093/molehr/gau114
Zhou S, Yi T, Shen K, Zhang B, Huang F, Zhao X. Hypoxia: The driving force of uterine myometrial stem cells differentiation into leiomyoma cells. Med Hypotheses. 2011; 77(6): 985-986. doi: 10.1016/j.mehy.2011.08.026
Maruyama T, Ono M, Yoshimura Y. Somatic stem cells in the myometrium and in myomas. Semin Reprod Med. 2013; 31(01): 77- 81. doi: 10.1055/s-0032-1331801 Mini Review | Volume 8 | Number 1|
Liu B, Chen G, He Q, et al. An HMGA2-p62-ERα axis reg-ulates uterine leiomyomas proliferation. FASEB J. 2020; 34(8): 10966-10983. doi: 10.1096/fj.202000520R
Ono M, Maruyama T, Masuda H, et al. Side population in human uterine myometrium displays phenotypic and functional characteristics of myometrial stem cells. Proc Natl Acad Sci U S A. 2007; 104(47): 18700-18705. doi: 10.1073/pnas.0704472104
Mohyeldin A, Garzón-Muvdi T, Quiñones-Hinojosa A. Oxygen in stem cell biology: A critical component of the stem cell niche. Cell Stem Cell. 2010; 7(2): 150-161. doi: 10.1016/j. stem.2010.07.007
Red-Horse K, Zhou Y, Genbacev O, et al. Trophoblast dif-ferentiation during embryo implantation and formation of the maternal-fetal interface. J Clin Invest. 2004; 114(6): 744-754. doi: 10.1172/JCI22991
Cervello I, Gil-Sanchis C, Mas A, et al. Human endometrial side population cells exhibit genotypic, phenotypic and functional features of somatic stem cells. PLoS One. 2010; 5(6): e10964. doi: 10.1371/journal.pone.0010964
Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: Ultrasound evidence. Am J Obstet Gynecol. 2003; 188(1): 100-107. doi: 10.1067/mob.2003.99
Okolo S. Incidence, aetiology and epidemiology of uterine fibroids. Best Pract Res Clin Obstet Gynaecol. 2008; 22(4): 571-588. doi: 10.1016/j.bpobgyn.2008.04.002
Wallach EE, Vlahos NF. Uterine myomas: An overview of de-velopment, clinical features, and management. Obstet Gynecol. 2004; 104(2): 393-406. doi: 10.1097/01.AOG.0000136079.62513.39
Ono M, Qiang W, Serna VN, et al. Role of stem cells in hu-man uterine leiomyoma growth. PLoS One. 2012; 7(5): e36935. doi: 10.1371/journal.pone.0036935
Ono M, Yin P, Navarro A, et al. Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells pro-motes tumor growth. Proc Natl Acad Sci U S A. 2013. 110(42): 17053-17058. doi: 10.1073/pnas.1313650110
Zhang P, Zhang C, Hao J, et al. Use of X-chromosome inac-tivation pattern to determine the clonal origins of uterine leiomy-oma and leiomyosarcoma. Hum Pathol. 2006; 37(10): 1350-1356. doi: 10.1016/j.humpath.2006.05.005
Linder D, Gartler SM. Glucose-6-phosphate dehydrogenase mosaicism: utilization as a cell marker in the study of leiomyomas. Science. 1965; 150(3692): 67-69. doi: 10.1126/science.150.3692.67
Liu S, Yin P, Xu J, et al. Progesterone receptor-DNA meth-ylation crosstalk regulates depletion of uterine leiomyoma stem Mini Review | Volume 8 | Number 1| Vafaei S cells: A potential therapeutic target. Stem Cell Reports. 2021; 16(9): 2099-2106. doi: 10.1016/j.stemcr.2021.07.013
Navarro A, Yin P, Monsivais D, et al. Genome-wide DNA methylation indicates silencing of tumor suppressor genes in uterine leiomyoma. PLoS One. 2012; 7(3): e33284. doi: 10.1371/ journal.pone.0033284
Georgieva B, Milev I, Minkov I, Dimitrova I, Bradford AP, Baev V. Characterization of the uterine leiomyoma microR-NAome by deep sequencing. Genomics. 2012; 99(5): 275-281. doi: 10.1016/j.ygeno.2012.03.003
Tomlinson IP, Alam NA, Rowan AJ, et al. Germline muta-tions in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002; 30(4): 406-410. doi: 10.1038/ng849
