Vincent Center for Reproductive Biology, Department of Obstetrics, Gynecology, and Reproductive Biology.
Carcinogenesis. 2014 Mar;35(3):546-53. doi: 10.1093/carcin/bgt357. Epub 2013 Oct 29.
Epithelial ovarian cancer presents mostly with serous, endometrioid or mucinous histology but is treated as a single disease. The development of histotype-specific therapy has been challenging because of the relative lack of studies attributing disrupted pathways to a distinct histotype differentiation. mTOR activation is frequently associated with poor prognosis in serous ovarian cancer, which is the most common and most deadly histotype. However, the mechanisms dysregulating mTOR in the pathogenesis of ovarian cancer are unknown. We detected copy number loss and correlated lower expression levels of LKB1, TSC1, TSC2 and PTEN tumor suppressor genes for upstream regulators of mTOR activity in up to 80% in primary ovarian serous tumor databases, with LKB1 allelic loss-predominant. Reduced LKB1 protein was usually associated with increased mTOR activity in both serous ovarian cancer cell lines and primary tumors. Conditional deletion of Lkb1 in murine ovarian surface epithelial (OSE) cells caused papillary hyperplasia and shedding but not tumors. Simultaneous deletion of Lkb1 and Pten, however, led to development of high-grade ovarian serous histotype tumors with 100% penetrance that expressed WT1, ERα, PAX8, TP53 and cytokeratin 8, typical markers used in the differential diagnosis of serous ovarian cancer. Neither hysterectomy nor salpingectomy interfered with progression of ovarian tumorigenesis, suggesting that neither uterine nor Fallopian tube epithelial cells were contributing to tumorigenesis. These results implicate LKB1 loss in the OSE in the pathogenesis of serous ovarian cancer and provide a compelling rationale for investigating the therapeutic potential of targeting LKB1 signaling in patients with this deadly disease.
上皮性卵巢癌主要表现为浆液性、子宫内膜样或黏液性组织学类型，但被视为一种单一疾病进行治疗。由于将异常通路归因于特定组织学分型的分化相对缺乏研究，因此开发组织学分型特异性治疗一直具有挑战性。mTOR 激活与浆液性卵巢癌的预后不良密切相关，而浆液性卵巢癌是最常见且最致命的组织学类型。然而，导致卵巢癌中 mTOR 失调的机制尚不清楚。我们在多达 80%的原发性卵巢浆液性肿瘤数据库中检测到 LKB1、TSC1、TSC2 和 PTEN 肿瘤抑制基因的拷贝数缺失，并与 mTOR 活性的上游调节剂的表达水平降低相关，其中 LKB1 等位基因缺失占优势。在浆液性卵巢癌细胞系和原发性肿瘤中，LKB1 蛋白减少通常与 mTOR 活性增加相关。在小鼠卵巢表面上皮（OSE）细胞中条件性缺失 Lkb1 会导致乳头状增生和脱落，但不会导致肿瘤。然而，同时缺失 Lkb1 和 Pten 会导致高级别浆液性卵巢组织学类型肿瘤的发展，其具有 100%的穿透率，表达 WT1、ERα、PAX8、TP53 和细胞角蛋白 8，这些是用于浆液性卵巢癌鉴别诊断的典型标志物。子宫切除术或输卵管切除术均不会干扰卵巢肿瘤发生的进展，这表明子宫或输卵管上皮细胞均不会促进肿瘤发生。这些结果表明，OSE 中的 LKB1 缺失在上皮性卵巢癌的发病机制中起作用，并为研究针对这种致命疾病的 LKB1 信号靶向治疗的潜在治疗提供了有力的依据。
