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

Masanori Ono, Ping Yin, Antonia Navarro, Molly B. Moravek, John S. Coon V, Stacy A. Druschitz, Vanida Ann Serna, Wenan Qiang, David C. Brooks, Saurabh S. Malpani, Jiajia Ma, Cihangir Mutlu Ercan, Navdha Mittal, Diana Monsivais, Matthew T. Dyson, Alex Yemelyanov, Tetsuo Maruyama, Debabrata Chakravarti, J. Julie Kim, Takeshi KuritaCara J. Gottardi, Serdar E. Bulun*

*Corresponding author for this work

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)17053-17058
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number42
DOIs
StatePublished - Oct 15 2013

    Fingerprint

Keywords

  • Paracrine signaling
  • Tumor biology
  • WNT/β-catenin signaling

ASJC Scopus subject areas

  • General

Cite this

Ono, M., Yin, P., Navarro, A., Moravek, M. B., Coon V, J. S., Druschitz, S. A., Serna, V. A., Qiang, W., Brooks, D. C., Malpani, S. S., Ma, J., Ercan, C. M., Mittal, N., Monsivais, D., Dyson, M. T., Yemelyanov, A., Maruyama, T., Chakravarti, D., Kim, J. J., ... Bulun, S. E. (2013). Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth. Proceedings of the National Academy of Sciences of the United States of America, 110(42), 17053-17058. https://doi.org/10.1073/pnas.1313650110