Mäkinen N, Mehine M, Tolvanen J, et al. MED12, the media-tor complex subunit 12 gene, is mutated at high frequency in uter-ine leiomyomas. Science. 2011; 334(6053): 252-255. doi: 10.1126/ science.1208930
de Graaff MA, Cleton-Jansen A-M, Szuhai K, Bovée JVMG. Mediator complex subunit 12 exon 2 mutation analysis in dif-ferent subtypes of smooth muscle tumors confirms genetic het-erogeneity. Hum Pathol. 2013; 44(8): 1597-1604. doi: 10.1016/j. humpath.2013.01.006
Rieker RJ, Agaimy A, Moskalev EA, et al. Mutation status of the mediator complex subunit 12 (MED12) in uterine leiomyo-mas and concurrent/metachronous multifocal peritoneal smooth muscle nodules (leiomyomatosis peritonealis disseminata). Pathol-ogy, 2013. 45(4): 388-392. doi: 10.1097/PAT.0b013e328360bf97
Ravegnini G, Mariño-Enriquez A, Slater J, et al. MED12 mutations in leiomyosarcoma and extrauterine leiomyoma. Mod Pathol. 2013; 26(5): 743-749. doi: 10.1038/modpathol.2012.203
Heinonen H-R, Sarvilinna NS, Sjöberg J, et al. MED12 mutation frequency in unselected sporadic uterine leiomyo-mas. Fertil Steril. 2014; 102(4): 1137-1142. doi: 10.1016/j.fertn-stert.2014.06.040
Markowski DN, Bartnitzke S, Löning T, Drieschner N, Helmke BM, Bullerdiek J. MED12 mutations in uterine fibroids—their relationship to cytogenetic subgroups. Int J Cancer. 2012; 131(7): 1528-1536. doi: 10.1002/ijc.27424
Shaik NA, Lone WG, Khan IA, et al. Detection of somatic mutations and germline polymorphisms in mitochondrial DNA of uterine fibroids patients. Genet Test Mol Biomarkers. 2011; 15(7- 8): 537-541. doi: 10.1089/gtmb.2010.0255
Mehine M, Kaasinen E, Mäkinen N, et al. Characterization of uterine leiomyomas by whole-genome sequencing. N Engl J Med. 2013; 369(1): 43-53. doi: 10.1056/NEJMoa1302736
Hodge JC, Pearce KE, Clayton AC, Taran FA, Stewart EA. Uterine cellular leiomyomata with chromosome 1p deletions rep-resent a distinct entity. Am J Obstet Gynecol. 2014; 210(6): 572.e1- 572.e7. doi: 10.1016/j.ajog.2014.01.011
Klemke M, Meyer A, Maliheh Hashemi Nezhad, et al. Over-expression of HMGA2 in uterine leiomyomas points to its gen-eral role for the pathogenesis of the disease. Genes Chromosomes Cancer. 2009. 48(2): 171-8. doi: 10.1002/gcc.20627
Mehine M, Kaasinen E, Heinonen H-R, et al. Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers. Proc Natl Acad Sci U S A. 2016; 113(5): 1315-1320. doi: 10.1073/pnas.1518752113
Nezhad MH, Drieschner N, Helms S, et al. 6p21 rearrange-ments in uterine leiomyomas targeting HMGA1. Cancer Genetics and Cytogenet. 2010; 203(2): 247-252. doi: 10.1016/j.cancergen-cyto.2010.08.005
Schoenmakers, E.F.P.M., et al. Identification of CUX1 as the recurrent chromosomal band 7q22 target gene in human uter-ine leiomyoma. Genes, Chromosomes Cancer. 2013. 52(1): 11-23. doi: 10.1002/gcc.22001
Nozu K, Minamikawa S, Yamada S, et al. Characterization of contiguous gene deletions in COL4A6 and COL4A5 in Alport syndrome-diffuse leiomyomatosis. J Human Genet. 2017; 62(7): 733-735. doi: 10.1038/jhg.2017.28
Laganà AS, Vergara D, Favilli A, et al. Epigenetic and genetic landscape of uterine leiomyomas: A current view over a common gynecological disease. Arch Gynecol Obstet. 2017; 296(5): 855-867. doi: 10.1007/s00404-017-4515-5
Miozzo, M., V. Vaira, and S.M. Sirchia, Epigenetic alterations in cancer and personalized cancer treatment. Future Oncology, 2015. 11(2): 333-348.
