Semin Reprod Med 2017; 35(06): 481-486
DOI: 10.1055/s-0037-1607205
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Origin of Uterine Fibroids: Conversion of Myometrial Stem Cells to Tumor-Initiating Cells

Hoda Elkafas
1   Pharmacology and Toxicology Department, National Organization for Drug Control and Research (NODCAR), Giza, Egypt
2   Obsteric and Gynecology Department, Medical College of Georgia, Augusta University, Augusta, Georgia
,
Yang Qiwei
2   Obsteric and Gynecology Department, Medical College of Georgia, Augusta University, Augusta, Georgia
,
Ayman Al-Hendy
2   Obsteric and Gynecology Department, Medical College of Georgia, Augusta University, Augusta, Georgia
› Author Affiliations
Further Information

Publication History

Publication Date:
03 November 2017 (online)

Abstract

Uterine fibroids (UFs) are the most frequent gynecologic tumors, affecting 70 to 80% of women over their lifetime, Although these tumors are benign, they can cause significant morbidity and may require invasive treatments such as myomectomy and hysterectomy in premenopausal women at a cost of up to $34 billion per year. Many risk factors for these tumors have been identified, including environmental exposures to endocrine-disrupting chemicals such as genistein and diethylstilbestrol (and other environmental agents) resulting in hyper-responsiveness to hormone in the adult uterus and promotion of hormone-dependent UFs. Although the molecular mechanisms underlying the pathogenesis of UFs is largely unknown, a growing body of evidence implicates unfavorable early-life environmental exposure and multiple biological pathways express as potentially import contributors. In this article, we will review the role of genetic and epigenetics in the conversion of myometrial stem cells to tumor (fibroid) initiating cells, and their role in UF development.

