Department of Pathology, UT Southwestern Medical Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Dis Model Mech. 2010 Mar-Apr;3(3-4):181-93. doi: 10.1242/dmm.004440. Epub 2010 Feb 8.
Endometrial cancer--the most common malignancy of the female reproductive tract--arises from the specialized epithelial cells that line the inner surface of the uterus. Although significant advances have been made in our understanding of this disease in recent years, one significant limitation has been the lack of a diverse genetic toolkit for the generation of mouse models. We identified a novel endometrial-specific gene, Sprr2f, and developed a Sprr2f-Cre transgene for conditional gene targeting within endometrial epithelium. We then used this tool to generate a completely penetrant Lkb1 (also known as Stk11)-based mouse model of invasive endometrial cancer. Strikingly, female mice with homozygous endometrial Lkb1 inactivation did not harbor discrete endometrial neoplasms, but instead underwent diffuse malignant transformation of their entire endometrium with rapid extrauterine spread and death, suggesting that Lkb1 inactivation was sufficient to promote the development of invasive endometrial cancer. Mice with heterozygous endometrial Lkb1 inactivation only rarely developed tumors, which were focal and arose with much longer latency, arguing against the idea--suggested by some prior studies--that Lkb1 is a haploinsufficient tumor suppressor. Lastly, the finding that endometrial cancer cell lines were especially sensitive to the mTOR (mammalian target of rapamycin) inhibitor rapamycin prompted us to test its efficacy against Lkb1-driven endometrial cancers. Rapamycin monotherapy not only greatly slowed disease progression, but also led to striking regression of pre-existing tumors. These studies demonstrate that Lkb1 is a uniquely potent endometrial tumor suppressor, but also suggest that the clinical responses of some types of invasive cancers to mTOR inhibitors may be linked to Lkb1 status.
子宫内膜癌——女性生殖道最常见的恶性肿瘤——起源于子宫内表面的特化上皮细胞。尽管近年来我们对这种疾病的认识取得了重大进展，但一个显著的局限性一直是缺乏用于生成小鼠模型的多样化遗传工具包。我们鉴定了一种新型的子宫内膜特异性基因 Sprr2f，并开发了一种用于子宫内膜上皮内条件性基因靶向的 Sprr2f-Cre 转基因。然后，我们使用该工具生成了一种完全穿透性的 Lkb1（也称为 Stk11）为基础的侵袭性子宫内膜癌小鼠模型。引人注目的是，杂合子子宫内膜 Lkb1 失活的雌性小鼠没有离散的子宫内膜肿瘤，而是经历了整个子宫内膜的弥漫性恶性转化，快速向子宫外扩散并死亡，表明 Lkb1 失活足以促进侵袭性子宫内膜癌的发展。杂合子子宫内膜 Lkb1 失活的小鼠只有极少数发展为肿瘤，这些肿瘤是局灶性的，潜伏期更长，这与一些先前的研究提出的观点相矛盾，即 Lkb1 是一种杂合不足的肿瘤抑制因子。最后，发现子宫内膜癌细胞系对 mTOR（哺乳动物雷帕霉素靶蛋白）抑制剂雷帕霉素特别敏感，促使我们测试其对 Lkb1 驱动的子宫内膜癌的疗效。雷帕霉素单药治疗不仅大大减缓了疾病进展，还导致了先前存在的肿瘤的显著消退。这些研究表明 Lkb1 是一种独特的有效的子宫内膜肿瘤抑制因子，但也表明某些类型的侵袭性癌症对 mTOR 抑制剂的临床反应可能与 Lkb1 状态有关。
