Constitutive Activation of PI3K in Oocyte Induces Ovarian Granulosa Cell Tumors.
Constitutive Activation of PI3K in Oocyte Induces Ovarian Granulosa Cell Tumors.
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PI3K在卵母细胞中的组成型激活诱导卵巢颗粒细胞肿瘤。
DOI：
10.1158/0008-5472.can-15-3358
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发表时间：
2016-07-01
期刊：
影响因子：
11.2
通讯作者：
Kurita T
中科院分区：
文献类型：
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作者：
Kim SY;Ebbert K;Cordeiro MH;Romero MM;Whelan KA;Suarez AA;Woodruff TK;Kurita T
细胞间的相互作用在维持组织稳态中起着至关重要的作用，组织稳态的丧失通常会导致各种疾病，包括癌症。在这里，我们报告了卵母细胞内不受控制的PI 3 K活性不可逆地转化颗粒细胞（GC），通过干扰局部细胞通讯引起GC肿瘤（GCT）。在此之前，我们报道了Gdf 9-iCre诱导原始卵母细胞表达组成型活性突变体PI 3 K的转基因小鼠的生殖表型。转基因小鼠（Cre+）表现出严重的卵巢表型，包括过多的卵泡过度生长和无排卵。令人惊讶的是，Cre+小鼠在出生后第80天由于双侧GCT而变得恶病质。虽然GCT细胞增殖独立的卵母细胞，局部相互作用与突变PI 3 K阳性卵母细胞在早期卵泡发育是必不可少的GC转化。生长的GCT细胞表达高水平的激活素βA和核SMAD 3，并且增殖率与高激活素A/激活素A比率正相关。这些结果表明，肿瘤细胞通过激活素A自分泌信号传导途径刺激其生长，这一假设由培养的GCT细胞中的激活素A分泌证实，所述GCT细胞响应增殖。虽然卵母细胞和周围体细胞之间的通信是至关重要的卵泡的正常发育，卵母细胞GC通信在卵泡发育早期的扰动可以诱导GCT通过激活GC中的自分泌生长回路程序。
Cell-cell interactions play crucial roles in the maintenance of tissue homeostasis, a loss of which often leads to varying diseases, including cancer. Here, we report that uncontrolled PI3K activity within oocytes irreversibly transforms granulosa cells (GC), causing GC tumors (GCT) through perturbed local cell-communication. Previously, we reported reproductive phenotypes of transgenic mice, in which expression of constitutively active mutant PI3K was induced in primordial oocytes by Gdf9-iCre. The transgenic mice (Cre+) demonstrated severe ovarian phenotypes, including the overgrowth of excess ovarian follicles and anovulation. Surprisingly, the Cre+ mice became cachectic by postnatal day 80 due to bilateral GCT. Although GCT cells proliferated independently of oocytes, local interactions with mutant PI3K-positive oocytes during early folliculogenesis were essential for the GC transformation. Growing GCT cells expressed high levels of inhibin βA and nuclear SMAD3, and the proliferation rate was positively correlated with a high activin A to inhibin A ratio. These results suggested that the tumor cells stimulated their growth through an activin A autocrine signaling pathway, a hypothesis confirmed by activin A secretion in cultured GCT cells which proliferated in response. Although communication between the oocyte and surrounding somatic cells is critical for the normal development of ovarian follicles, perturbations in oocyte-GC communication during early folliculogenesis can induce GCT by activating an autocrine growth circuit program in GC.