β-catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and aggressive fibromatosis and hyperplastic cutaneous wounds
β-catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and aggressive fibromatosis and hyperplastic cutaneous wounds
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DOI：
10.1073/pnas.102657399
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发表时间：
2002-05-14
影响因子：
11.1
通讯作者：
Alman, BA
中科院分区：
文献类型：
--
作者：
Cheon, SS;Cheah, AYL;Alman, BA
纤维增生性过程是一组梭形细胞（间充质成纤维细胞样）过度增殖的疾病。它们的范围从增生性疤痕到肿瘤，如侵袭性纤维瘤病。来自这些疾病的细胞与在伤口愈合增殖阶段存在的成纤维细胞具有细胞学上的相似性，这表明它们代表了一种长期的伤害反应。在侵袭性纤维瘤病中，β -连环蛋白在间充质细胞的纤维增殖过程中起着关键作用，其高体细胞突变率表明。使用tcf报告小鼠，我们发现-连环蛋白水平和tcf转录活性在成纤维细胞愈合的增殖阶段升高。我们培育了一只转基因小鼠，在四环素调控启动子的控制下，稳定的-连环蛋白在间充质细胞中表达。转基因小鼠的成纤维细胞在表达稳定的β -连环蛋白时表现出增强的增殖、运动性和侵袭性，并在转基因诱导后移植到裸鼠体内诱导肿瘤。转基因诱导小鼠3个月后出现侵袭性纤维瘤病和胃肠道增生性息肉，与对照组小鼠相比，其皮肤创面愈合增生性较好，这表明β -连环蛋白在间充质细胞中具有重要功能，在创面愈合和纤维增生性疾病中发挥核心作用。
Fibroproliferative processes are a group of disorders in which there is excessive proliferation of spindle (mesenchymal fibroblast-like) cells. They range from hypertrophic scars to neoplasms such as aggressive fibromatosis. Cells from these disorders share cytologic similarity with fibroblasts present during the proliferative phase of wound healing, suggesting that they represent a prolonged wounding response. A critical role for beta-catenin in mesenchymal cells in fibroproliferative processes is suggested by its high rate of somatic mutation in aggressive fibromatosis. Using a Tcf-reporter mouse we found that beta-catenin protein level and Tcf-transcriptional activity are elevated in fibroblasts during the proliferative phase of healing. We generated a transgenic mouse in which stabilized beta-catenin is expressed in mesenchymal cells under control of a tetracycline-regulated promoter. Fibroblasts from the transgenic mice exhibited increased proliferation, motility, and invasiveness when expressing stabilized beta-catenin and induced tumors after induction of the transgene when grafted into nude mice. Mice developed aggressive fibromatoses and hyperplastic gastrointestinal polyps after 3 months of transgene induction and healed with hyperplastic cutaneous wounds compared with control mice, which demonstrates an important function for beta-catenin in mesenchymal cells and shows a central role for beta-catenin in wound healing and fibroproliferative disorders.