Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling
Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling
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DOI：
10.1073/pnas.1217982109
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发表时间：
2012-12-11
影响因子：
11.1
通讯作者：
Witte, Owen N.
中科院分区：
文献类型：
--
作者：
Zong, Yang;Huang, Jiaoti;Witte, Owen N.
癌通常是由于上皮细胞内遗传改变的逐步获得而引起的。周围的基质也可以在癌症的发生和发展中发挥重要作用。鉴于在癌症相关基质中鉴定的遗传事件的罕见频率，肿瘤微环境中的表观遗传变化可能有助于其促肿瘤活性。我们使用Hmga 2（高迁移率组AT钩2）的表观遗传调节，修改前列腺基质细胞，并证明，扰动的微环境的基质特异性过度表达的染色质重塑蛋白单独是足以诱导戏剧性增生和多灶性前列腺上皮内瘤病变从邻近的幼稚上皮细胞。重要的是，我们发现这种作用主要是通过增加Wnt/β-连环蛋白信号传导介导的。间质中雄激素受体过表达增强Hmga 2诱导的旁分泌信号传导驱动邻近上皮组织中的小鼠前列腺腺癌。我们的研究结果为基质细胞的表观遗传变化对多灶性肿瘤发生的关键贡献提供了令人信服的证据。
Carcinomas most often result from the stepwise acquisition of genetic alterations within the epithelial compartment. The surrounding stroma can also play an important role in cancer initiation and progression. Given the rare frequencies of genetic events identified in cancer-associated stroma, it is likely that epigenetic changes in the tumor microenvironment could contribute to its tumor-promoting activity. We use Hmga2 (High-mobility group AT-hook 2) an epigenetic regulator, to modify prostate stromal cells, and demonstrate that perturbation of the microenvironment by stromal-specific overexpression of this chromatin remodeling protein alone is sufficient to induce dramatic hyperplasia and multifocal prostatic intraepithelial neoplasia lesions from adjacent naive epithelial cells. Importantly, we find that this effect is predominantly mediated by increased Wnt/beta-catenin signaling. Enhancement of Hmga2-induced paracrine signaling by overexpression of androgen receptor in the stroma drives frank murine prostate adenocarcinoma in the adjacent epithelial tissues. Our findings provide compelling evidence for the critical contribution of epigenetic changes in stromal cells to multifocal tumorigenesis.