title: Role of stem cells in human uterine leiomyoma growth.
abstract: BACKGROUND
  Uterine leiomyoma is the most common benign tumor in reproductive-age women. Each leiomyoma is thought to be a benign monoclonal tumor arising from a single transformed myometrial smooth muscle cell; however, it is not known what leiomyoma cell type is responsible for tumor growth. Thus, we tested the hypothesis that a distinct stem/reservoir cell-enriched population, designated as the leiomyoma-derived side population (LMSP), is responsible for cell proliferation and tumor growth.
  
  
  RESULTS
  LMSP comprised approximately 1% of all leiomyoma and 2% of all myometrium-derived cells. All LMSP and leiomyoma-derived main population (LMMP) but none of the side or main population cells isolated from adjacent myometrium carried a mediator complex subunit 12 mutation, a genetic marker of neoplastic transformation. Messenger RNA levels for estrogen receptor-α, progesterone receptor and smooth muscle cell markers were barely detectable and significantly lower in the LMSP compared with the LMMP. LMSP alone did not attach or survive in monolayer culture in the presence or absence of estradiol and progestin, whereas LMMP readily grew under these conditions. LMSP did attach and survive when directly mixed with unsorted myometrial cells in monolayer culture. After resorting and reculturing, LMSP gained full potential of proliferation. Intriguingly, xenografts comprised of LMSP and unsorted myometrial smooth muscle cells grew into relatively large tumors (3.67 ± 1.07 mm(3)), whereas xenografts comprised of LMMP and unsorted myometrial smooth muscle cells produced smaller tumors (0.54 ± 0.20 mm(3), p<0.05, n = 10 paired patient samples). LMSP xenografts displayed significantly higher proliferative activity compared with LMMP xenografts (p<0.05).
  
  
  CONCLUSIONS
  Our data suggest that LMSP, which have stem/reservoir cell characteristics, are necessary for in vivo growth of leiomyoma xenograft tumors. Lower estrogen and progesterone receptor levels in LMSP suggests an indirect paracrine effect of steroid hormones on stem cells via the mature neighboring cells.
authors.affiliation: Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Ono
authors.forename: Wenan
authors.initials: W
authors.lastname: Qiang
authors.forename: Vanida Ann
authors.initials: VA
authors.lastname: Serna
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.forename: John S
authors.initials: JS
authors.lastname: Coon
authors.forename: Antonia
authors.initials: A
authors.lastname: Navarro
authors.forename: Diana
authors.initials: D
authors.lastname: Monsivais
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kakinuma
authors.forename: Matthew
authors.initials: M
authors.lastname: Dyson
authors.forename: Stacy
authors.initials: S
authors.lastname: Druschitz
authors.forename: Kenji
authors.initials: K
authors.lastname: Unno
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kurita
authors.forename: Serdar E
authors.initials: SE
authors.lastname: Bulun
mesh_terms: D000328:Adult; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001483:Base Sequence; D001773:Blood Cells / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D007889:Leiomyoma / Q000235:genetics / Q000378:metabolism*; D056892:Mediator Complex / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D009215:Myometrium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D000954:Antigens, Surface; C460107:MED12 protein, human; D056892:Mediator Complex