Departments of Obstetrics and Gynecology and Medicine, Feinberg School of Medicine at Northwestern University, Chicago, IL 60611.
Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):17053-8. doi: 10.1073/pnas.1313650110. Epub 2013 Sep 30.
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.
子宫肌瘤是一种极为常见的子宫平滑肌来源的雌激素和孕激素依赖性肿瘤，可导致 15%-30%的育龄期妇女出现子宫不规则出血、严重贫血和反复妊娠丢失。每一个子宫肌瘤都被认为是由一个单一的突变的子宫平滑肌干细胞引起的。占所有肿瘤细胞 1%的子宫肌瘤侧群（LMSP）细胞具有肿瘤起始干细胞特征，对于雌激素和孕激素依赖性肿瘤的体内生长是必需的，尽管它们的雌激素/孕激素受体水平明显低于成熟的平滑肌或子宫肌瘤细胞。然而，雌激素/孕激素如何通过成熟的邻近细胞调节 LMSP 细胞的生长尚不清楚。在这里，我们证明了 WNT/β-catenin 通路在雌激素/孕激素依赖性肿瘤发生中的关键旁分泌作用，涉及 LMSP 和分化的平滑肌或子宫肌瘤细胞。成熟的平滑肌细胞用雌激素/孕激素处理后，诱导 WNT11 和 WNT16 的表达，而这些在子宫肌瘤组织中持续高表达。在与成熟的平滑肌细胞共培养的 LMSP 细胞中，雌激素/孕激素选择性诱导β-catenin 的核易位，并诱导其异二聚体伙伴 T 细胞因子及其靶基因 AXIN2 的转录活性，导致 LMSP 细胞的增殖。这种作用可以被 WNT 拮抗剂阻断。在 LMSP 细胞中异位表达β-catenin 和 T 细胞因子 4 的抑制剂，但不在成熟的子宫肌瘤细胞中，可阻断体内人肿瘤对雌激素/孕激素的依赖性生长。我们揭示了 WNT/β-catenin 通路的旁分泌作用，使成熟的平滑肌或子宫肌瘤细胞能够在雌激素和孕激素的作用下，向邻近的组织干细胞发送有丝分裂信号，导致子宫子宫肌瘤的生长。