Styer AK, Rueda BR. The epidemiology and genetics of uter-ine leiomyoma. Best Pract Res Clin Obstet Gynaecol. 2016. 34: 3-12. doi: 10.1016/j.bpobgyn.2015.11.018
Maekawa, R., Shun Sato, Yoshiaki Yamagata, et al. Genome-wide DNA methylation analysis reveals a potential mechanism for the pathogenesis and development of uterine leiomyomas. PLoS One. 2013; 8(6): e66632. doi: 10.1371/journal.pone.0066632
George JW, Fan H, Johnson B, et al. Integrated epigenome, exome, and transcriptome analyses reveal molecular subtypes and homeotic transformation in uterine fibroids. Cell Reports. 2019; 29(12): 4069-4085.e6. doi: 10.1016/j.celrep.2019.11.077
Liu S, Yin P, Kujawa SA, Coon JS, Okeigwe I, Bulun SE. Pro-gesterone receptor integrates the effects of mutated MED12 and altered DNA methylation to stimulate RANKL expression and stem cell proliferation in uterine leiomyoma. Oncogene. 2019; 8(15): 17 Vafaei S 2722-2735. doi: 10.1038/s41388-018-0612-6
Ali M, Ciebiera M, Vafaei S, et al. Progesterone signaling and uterine fibroid pathogenesis; Molecular mechanisms and potential therapeutics. Cells. 2023; 12(8): 1117. doi: 10.3390/cells12081117
Vaiman D. Towards an epigenetic treatment of leiomyomas? Endocrinology. 2020; 161(12): bqaa172. doi: 10.1210/endocr/ bqaa172
Albert M, Helin K. Histone methyltransferases in can-cer. Semin Cell Dev Biol. 2010; 21(2): 209-220. doi: 10.1016/j. semcdb.2009.10.007
Wei L-H, Torng P-L, Hsiao S-M, Jeng Y-M, Chen M-W, Chen C-A. Histone deacetylase 6 regulates estrogen receptor α in uterine leiomyoma. Reprod Sci. 2011; 18(8): 755-762. doi: 10.1177/1933719111398147
Segars JH, Al-Hendy A. Uterine leiomyoma: New perspec-tives on an old disease. Semin Reprod Med. 2017; 35(06): 471-472. doi: 10.1055/s-0037-1606569
Borahay MA, Al-Hendy A, Kilic GS, Boehning D. Signaling pathways in leiomyoma: Understanding pathobiology and impli-cations for therapy. Mol Med. 2015; 21(1): 242-256. doi: 10.2119/ molmed.2014.00053
Chuang TD, Rehan A, Khorram O, Functional role of the long noncoding RNA X-inactive specific transcript in leiomyoma pathogenesis. Fertil Steril. 2021; 115(1): 238-247. doi: 10.1016/j. fertnstert.2020.07.024
Ciarmela P, Petraglia F. New epigenetic mechanism involved in leiomyoma formation. Fertili Steril. 2021; 115(1): 94-95. doi: 10.1016/j.fertnstert.2020.09.143
Rinaldi L, Benitah SA. Epigenetic regulation of adult stem cell function. FEBS J. 2015; 282(9): 1589-1604. doi: 10.1111/ febs.12946
Mazzarella L, Jørgensen HF, Soza-Ried J, et al. Embryonic stem cell–derived hemangioblasts remain epigenetically plastic and require PRC1 to prevent neural gene expression. Blood. 2011; 117(1): 83-87. doi: 10.1182/blood-2010-03-273128
Laugesen A, Helin K. Chromatin repressive complexes in stem cells, development, and cancer. Cell Stem Cell. 2014; 14(6): 735-751. doi: 10.1016/j.stem.2014.05.006
