Constitutive Activation of Beta-Catenin in Uterine Stroma and Smooth Muscle Leads to the Development of Mesenchymal Tumors in Mice
Constitutive Activation of Beta-Catenin in Uterine Stroma and Smooth Muscle Leads to the Development of Mesenchymal Tumors in Mice
复制标题
DOI：
10.1095/biolreprod.108.075648
复制
发表时间：
2009-09-01
影响因子：
3.6
通讯作者：
Teixeira, Jose M.
中科院分区：
文献类型：
--
作者：
Tanwar, Pradeep S.;Lee, Ho-Joon;Teixeira, Jose M.
平滑肌瘤和其他间质源性肿瘤是女性生殖道最常见的肿瘤。目前，对这些肿瘤的病因和进展知之甚少，而这些肿瘤是直肠癌切除术的主要适应症。通过β-连环蛋白的WNT信号转导失调是肿瘤发生的一种公认机制。我们已经开发了一种小鼠模型，在子宫间质中表达组成型激活的β-连环蛋白，该模型由敲入苗勒管抑制物质11型受体启动子位点的Cre重组酶的表达驱动，以研究其对子宫内膜基质和子宫肌层的影响。这些小鼠表现出子宫肌层增生，并以100%的阳性率发展间质肿瘤，表现出人类平滑肌瘤和子宫内膜间质肉瘤的组织学和分子特征。通过免疫组织化学，我们还表明，转化生长因子β和哺乳动物雷帕霉素的目标诱导的组成性激活betacatenin。肿瘤的患病率在经产小鼠中更高，这表明它们的发展可能是一个生殖驱动的过程，或者妊娠期间和分娩后子宫形态的变化诱导损伤和修复机制，刺激干/祖细胞的肿瘤发生，而干/祖细胞通常不表达组成性激活的β-连环蛋白。此外，在一些小鼠中偶尔观察到子宫腺肌病和子宫内膜腺增生。这些结果表明，有证据表明，失调，基质，子宫肌层WNT/β-连环蛋白信号对子宫功能和肿瘤发生具有多效性作用。
Leiomyomas and other mesenchymally derived tumors are the most common neoplasms of the female reproductive tract. Presently, very little is known about the etiology and progression of these tumors, which are the primary indication for hysterectomies. Dysregulated WNT signaling through beta-catenin is a well-established mechanism for tumorigenesis. We have developed a mouse model that expresses constitutively activated beta-catenin in uterine mesenchyme driven by the expression of Cre recombinase knocked into the Mullerian-inhibiting substance type 11 receptor promoter locus to investigate its effects on uterine endometrial stroma and myometrium. These mice show myometrial hyperplasia and develop mesenchymal tumors with 100% penetrance that exhibit histological and molecular characteristics of human leiomyomas and endometrial stromal sarcomas. By immunohistochemistry, we also show that both transforming growth factor beta and the mammalian target of rapamycin are induced by constitutive activation of betacatenin. The prevalence of the tumors was greater in multiparous mice, suggesting that their development may be a hormonally driven process or that changes in uterine morphology during pregnancy and after parturition induce injury and repair mechanisms that stimulate tumorigenesis from stem/progenitor cells, which normally do not express constitutively activated beta-catenin. Additionally, adenomyosis and endometrial gland hyperplasia were occasionally observed in some mice. These results show evidence suggesting that dysregulated, stromal, and myometrial WNT/beta-catenin signaling has pleiotropic effects on uterine function and tumorigenesis.