Activin-like kinase 5 (ALK5) inactivation in the mouse uterus results in metastatic endometrial carcinoma
Activin-like kinase 5 (ALK5) inactivation in the mouse uterus results in metastatic endometrial carcinoma
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DOI：
10.1073/pnas.1806838116
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发表时间：
2019-02-26
影响因子：
11.1
通讯作者：
Matzuk, Martin M.
中科院分区：
文献类型：
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作者：
Monsivais, Diana;Peng, Jia;Matzuk, Martin M.
子宫腔的子宫内膜是一个高度动态的组织，它受到卵巢类固醇激素、雌激素和孕激素的持续控制。子宫内膜腺癌是由子宫内膜腺体不受控制的生长引起的，通常与雌激素的作用有关，常发生于绝经后的老年妇女。由于肥胖率的增加，年轻妇女中子宫内膜癌的发病率一直在上升，肥胖是该疾病的主要危险因素。转化生长因子β（TGF β）家族是一组高度保守的蛋白质，在细胞分化、增殖和癌症中发挥作用。已在各种人类癌症中检测到编码TGF β细胞表面受体（TGFBR 1/ALK 5和TGFBR 2）的基因的失活突变，表明功能性TGF β信号传导途径是避免肿瘤发生所必需的。在这项研究中，我们提出了一种小鼠模型，在小鼠子宫中使用孕激素受体cre（“Alk 5 cKO”）条件性失活激活素受体样激酶5（ALK 5），其发展子宫内膜腺癌并转移到肺。癌症和转移性肺结节是雌激素依赖性的，并保留雌激素受体α（ER α）反应性，但孕酮受体（PR）蛋白水平降低。子宫内膜肿瘤仅在与有生育能力的雄性交配的Alk 5 cKO小鼠中发生，表明TGF β介导的产后子宫内膜修复对子宫内膜功能至关重要。总之，这些研究表明，子宫内膜中通过TGFBR 1/ALK 5的TGF β信号传导是子宫内膜稳态、肿瘤抑制和产后子宫内膜再生所必需的。
The endometrial lining of the uterine cavity is a highly dynamic tissue that is under the continuous control of the ovarian steroid hormones, estrogen and progesterone. Endometrial adenocarcinoma arises from the uncontrolled growth of the endometrial glands, which is typically associated with unopposed estrogen action and frequently occurs in older postmenopausal women. The incidence of endometrial cancer among younger women has been rising due to increasing rates of obesity, a major risk factor for the disease. The transforming growth factor beta (TGF beta) family is a highly conserved group of proteinswith roles in cellular differentiation, proliferation, and cancer. Inactivating mutations in the genes encoding the TGF beta cell surface receptors (TGFBR1/ALK5 and TGFBR2) have been detected in various human cancers, indicating that a functional TGF beta signaling pathway is required for evading tumorigenesis. In this study, we present a mouse model with conditional inactivation of activin receptor-like kinase 5 (ALK5) in the mouse uterus using progesterone receptor cre ("Alk5 cKO") that develops endometrial adenocarcinoma with metastasis to the lungs. The cancer and metastatic lung nodules are estrogen dependent and retain estrogen receptor a (ER alpha) reactivity, but have decreased levels of progesterone receptor (PR) protein. The endometrial tumors develop only in Alk5 cKO mice that are mated to fertile males, indicating that TGF beta-mediated postpartumendometrial repair is critical for endometrial function. Overall, these studies indicate that TGF beta signaling through TGFBR1/ALK5 in the endometrium is required for endometrial homeostasis, tumor suppression, and postpartum endometrial regeneration.