The signaling events involved in the onset of ovarian cancer from the fallopian tube epithelium (FTE) are crucial for early detection and treatment of the disease, but they remain poorly defined. Conditional homozygous knockout of PTEN mediated by PAX8-cre recombinase was sufficient to drive endometrioid and serous borderline ovarian carcinoma, providing the first model of FTE-derived borderline tumors. In addition, heterozygous PTEN deletion in the FTE resulted in hyperplasia, providing a model to study early events of human ovarian pathogenesis. To uncover the mechanism underlying the invasion of cancerous oviductal cells to the ovary, PTEN-deficient murine oviductal cells were developed and tagged with green fluorescent protein. Loss of PTEN increased cell migration, invasion, and upregulated WNT4, a key regulator of Müllerian duct development during embryogenesis. Further investigation revealed that WNT4 was required for increased migration and colonization of the ovary by PTEN-deficient oviductal cells in a β-catenin independent manner. Human tumor microarrays and ovarian cancer cells lines confirmed WNT4 expression in cancer and its role in migration. Together, these findings provide a novel model to study the mechanism of fallopian tube tumor initiation and invasion to the ovary mediated by loss of PTEN, which may help to define early events of human ovarian carcinogenesis.

中文翻译：

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输卵管中PTEN的丢失会导致增生和卵巢肿瘤的形成。

输卵管上皮癌（FTE）参与卵巢癌发作的信号事件对于疾病的早期发现和治疗至关重要，但仍缺乏明确的定义。由PAX8-cre重组酶介导的PTEN的条件纯合敲除足以驱动子宫内膜样和浆液性交界性卵巢癌，提供了FTE衍生的交界性肿瘤的第一个模型。此外，FTE中杂合的PTEN缺失导致增生，为研究人类卵巢发病机制的早期事件提供了模型。为了揭示癌性输卵管侵袭卵巢的潜在机制，开发了PTEN缺陷型鼠输卵管细胞并用绿色荧光蛋白标记。PTEN的丢失会增加细胞迁移，侵袭和WNT4的上调，胚胎发生过程中苗勒管发育的关键调控因子。进一步的研究表明，需要WNT4以β-catenin独立的方式增加PTEN缺陷型输卵管细胞对卵巢的迁移和定植。人肿瘤微阵列和卵巢癌细胞系证实了WNT4在癌症中的表达及其在迁移中的作用。在一起，这些发现提供了一个新颖的模型，用于研究输卵管肿瘤的发生和由PTEN丢失介导的卵巢侵袭的机制，这可能有助于确定人类卵巢癌发生的早期事件。人肿瘤微阵列和卵巢癌细胞系证实了WNT4在癌症中的表达及其在迁移中的作用。在一起，这些发现提供了一个新颖的模型，用于研究输卵管肿瘤的发生和由PTEN丢失介导的卵巢侵袭的机制，这可能有助于确定人类卵巢癌发生的早期事件。人肿瘤微阵列和卵巢癌细胞系证实了WNT4在癌症中的表达及其在迁移中的作用。在一起，这些发现提供了一个新颖的模型，用于研究输卵管肿瘤的发生和由PTEN丢失介导的卵巢侵袭的机制，这可能有助于确定人类卵巢癌发生的早期事件。