Origins of Ovarian Carcinoma

卵巢癌的起源

• 批准号: 9257361
• 负责人: Alexander Y Nikitin
• 金额: $ 35.88万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-18 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9257361
• 关键词: Address; Affect; Aggressive behavior; Area; BMP6 gene; Biological Assay; Cancer Etiology; Cell Compartmentation; Cell Differentiation process; Cells; Cessation of life; Characteristics; Clinical Research; Development; Diagnosis; Diagnostic; Disease; Distal; Epithelial Attachment; Epithelial ovarian cancer; Epithelium; Exhibits; Family; Gene Expression; Generations; Genomics; Hilar; Human; Lead; Lesion; Link; Location; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mesothelium; MicroRNAs; Molecular; Molecular Abnormality; Molecular Profiling; Mus; Natural regeneration; Neoplasms; Ovarian; Ovarian Carcinoma; Ovarian Serous Adenocarcinoma; Ovary; Pathogenesis; Pathway interactions; Patients; Population; Predisposition; Prognostic Marker; Property; Receptor Protein-Tyrosine Kinases; Role; Serous Cystadenocarcinoma; Source; Stem cells; Surface; System; TP53 Gene Inactivation; TP53 gene; Testing; Text; Therapeutic; Time; Transplantation; Tube; Tumor Suppressor Genes; Tumorigenicity; United States; Woman; Work; base; carcinogenesis; cohort; comparative; diagnostic biomarker; experimental study; in vivo; insight; neoplastic; novel diagnostics; novel marker; progenitor; public health relevance; regenerative; self-renewal; stem; stem cell niche; therapeutic target; tumorigenic

 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.

 描述（由适用提供）：上皮卵巢癌（EOC）是美国女性癌症死亡的第五个主要原因。最近对高级浆液卵巢腺癌的广泛综合基因组分析为此提供了有关分子畸变曲目的重要见解，最常见和最致命的EOC形式。但是，对发现的畸变的解释是复杂的，因为该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Hilum区域，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/连接区是先前未识别的OSE的干细胞细胞。正如我们已经表明的那样，这些细胞根据串行球的产生和长期的谱系追踪测定法表达了干细胞标记并在体内和体内显示长期的干细胞特性。重要的是，肺部细胞暴露于肿瘤抑制基因失活后增加转化潜力 p53（TRP53）和RB（RB1），在高级浆液腺癌中经常改变的途径。我们的初步结果表明，在小鼠管上皮中存在干细胞生态位，并且在子宫上周二最圆盘的部分中，特定的细胞积聚，靠近输卵管上皮/间层交界区域。值得注意的是，OSE和TE干细胞壁ni的特征是miR-34/MET网络的高活性。由于在小鼠和人类中，ose和tubal上皮都具有卵巢上皮的共同起源，因此我们推测，卵巢癌源自OSE/介入/介质/te交界区域内的几个已发达的连接的干细胞壁细胞壁细胞，而干细胞更容易转化，因为它更容易转化，因为具有本地的Active Mir-34/MET MET MET/MET MET MET MET。为了解决这一假设，我们提出（1）表征TE中推定的干细胞小众，并确定其在EOC形成中的作用，（2）对OSE-SC和TE-SC壁ches进行比较的分子表征，（3）识别和表征人类OSE和TE中的干细胞生态位。预计我们的工作将在卵巢癌起源的临床和实验研究之间提供关键的缺失联系。重要的是，它应导致鉴定新的诊断和预后标记和治疗靶标。