PLoS One：单一的干细胞突变可致妇女患子宫肌瘤

在美国，子宫肌瘤影响着1500万妇女的健康状况，子宫肌瘤可引起妇女不规则子宫出血、贫血、疼痛以及不育。这种肿瘤的高发率（60%发生在45岁时的妇女身上），其分子机制目前并不知晓。近日，来自美国西北大学范伯格医学院的研究者首次发现了子宫肌瘤的分子引发机制，引发这种疾病实际上是单一干细胞的突变所引起的，致使肿瘤细胞无限制生长并且激活其它细胞使其扩散。

研究者Serdar Bulun表示，之前并没有人知道子宫肌瘤的发病机制，干细胞在肿瘤细胞中只占到了1/2的比例，然而干细胞却是引发肿瘤细胞无限增殖的助推器。相关研究成果刊登在了近日的国际杂志PLoS One上。

干细胞启动肿瘤细胞，使其携带一种称为MED12的突变；近日，MED12基因的突变在大部分的子宫肌瘤组织中被发现，一旦突变开始进行异常的扩散，肿瘤则会对类固醇激素尤其是黄体酮产生反应，进行快速增长。

这项研究中，研究者将子宫肌瘤干细胞（fibroid stem cells）移植入小鼠体内，然后检测其表现。子宫肌瘤干细胞具有产生肿瘤的能力，而且来源于子宫肌瘤干细胞的肿瘤细胞的生长速度是其它肿瘤的10倍，这就揭示了这些子宫肌瘤干细胞产生并且维持肿瘤生长的一个重要角色。

最后，研究者Bulun表示，理解突变直接影响肿瘤细胞的生长给我们未来开发出新的治疗方法提供了方向和一些建议。（生物谷：T.Shen编译）

doi:​10.1371/journal.pone.0036935
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Role of Stem Cells in Human Uterine Leiomyoma Growth

Masanori Ono, Wenan Qiang, Vanida Ann Serna, Ping Yin, John S. Coon V, Antonia Navarro, Diana Monsivais, Toshiyuki Kakinuma, Matthew Dyson, Stacy Druschitz, Kenji Unno, Takeshi Kurita, Serdar E. Bulun*

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.

Principal Findings 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 mm3), whereas xenografts comprised of LMMP and unsorted myometrial smooth muscle cells produced smaller tumors (0.54±0.20 mm3, 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.