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Paracrine Activation of WNT/Β-Catenin Pathway in Uterine Leiomyoma Stem Cells Promotes Tumor Growth

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Paracrine Activation of WNT/Β-Catenin Pathway in Uterine Leiomyoma Stem Cells Promotes Tumor Growth Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth Masanori Onoa,b, Ping Yina, Antonia Navarroa, Molly B. Moraveka, John S. Coon Va, Stacy A. Druschitza, Vanida Ann Sernaa, Wenan Qianga, David C. Brooksa, Saurabh S. Malpania, Jiajia Maa, Cihangir Mutlu Ercana, Navdha Mittala, Diana Monsivaisa, Matthew T. Dysona, Alex Yemelyanovc, Tetsuo Maruyamab, Debabrata Chakravartia, J. Julie Kima, Takeshi Kuritaa, Cara J. Gottardic, and Serdar E. Buluna,1 Departments of aObstetrics and Gynecology and cMedicine, Feinberg School of Medicine at Northwestern University, Chicago, IL 60611; and bDepartment of Obstetrics and Gynecology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan Edited by Jan-Åke Gustafsson, University of Houston, Houston, Texas, and approved September 5, 2013 (received for review July 18, 2013) Uterine leiomyomas are extremely common estrogen and proges- somatic stem cells and has been used to isolate them from many terone-dependent tumors of the myometrium and cause irregular adult tissues, such as the myometrium, endometrium, and mam- – uterine bleeding, severe anemia, and recurrent pregnancy loss in mary gland (9 12). We and another group have reported that SP 15–30% of reproductive-age women. Each leiomyoma is thought cells from human LM exhibit key features of the tumor-initiating to arise from a single mutated myometrial smooth muscle stem cells (13, 14). It has been proposed that each LM originates from a single cell. Leiomyoma side-population (LMSP) cells comprising 1% of all transformed somatic stem cell of the myometrium in an ovarian tumor cells and displaying tumor-initiating stem cell characteristics steroid-dependent manner (15); however, this suggestion has not are essential for estrogen- and progesterone-dependent in vivo been proven definitively. Human and mouse myometrial (MM) growth of tumors, although they have remarkably lower estro- tissues contain multipotent somatic stem cells, a subset of tissue gen/progesterone receptor levels than mature myometrial or leio- responsible for regeneration in an estrogen-and-progesterone myoma cells. However, how estrogen/progesterone regulates the (E+P)-dependent fashion (5, 10, 16). E+P-dependent in vivo growth of LMSP cells via mature neighboring cells is unknown. growth of human LM tissue requires the presence of these mul- Here, we demonstrate a critical paracrine role of the wingless-type tipotent somatic stem cells (13, 14). Compared with the main, β mature LM cell population or normal MM cells, however, LM (WNT)/ -catenin pathway in estrogen/progesterone-dependent MEDICAL SCIENCES tumorigenesis, involving LMSP and differentiated myometrial stem cells express remarkably lower levels of estrogen and pro- or leiomyoma cells. Estrogen/progesterone treatment of mature gesterone receptors (13, 14), and their growth requires the pres- myometrial cells induced expression of WNT11 and WNT16, which ence of mature MM or LM cells with higher levels of the steroid receptors and their ligands. This requirement suggests that steroid remained constitutively elevated in leiomyoma tissues. In LMSP hormone action on LM stem cells is mediated via mature MM cells cocultured with mature myometrial cells, estrogen-progester- β cells (tumor initiation) or mature LM cells (growth maintenance) one selectively induced nuclear translocation of -catenin and in- in a paracrine fashion. It is likely that this paracrine interaction duced transcriptional activity of its heterodimeric partner T-cell with the surrounding cells supports the self-renewal of LM stem factor and their target gene AXIN2, leading to the proliferation cells (10, 14). of LMSP cells. This effect could be blocked by a WNT antagonist. β-Catenin exists in multiple cellular pools and serves diverse Ectopic expression of inhibitor of β-catenin and T-cell factor 4 in LMSP functions. In its basal state, β-catenin is localized mainly to the cells, but not in mature leiomyoma cells, blocked the estrogen/ intercellular (adherens) junctions, where it is bound to the progesterone-dependent growth of human tumors in vivo. We cytoplasmic domain of E-cadherin and plays a role in the regu- uncovered a paracrine role of the WNT/β-catenin pathway that lation of cell–cell adhesion (17). In the presence of canonical wingless-type (WNT) MMTV integration site family signaling or enables mature myometrial or leiomyoma cells to send mitogenic – signals to neighboring tissue stem cells in response to estrogen and as a consequence of the destabilization of the cadherin catenin progesterone, leading to the growth of uterine leiomyomas. Significance WNT/β-catenin signaling | paracrine signaling | tumor biology Stem cells and the ovarian steroids estrogen and progesterone terine leiomyomas (LM), the most common pelvic tumor in are essential for leiomyoma tissue growth. The underlying Uwomen, are