Subtype-Specific Tumor-Associated Fibroblasts Contribute to the Pathogenesis of Uterine Leiomyoma.
Subtype-Specific Tumor-Associated Fibroblasts Contribute to the Pathogenesis of Uterine Leiomyoma.
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DOI：
10.1158/0008-5472.can-17-1744
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发表时间：
2017-12-15
期刊：
影响因子：
11.2
通讯作者：
Kurita T
中科院分区：
文献类型：
--
作者：
Wu X;Serna VA;Thomas J;Qiang W;Blumenfeld ML;Kurita T
最近的基因组研究已经确定了具有独特遗传改变的子宫平滑肌瘤（LM）亚型。在这里，我们报道了两种最常见的LM亚型，MED12突变型（MED12-LM）和hmga2过表达型（HMGA2-LM） LM的生物学特性。由于每个肿瘤只携带一种基因改变，因此这两种亚型都被认为是单克隆的。HMGA2- lm中约90%的细胞是HMGA2过表达的平滑肌细胞（SMC）。相比之下，MED12-LM由相似数量的SMC和非SMC组成，其中大部分是肿瘤相关成纤维细胞（TAF）。矛盾的是，TAF在MED12中没有携带突变，这表明SMC和TAF之间相互作用以协调它们的生长。MED12-LM中ECM的含量高于HMGA2-LM，部分原因是产生胶原蛋白的TAF浓度较高。在异种移植试验中，两种LM亚型的SMC生长都是由黄体酮驱动的。相比之下，MED12-LM中的TAF对雌二醇有增殖反应，而黄体酮没有影响。MED12-LM中高浓度的雌激素应答TAF解释了体内和体外研究中雌激素有丝分裂作用的不一致发现，并对先前利用MED12-LM细胞培养的研究的准确性提出了质疑。此外，雌二醇和黄体酮对这些LM亚型的不同影响强调了亚型和基因型在设计LM非手术治疗策略中的重要性。
Recent genomic studies have identified subtypes of uterine leiomyoma (LM) with distinctive genetic alterations. Here we report the elucidation of the biological characteristics of the two most prevalent LM subtypes, MED12 mutant (MED12-LM) and HMGA2-overexpressing (HMGA2-LM) LM. Since each tumor carries only one genetic alteration, both subtypes are considered to be monoclonal. Approximately 90% of cells in HMGA2-LM were smooth muscle cells (SMC) with HMGA2 overexpression. In contrast, MED12-LM consisted of similar numbers of SMC and non-SMC, which were mostly tumor-associated fibroblasts (TAF). Paradoxically, TAF carried no mutations in MED12, suggesting an interaction between SMC and TAF to coordinate their growth. The higher amount of ECM in MED12-LM than HMGA2-LM was partially due to the high concentration of collagen-producing TAF. SMC growth in a xenograft assay was driven by progesterone in both LM subtypes. In contrast, TAF in MED12-LM proliferated in response to estradiol, whereas progesterone had no effect. The high concentration of estrogen-responsive TAF in MED12-LM explains the inconsistent discoveries between in vivo and in vitro studies on the mitogenic effect of estrogen and raises questions regarding the accuracy of previous studies utilizing MED12-LM cell culture. In addition, the differential effects of estradiol and progesterone on these LM subtypes emphasize the importance of subtypes and genotypes in designing non-surgical therapeutic strategies for LM.