Origins of Ovarian Carcinoma

 描述（由申请人提供）： 上皮性卵巢癌（EOC）是美国女性癌症死亡的第五大原因。最近对高级别浆液性卵巢腺癌进行的广泛的综合基因组分析为这种最常见和最致命的EOC形式的分子畸变特征提供了重要的见解。然而，对发现的畸变的解释是复杂的，因为这种疾病的起源细胞尚未明确定义。最近，我们已经确定了小鼠卵巢的门区，卵巢表面上皮（OSE），间皮和输卵管（输卵管或输卵管）上皮之间的过渡/交界区作为以前未被识别的干细胞壁龛的OSE。正如我们所示，这些细胞表达干细胞标记物，并显示出长期的干细胞特性离体和体内，根据连续球生成和长期谱系追踪测定，分别。重要的是，门细胞在肿瘤抑制基因失活后表现出增加的转化潜力 p53（Trp 53）和Rb（Rb 1），在高级别浆液性腺癌中经常改变的途径。我们的初步研究结果表明，在小鼠输卵管上皮中存在干细胞龛，在输卵管的最远端部分，靠近输卵管上皮/间皮交界区的细胞有特定的积累。值得注意的是，OSE和TE干细胞小生境的特征在于miR-34/MET网络的高活性。由于OSE和输卵管上皮在小鼠和人类中具有共同的体腔上皮起源，我们假设卵巢癌起源于OSE/间皮/TE交界区内的几个发育相关的干细胞小生境，其中干细胞更容易转化，因为天生活跃的miR-34/MET网络。为了解决这一假设，我们建议（1）表征TE中假定的干细胞小生境并确定其在EOC形成中的作用，（2）对OSE-SC和TE-SC小生境进行比较分子表征，以及（3）鉴定和表征人OSE和TE中的干细胞小生境。预计我们的工作将提供卵巢癌起源的临床和实验研究之间的关键缺失环节。重要的是，它应该导致识别新的诊断和预后标志物和治疗靶点。

 DESCRIPTION (provided by applicant): Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer death among women in the United States. Recent extensive integrated genomic analysis of high-grade serous ovarian adenocarcinomas has provided important insights about the repertoire of molecular aberrations characteristic for this, the most common and deadly, form of EOC. However, interpretation of the discovered aberrations is complicated because the cell of origin of this disease has not yet been unequivocally defined. Recently, we have identified the hilum region of the mouse ovary, the transitional/junction area between the ovarian surface epithelium (OSE), mesothelium and tubal (Fallopian or oviductal) epithelium as a previously unrecognized stem cell niche of the OSE. As we have shown, these cells express stem cell markers and display long-term stem cell properties ex vivo and in vivo, according to serial sphere generation and to long-term lineage tracing assays, respectively. Importantly, the hilar cells exhibit increased transformation potential after inactivation of tumor suppressor genes p53 (Trp53) and Rb (Rb1), pathways that are frequently altered in high grade serous adenocarcinoma. Our preliminary results indicate existence of stem cell niche in the mouse tubal epithelium, with a particular accumulation of cells in the most distal part of the uterine tue, near the tubal epithelium/mesothelium junction area. Notably both OSE and TE stem cell niches are characterized by high activity of the miR-34/MET network. Since OSE and tubal epithelium have a common origin from the coelomic epithelium both in mice and humans, we hypothesize that ovarian carcinomas arise from several developmentally connected stem cell niches within OSE/mesothelium/TE junction areas, where stem cells are more prone to transformation because of the innately active miR-34/MET network. To address this hypothesis we propose to (1) characterize a putative stem cell niche in the TE and establish its role in EOC formation, (2) perform comparative molecular characterization of OSE-SC and TE-SC niches, and (3) identify and characterize stem cell niches in human OSE and TE. It is expected that our work will provide critical missing links between clinical and experimental studies of ovarian carcinoma origin. Importantly, it should lead to identification of new diagnostic and prognostic markers and therapeutic targets.