Boerboom Derek, Paquet Marilene, Hsieh Minnie, Liu Jinsong, Jamin Soazik P, Behringer Richard R, Sirois Jean, Taketo Makoto M, Richards Joanne S
Department of Molecular and Cellular Biology and Center for Comparative Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Cancer Res. 2005 Oct 15;65(20):9206-15. doi: 10.1158/0008-5472.CAN-05-1024.
Misregulation of the Wnt/beta-catenin signaling pathway is a hallmark of several forms of cancer. Components of the Wnt/beta-catenin pathway are expressed in ovarian granulosa cells; nevertheless, its potential involvement in granulosa cell tumorigenesis has not been examined. To this end, human (n = 6) and equine (n = 18) granulosa cell tumors (GCT) were analyzed for beta-catenin expression by immunohistochemistry. Unlike granulosa cells of normal ovaries, most (15 of 24) GCT samples showed nuclear localization of beta-catenin, suggesting that activation of the Wnt/beta-catenin pathway plays a role in the etiology of GCT. To confirm this hypothesis, Catnb(flox(ex3)/+); Amhr2(cre/+) mice that express a dominant stable beta-catenin mutant in their granulosa cells were generated. These mice developed follicle-like structures containing disorganized, pleiomorphic granulosa by 6 weeks of age. Even in older mice, these follicle-like lesions grew no larger than the size of antral follicles and contained very few proliferating cells. Similar to corpora lutea, the lesions were highly vascularized, although they did not express the luteinization marker Cyp11a1. Catnb(flox(ex3)/+); Amhr2(cre/+) females were also found to be severely subfertile, and fewer corpora lutea were found to form in response to exogenous gonadotropin compared with control mice. In older mice, the ovarian lesions often evolved into GCT, indicating that they represent a pretumoral intermediate stage. The GCT in Catnb(flox(ex3)/+); Amhr2(cre/+) mice featured many histopathologic similarities to the human disease, and prevalence of tumor development attained 57% at 7.5 months of age. Together, these studies show a causal link between misregulated Wnt/beta-catenin signaling and GCT development and provide a novel model system for the study of GCT biology.
Wnt/β-连环蛋白信号通路的失调是多种癌症的一个标志。Wnt/β-连环蛋白通路的成分在卵巢颗粒细胞中表达；然而，其在颗粒细胞瘤发生中的潜在作用尚未得到研究。为此，通过免疫组织化学分析了人（n = 6）和马（n = 18）颗粒细胞瘤（GCT）中的β-连环蛋白表达。与正常卵巢的颗粒细胞不同，大多数（24个样本中的15个）GCT样本显示β-连环蛋白的核定位，表明Wnt/β-连环蛋白通路的激活在GCT的病因中起作用。为了证实这一假设，构建了在其颗粒细胞中表达显性稳定β-连环蛋白突变体的Catnb(flox(ex3)/+); Amhr2(cre/+)小鼠。这些小鼠在6周龄时发育出含有无序、多形性颗粒细胞的卵泡样结构。即使在老年小鼠中，这些卵泡样病变也不会生长到超过窦状卵泡的大小，并且增殖细胞很少。与黄体相似，这些病变血管高度丰富，尽管它们不表达黄体化标志物Cyp11a1。还发现Catnb(flox(ex3)/+); Amhr2(cre/+)雌性小鼠严重不育，与对照小鼠相比，对外源性促性腺激素反应形成的黄体较少。在老年小鼠中，卵巢病变常演变为GCT，表明它们代表肿瘤前中间阶段。Catnb(flox(ex3)/+); Amhr2(cre/+)小鼠中的GCT在许多组织病理学特征上与人疾病相似，在7.5月龄时肿瘤发生的患病率达到57%。总之，这些研究表明Wnt/β-连环蛋白信号失调与GCT发生之间存在因果关系，并为GCT生物学研究提供了一个新的模型系统。