 
  • References

  • 1 Al-Hendy A, Salama S. Gene therapy and uterine leiomyoma: a review. Hum Reprod Update 2006; 12 (04) 385-400
  • 2 Yang Q, Mas A, Diamond MP, Al-Hendy A. The mechanism and function of epigenetics in uterine leiomyoma development. Reprod Sci 2016; 23 (02) 163-175
  • 3 Mas A, Stone L, O’Connor PM. , et al. Developmental exposure to endocrine disruptors expands murine myometrial stem cell compartment as a prerequisite to leiomyoma tumorigenesis. Stem Cells 2017; 35 (03) 666-678
  • 4 Wilson AC, Meethal SV, Bowen RL, Atwood CS. Leuprolide acetate: a drug of diverse clinical applications. Expert Opin Investig Drugs 2007; 16 (11) 1851-1863
  • 5 Ishikawa H, Ishi K, Serna VA, Kakazu R, Bulun SE, Kurita T. Progesterone is essential for maintenance and growth of uterine leiomyoma. Endocrinology 2010; 151 (06) 2433-2442
  • 6 Mäkinen N, Mehine M, Tolvanen J. , et al. MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science 2011; 334 (6053): 252-255
  • 7 Markowski DN, von Ahsen I, Nezhad MH, Wosniok W, Helmke BM, Bullerdiek J. HMGA2 and the p19Arf-TP53-CDKN1A axis: a delicate balance in the growth of uterine leiomyomas. Genes Chromosomes Cancer 2010; 49 (08) 661-668
  • 8 Fuchs E, Segre JA. Stem cells: a new lease on life. Cell 2000; 100 (01) 143-155
  • 9 Li L, Neaves WB. Normal stem cells and cancer stem cells: the niche matters. Cancer Res 2006; 66 (09) 4553-4557
  • 10 Walker CL, Ho SM. Developmental reprogramming of cancer susceptibility. Nat Rev Cancer 2012; 12 (07) 479-486
  • 11 Prins GS, Calderon-Gierszal EL, Hu W-Y. Stem cells as hormone targets that lead to increased cancer susceptibility. Endocrinology 2015; 156 (10) 3451-3457
  • 12 Bulun SE. Uterine fibroids. N Engl J Med 2013; 369 (14) 1344-1355
  • 13 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
  • 14 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
  • 15 Chang HL, Senaratne TN, Zhang L. , et al. Uterine leiomyomas exhibit fewer stem/progenitor cell characteristics when compared with corresponding normal myometrium. Reprod Sci 2010; 17 (02) 158-167
  • 16 Mas A, Cervelló I, Gil-Sanchis C. , et al. Identification and characterization of the human leiomyoma side population as putative tumor-initiating cells. Fertil Steril 2012; 98 (03) 741-751.e6
  • 17 Ono M, Qiang W, Serna VA. , et al. Role of stem cells in human uterine leiomyoma growth. PLoS One 2012; 7 (05) e36935
  • 18 Mäkinen N, Heinonen HR, Moore S, Tomlinson IP, van der Spuy ZM, Aaltonen LA. MED12 exon 2 mutations are common in uterine leiomyomas from South African patients. Oncotarget 2011; 2 (12) 966-969
  • 19 Halder SK, Laknaur A, Miller J, Layman LC, Diamond M, Al-Hendy A. Novel MED12 gene somatic mutations in women from the Southern United States with symptomatic uterine fibroids. Mol Genet Genomics 2015; 290 (02) 505-511
  • 20 Stewart EA, Laughlin-Tommaso SK, Catherino WH, Lalitkumar S, Gupta D, Vollenhoven B. Uterine fibroids. Nat Rev Dis Primers 2016; 2: 16043
  • 21 Islam MS, Protic O, Stortoni P. , et al. Complex networks of multiple factors in the pathogenesis of uterine leiomyoma. Fertil Steril 2013; 100 (01) 178-193
  • 22 Tomlinson IP, Alam NA, Rowan AJ. , et al; Multiple Leiomyoma Consortium. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002; 30 (04) 406-410
  • 23 Stewart L, Glenn GM, Stratton P. , et al. Association of germline mutations in the fumarate hydratase gene and uterine fibroids in women with hereditary leiomyomatosis and renal cell cancer. Arch Dermatol 2008; 144 (12) 1584-1592
  • 24 Mittal P, Shin YH, Yatsenko SA, Castro CA, Surti U, Rajkovic A. Med12 gain-of-function mutation causes leiomyomas and genomic instability. J Clin Invest 2015; 125 (08) 3280-3284
  • 25 Katz TA, Yang Q, Treviño LS, Walker CL, Al-Hendy A. Endocrine-disrupting chemicals and uterine fibroids. Fertil Steril 2016; 106 (04) 967-977
  • 26 Gore AC, Chappell VA, Fenton SE. , et al. EDC-2: the endocrine society's second scientific statement on endocrine-disrupting chemicals. Endocr Rev 2015; 36 (06) E1-E150
  • 27 Gore AC, Heindel JJ, Zoeller RT. Endocrine disruption for endocrinologists (and others). Endocrinology 2006; 147 (6, Suppl): S1-S3
  • 28 Kuiper GG, Lemmen JG, Carlsson B. , et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology 1998; 139 (10) 4252-4263
  • 29 Sengupta S, Obiorah I, Maximov PY, Curpan R, Jordan VC. Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol 2013; 169 (01) 167-178
  • 30 Sui Y, Ai N, Park SH. , et al. Bisphenol A and its analogues activate human pregnane X receptor. Environ Health Perspect 2012; 120 (03) 399-405
  • 31 Matsushima A, Kakuta Y, Teramoto T. , et al. Structural evidence for endocrine disruptor bisphenol A binding to human nuclear receptor ERR γ∙. J Biochem 2007; 142 (04) 517-524
  • 32 Benninghoff AD, Bisson WH, Koch DC, Ehresman DJ, Kolluri SK, Williams DE. Estrogen-like activity of perfluoroalkyl acids in vivo and interaction with human and rainbow trout estrogen receptors in vitro. Toxicol Sci 2011; 120 (01) 42-58
