Constitutively active transforming growth factor β receptor 1 in the mouse ovary promotes tumorigenesis.
Constitutively active transforming growth factor β receptor 1 in the mouse ovary promotes tumorigenesis.
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DOI：
10.18632/oncotarget.10149
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发表时间：
2016-07-05
期刊：
影响因子：
--
通讯作者：
Li Q
中科院分区：
文献类型：
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作者：
Gao Y;Vincent DF;Davis AJ;Sansom OJ;Bartholin L;Li Q
尽管TGFβ蛋白具有公认的肿瘤抑制作用，但小鼠卵巢中关键TGFβ信号传导组分的耗竭不会诱导生长优势。为了明确TGFβ信号在卵巢肿瘤发生中的作用，我们使用条件性功能获得方法建立了在卵巢体细胞中表达组成型活性TGFβ受体1（TGFβ receptor 1，TGFBR 1）的小鼠模型。值得注意的是，这些小鼠出现了完全外显的卵巢性索间质肿瘤，导致生殖失败和死亡。肿瘤表达多种颗粒细胞标记物，并引起血清雌二醇和雌二醇水平升高，使人联想到颗粒细胞瘤。与致瘤效应一致，TGFBR1的过度活化通过促进血管生成和增强卵巢细胞增殖改变肿瘤微环境，伴随着细胞分化受损和卵巢功能中关键基因的表达失调。通过进一步利用互补的遗传模型，我们证实了我们的发现，组成型活性TGFBR1是一个有效的致癌开关在小鼠颗粒细胞。总之，TGFBR1的过度激活驱动性腺肿瘤的发展。TGFBR1组成型活性小鼠模型表型模仿了人类颗粒细胞肿瘤的许多形态学、激素和分子特征，并且对于治疗颗粒细胞肿瘤（一类定义不明确的卵巢恶性肿瘤）的靶向疗法的临床前测试具有潜在价值。
Despite the well-established tumor suppressive role of TGFβ proteins, depletion of key TGFβ signaling components in the mouse ovary does not induce a growth advantage. To define the role of TGFβ signaling in ovarian tumorigenesis, we created a mouse model expressing a constitutively active TGFβ receptor 1 (TGFBR1) in ovarian somatic cells using conditional gain-of-function approach. Remarkably, these mice developed ovarian sex cord-stromal tumors with complete penetrance, leading to reproductive failure and mortality. The tumors expressed multiple granulosa cell markers and caused elevated serum inhibin and estradiol levels, reminiscent of granulosa cell tumors. Consistent with the tumorigenic effect, overactivation of TGFBR1 altered tumor microenvironment by promoting angiogenesis and enhanced ovarian cell proliferation, accompanied by impaired cell differentiation and dysregulated expression of critical genes in ovarian function. By further exploiting complementary genetic models, we substantiated our finding that constitutively active TGFBR1 is a potent oncogenic switch in mouse granulosa cells. In summary, overactivation of TGFBR1 drives gonadal tumor development. The TGFBR1 constitutively active mouse model phenocopies a number of morphological, hormonal, and molecular features of human granulosa cell tumors and are potentially valuable for preclinical testing of targeted therapies to treat granulosa cell tumors, a class of poorly defined ovarian malignancies.