Conditional abrogation of transforming growth factor-β receptor 1 in PTEN-inactivated endometrium promotes endometrial cancer progression in mice.
Conditional abrogation of transforming growth factor-β receptor 1 in PTEN-inactivated endometrium promotes endometrial cancer progression in mice.
复制标题
在PTEN灭活的子宫内膜中转化生长因子-β受体1的条件废除可促进小鼠的子宫内膜癌进展。
DOI：
10.1002/path.4930
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Gao Y;Lin P;Lydon JP;Li Q
尽管TGF β（TGFB）信号在人子宫内膜癌发病机制中的假定作用早已被提出，但TGFB信号在子宫内膜癌的发展和进展中的精确功能仍然是难以捉摸的。小鼠子宫中PTEN的缺失导致子宫内膜癌。为了确定TGFB信号在子宫内膜癌中的潜在作用，我们使用孕酮受体驱动的Cre重组酶（称为Ptend/d; Tgfbr 1d/d）同时删除小鼠子宫中的TGFB受体1（Tgfbr 1）和Pten。我们发现Ptend/d; Tgfbr1d/d小鼠发生了严重的子宫内膜病变，与单独条件性缺失Pten的子宫内膜病变相比，进展更快，这表明TGFB信号转导与PTEN协同作用抑制子宫内膜癌进展。值得注意的是，Ptend/d; Tgfbr 1d/d小鼠发生了远处肺转移，导致寿命显著缩短。在Ptend/d; Tgfbr 1d/d小鼠中发生转移和加速肿瘤进展与促炎趋化因子的产生增加、子宫肌层浸润和破坏证明的癌细胞运动性增强以及肿瘤相关巨噬细胞募集特征的肿瘤微环境改变相关。因此，在PTEN失活的子宫内膜中Tgfbr 1的条件性缺失导致重演侵袭性和致死性人类子宫内膜癌的疾病。这种小鼠模型对于新的癌症疗法的临床前测试可能是有价值的，特别是那些针对转移的疗法，转移是癌症的标志之一，也是子宫内膜癌患者死亡的主要原因。
Although a putative role for TGF beta (TGFB) signaling in the pathogenesis of human endometrial cancer has long been proposed, the precise function of TGFB signaling in the development and progression of endometrial cancer remains elusive. Depletion of PTEN in the mouse uterus causes endometrial cancer. To identify the potential role of TGFB signaling in endometrial cancer, we simultaneously deleted TGFB receptor 1 (Tgfbr1) and Pten in the mouse uterus using Cre-recombinase driven by the progesterone receptor (termed Ptend/d; Tgfbr1d/d). We found that Ptend/d; Tgfbr1d/d mice developed severe endometrial lesions that progressed more rapidly compared with those resulting from conditional deletion of Pten alone, suggesting that TGFB signaling synergizes with PTEN to suppress endometrial cancer progression. Remarkably, the Ptend/d; Tgfbr1d/d mice developed distant pulmonary metastases, leading to significantly reduced life span. The development of metastasis and accelerated tumor progression in Ptend/d; Tgfbr1d/d mice are associated with increased production of pro-inflammatory chemokines, enhanced cancer cell motility evidenced by myometrial invasion and disruption, and altered tumor microenvironment characterized by recruitment of tumor-associated macrophages. Thus, conditional deletion of Tgfbr1 in PTEN-inactivated endometrium leads to a disease that recapitulates invasive and lethal human endometrial cancer. This mouse model may be valuable for preclinical testing of new cancer therapies, particularly those targeting metastasis, one of the hallmarks of cancer and a major cause of death in endometrial cancer patients.
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DOI：
10.4049/jimmunol.179.7.4849
发表时间：
2007-10-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Duchene J;Lecomte F;Ahmed S;Cayla C;Pesquero J;Bader M;Perretti M;Ahluwalia A
通讯作者：
Ahluwalia A
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
--
作者：
Gao Y;Vincent DF;Davis AJ;Sansom OJ;Bartholin L;Li Q
通讯作者：
Li Q
影响因子：
8
作者：
Kim, T. H.;Franco, H. L.;Jung, S. Y.;Qin, J.;Broaddus, R. R.;Lydon, J. P.;Jeong, J-W
通讯作者：
Jeong, J-W
DOI：
10.1016/0960-0760(92)90256-i
发表时间：
1992-06-01
影响因子：
4.1
作者：
ANZAI, Y;GONG, YW;GURPIDE, E
通讯作者：
GURPIDE, E