  • 33 McGuire MM, Yatsenko A, Hoffner L, Jones M, Surti U, Rajkovic A. Whole exome sequencing in a random sample of North American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas. PLoS One 2012; 7 (03) e33251
  • 34 Yamada T, Nakago S, Kurachi O. , et al. Progesterone down-regulates insulin-like growth factor-I expression in cultured human uterine leiomyoma cells. Hum Reprod 2004; 19 (04) 815-821
  • 35 Greathouse KL, Bredfeldt T, Everitt JI. , et al. Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis. Mol Cancer Res 2012; 10 (04) 546-557
  • 36 Ono M, Yin P, Navarro A. , et al. Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth. Proc Natl Acad Sci U S A 2013; 110 (42) 17053-17058
  • 37 Tanwar PS, Lee HJ, Zhang L. , et al. Constitutive activation of Beta-catenin in uterine stroma and smooth muscle leads to the development of mesenchymal tumors in mice. Biol Reprod 2009; 81 (03) 545-552
  • 38 Mosimann C, Hausmann G, Basler K. β-catenin hits chromatin: regulation of Wnt target gene activation. Nat Rev Mol Cell Biol 2009; 10 (04) 276-286
  • 39 Borahay MA, Asoglu MR, Mas A, Adam S, Kilic GS, Al-Hendy A. Estrogen receptors and signaling in fibroids: role in pathobiology and therapeutic implications. Reprod Sci 2017; 24 (09) 1235-1244
  • 40 Cook JD, Davis BJ, Cai SL, Barrett JC, Conti CJ, Walker CL. Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance. Proc Natl Acad Sci U S A 2005; 102 (24) 8644-8649
  • 41 Greathouse KL, Cook JD, Lin K. , et al. Identification of uterine leiomyoma genes developmentally reprogrammed by neonatal exposure to diethylstilbestrol. Reprod Sci 2008; 15 (08) 765-778
  • 42 Yang Q, Diamond MP, Al-Hendy A. Early life adverse environmental exposures increase the risk of uterine fibroid development: role of epigenetic regulation. Front Pharmacol 2016; 7: 40
  • 43 Moravek MB, Yin P, Ono M. , et al. Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications. Hum Reprod Update 2015; 21 (01) 1-12
  • 44 Janzen DM, Cheng D, Schafenacker AM. , et al. Estrogen and progesterone together expand murine endometrial epithelial progenitor cells. Stem Cells 2013; 31 (04) 808-822
  • 45 Ge LC, Chen ZJ, Liu HY. , et al. Involvement of activating ERK1/2 through G protein coupled receptor 30 and estrogen receptor α/β in low doses of bisphenol A promoting growth of Sertoli TM4 cells. Toxicol Lett 2014; 226 (01) 81-89
  • 46 Li X, Zhang S, Safe S. Activation of kinase pathways in MCF-7 cells by 17β-estradiol and structurally diverse estrogenic compounds. J Steroid Biochem Mol Biol 2006; 98 (2-3): 122-132
  • 47 Hewitt SC, Deroo BJ, Hansen K. , et al. Estrogen receptor-dependent genomic responses in the uterus mirror the biphasic physiological response to estrogen. Mol Endocrinol 2003; 17 (10) 2070-2083
  • 48 Winuthayanon W, Hewitt SC, Korach KS. Uterine epithelial cell estrogen receptor alpha-dependent and -independent genomic profiles that underlie estrogen responses in mice. Biol Reprod 2014; 91 (05) 110
  • 49 Burns KA, Korach KS. Estrogen receptors and human disease: an update. Arch Toxicol 2012; 86 (10) 1491-1504
  • 50 Kelly MJ, Qiu J, Rønnekleiv OK. Estrogen modulation of G-protein-coupled receptor activation of potassium channels in the central nervous system. Ann N Y Acad Sci 2003; 1007 (01) 6-16
  • 51 Borahay MA, Al-Hendy A, Kilic GS, Boehning D. Signaling pathways in leiomyoma: understanding pathobiology and implications for therapy. Mol Med 2015; 21 (01) 242-256
  • 52 Singh M, Su C, Ng S. Non-genomic mechanisms of progesterone action in the brain. Front Neurosci 2013; 7: 159
  • 53 Migliaccio A, Piccolo D, Castoria G. , et al. Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor. EMBO J 1998; 17 (07) 2008-2018
  • 54 Patel B, Elguero S, Thakore S, Dahoud W, Bedaiwy M, Mesiano S. Role of nuclear progesterone receptor isoforms in uterine pathophysiology. Hum Reprod Update 2015; 21 (02) 155-173
  • 55 Al-Hendy A, Diamond MP, Boyer TG, Halder SK. Vitamin D3 inhibits Wnt/β-catenin and mTOR signaling pathways in human uterine fibroid cells. J Clin Endocrinol Metab 2016; 101 (04) 1542-1551
  • 56 Goyeneche AA, Telleria CM. Antiprogestins in gynecological diseases. Reproduction 2015; 149 (01) R15-R33
  • 57 Yang Q. , et al. Early life developmental exposure to endocrine disrupting chemicals increases the risk of adult onset of uterine fibroids by permanently reprograming the epigenome of myometrial stem cells towards a pro-fibroid landscape. Fertil Steril 2016; 106 (03) e2
  • 58 Yang Q, Al-Hendy A. Developmental environmental exposure alters the epigenetic features of myometrial stem cells. Gynecol Obstet Res 2016; 3 (02) e1-e4
  • 59 Yang Q. , et al. Identification of novel epigenetic reprogrammed genes in myometrial stem cells developmentally exposed to endocrine disrupting chemicals. Reprod Sci 2017; 24: 103A