benign smooth muscle tumors originating from mechanisms are unknown, particularly because leiomyoma stem the myometrium (1). Uterine LMs occur in ∼70% of white women cells are deficient in estrogen and progesterone receptors. Ex- and more than 80% of African-American women by age 50 y and pression of these receptors is much higher in surrounding ma- cause excessive uterine bleeding, anemia, recurrent pregnancy ture myometrial or leiomyoma smooth muscle cells. Here, we loss, preterm labor, pelvic discomfort, and urinary incontinence demonstrate that wingless-type (WNT) acts as a paracrine signal in ∼15–30% of cases (2, 3). They are the most common indication from estrogen/progesterone receptor-rich mature cells to acti- β for hysterectomies (2, 4). Despite their high prevalence, the cellular vate the canonical -catenin pathway in leiomyoma stem cells. fi and molecular origins of uterine LM remain poorly understood. Our ndings suggest a paracrine role for the canonical WNT Somatic stem cells are a subset of cells residing in normal adult pathway in the growth of leiomyoma tumor. tissues that, through asymmetric division, retain their ability to self-renew while producing daughter cells that go on to differen- Author contributions: M.O., C.J.G., and S.E.B. designed research; M.O., P.Y., A.N., M.B.M., tiate and play a role in tissue regeneration and repair (5, 6). J.S.C., S.A.D., V.A.S., D.C.B., S.S.M., J.M., C.M.E., N.M., D.M., M.T.D., and S.E.B. performed research; W.Q., A.Y., T.K., and C.J.G. contributed new reagents/analytic tools; M.O., P.Y., Likewise, tumor-initiating cells are a subset of cells within a tumor T.M., and S.E.B. analyzed data; and M.O., J.S.C., D.C., J.J.K., and S.E.B. wrote the paper. cell population, which also through asymmetric division retain the The authors declare no conflict of interest. ability to sustain tumors (7, 8). The side population (SP) cell phenotype was described first in bone marrow, where a somatic This article is a PNAS Direct Submission. stem cell population was identified based on its ability to extrude Freely available online through the PNAS open access option. the DNA-binding dye Hoechst 33342, a phenomenon that is as- 1To whom correspondence should be addressed. E-mail: [email protected]. sociated with the expression of ATP-binding cassette transporter This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. G2 (8). The SP phenotype is thought to be a universal marker of 1073/pnas.1313650110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1313650110 PNAS Early Edition | 1of6 Downloaded by guest on September 23, 2021 complex, activated β-catenin translocates to the nucleus and A OVX and GRAFT 106 LM cells binds to the T-cell factor (TCF)/lymphocyte enhancer factor E+P IMPLANT TUMOR SIZE (LEF) family of transcription factors, resulting in the expression 8 wks. of specific target genes (17, 18). Because many β-catenin target genes, such as c-Myc, WISP1, and cyclin D1, are involved in cell B C 3 Tumor Volume proliferation, β-catenin signaling plays an important role in de- LM Ad-GFP LM Ad-ICAT mm *P<0.05 velopment and neoplasia (17). Selective overexpression of con- 3 * stitutively activated β-catenin in uterine mesenchyme during 2 embryonic development and in adults gives rise to LM-like 1 tumors in the uterus of all female mice (19), suggesting that signaling by WNT/β-catenin may play a role in somatic stem cell 0 LM Ad-GFP LM Ad-ICAT function in the myometrium and in uterine LM tissue. Selective n=5 n=5 deletion of β-catenin in uterine mesenchyme during the embry- onic development significantly reduces uterine size and replaces Fig. 1. Blocking WNT activity inhibits the growth of LM tumors in NOD-SCID it with adipocytes, thus completely disrupting the normal MM (IL2Rγnull) mice. (A) Experimental design and hormone treatment. Mice were smooth muscle differentiation and regeneration (16). This effect ovariectomized and xenotransplanted with LM cells infected by Ad-GFP or suggests that β-catenin plays a key role in stem cell renewal and Ad-ICAT and then were treated with s.c. implantation of E2 and P4 pellets. differentiation to the smooth muscle phenotype observed in MM The mice underwent nephrectomy 8 wk after xenotransplantation. (B) Mac- and LM tissues (5). The size and number of β-catenin–driven roscopic visualization of the transplanted site 8 wk after xenotransplantation. LM-like tumors increases with parity in mice, suggesting that (C) Xenografts were analyzed in terms of tumor volume. Error bars indicate steroid hormones may interact with activated β-catenin to ac- SD; *P < 0.05; n = 5 paired patient samples. celerate tumorigenesis (19). Moreover, activated β-catenin in- duced the expression of TGF-β3, which was shown to induce proliferation and ECM formation in human LM tissue (19). from the TCF/LEF reporter gene with an average twofold in- crease in luciferase activity in MM and LM cells compared with These observations indicate that unique interactions exist be- n = P < B tween β-catenin activation, estrogen and progesterone action, NaCl-treated controls ( 6, 0.05) (Fig.
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