Ezura, Y., et al. Methylation status of CpG islands in the pro-moter regions of signature genes during chondrogenesis of hu-man synovium–derived mesenchymal stem cells. Arthritis Rheum. 2009; 60(5): 1416-1426. doi: 10.1002/art.24472
Bulun SE. Uterine fibroids. N Engl J Med. 2013; 369(14): 1344- 1355. doi: 10.1056/NEJMra1209993 Mini Review | Volume 8 | Number 1|
Linehan WM, Rouault TA. Molecular pathways: Fumarate hydratase-deficient kidney cancer—targeting the Warburg ef-fect in cancer. Clin Cancer Res. 2013; 19(13): 3345-3352. doi: 10.1158/1078-0432.CCR-13-0304
Maruyama T, Ono M, Yoshimura Y. Somatic stem cells in the myometrium and in myomas. Semin Reprod Med. 2013; 31(1): 77- 81. doi: 10.1055/s-0032-1331801
Szotek PP, Chang HL, Zhang L, et al. Adult mouse myo-metrial label-retaining cells divide in response to gonadotropin stimulation. Stem Cells. 2007; 25(5): 1317-1325. doi: 10.1634/ stemcells.2006-0204
Ono M, Yin P, Navarro A, et al. Inhibition of canonical WNT signaling attenuates human leiomyoma cell growth. Fertil Steril. 2014; 101(5): 1441-1449. e1. doi: 10.1016/j.fertnstert.2014.01.017
Włodarczyk M, Nowicka G, Ciebiera M, Ali M, Yang Q, Al-Hendy A. Epigenetic regulation in uterine fibroids—the role of ten-eleven translocation enzymes and their potential therapeu-tic application. Int J Mol Sci. 2022; 23(5): 2720. doi: 10.3390/ ijms23052720 Submit your article to this journal | https://openventio.org/submit-manuscript/ Mini Review | Volume 8 | Number 1| Vafaei S
Ali M, Bariani MV, Vafaei S, et al. Prevention of uterine fi-broids: Molecular mechanisms and potential clinical applica-tion. J Endometr Uterine Disord. 2023; 1: 100018. doi: 10.1016/j. jeud.2023.100018
Bertsch E, Qiang W, Zhang Q, et al. MED12 and HMGA2 mutations: Two independent genetic events in uterine leiomyoma and leiomyosarcoma. Mod Pathol. 2014; 27(8): 1144-1153. doi: 10.1038/modpathol.2013.243
Schwetye KE, Pfeifer JD, Duncavage EJ. MED12 exon 2 mu-tations in uterine and extrauterine smooth muscle tumors. Hum Pathol. 2014; 45(1): 65-70. doi: 10.1016/j.humpath.2013.08.005
Sá MJN, Fieremans N, de Brouwer APM, et al. Deletion of the 5’ exons of COL4A6 is not needed for the development of dif-fuse leiomyomatosis in patients with Alport syndrome. J Med Gen-et. 2013; 50(11): 745-753. doi: 10.1136/jmedgenet-2013-101670
Vanharanta S, Pollard PJ, Lehtonen HJ, et al. Distinct expres-sion profile in fumarate-hydratase-deficient uterine fibroids. Hum Mol Genet. 2006; 15(1): 97-103. doi: 10.1093/hmg/ddi431
Downloads
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
All content published in Cancer Studies and Molecular Medicine (CSMM) is licensed under the Creative Commons Attribution 4.0 International License (CC BY 4.0). This license allows anyone to copy, distribute, transmit, and adapt the work — including for commercial purposes — provided appropriate credit is given to the original author(s) and source.
