Understanding the origin and pathogenesis of epithelial ovarian cancer

了解上皮性卵巢癌的起源和发病机制

• 批准号: 8507465
• 负责人: Jaeyeon Kim
• 金额: $ 5.57万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507465
• 关键词: 1-Phosphatidylinositol 3-Kinase; 3' Untranslated Regions; Abdominal Cavity; Advanced Malignant Neoplasm; Affect; Anabolism; Binding; Biological Markers; Cancer Etiology; Cancer Model; Cancer Patient; Cancer Relapse; Cessation of life; Clinical; Critical Pathways; DICER1 gene; Death Rate; Development; Disabled Persons; Drug Delivery Systems; Early Diagnosis; Environment; Enzymes; Epithelial; Epithelial ovarian cancer; Fallopian Tube Neoplasms; Functional RNA; Future; Gene Expression; Gene Mutation; Genes; Genetic Translation; Genetically Engineered Mouse; Goals; Hemorrhagic Ascites; Histologic; Human; Infertility; Knockout Mice; Knowledge; Link; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mammalian Oviducts; Messenger RNA; MicroRNAs; Modeling; Molecular; Mullerian-inhibiting substance receptor; Mus; Mutant Strains Mice; Mutation; National Research Service Awards; Nature; Neoplasm Metastasis; Nucleotides; Operative Surgical Procedures; Ovarian; Ovarian Serous Adenocarcinoma; Ovary; PTEN gene; Pathogenesis; Pathway interactions; Patients; Phenotype; Protein p53; RNA Interference; Relapse; Repression; Research; Screening for Ovarian Cancer; Screening for cancer; Screening procedure; Serous; Signal Transduction; Site; Small RNA; Staging; Structure; TP53 gene; Tissue Sample; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor Tissue; Tumor-Associated Process; United States; Woman; cancer gene expression; chemotherapy; effective therapy; human DICER1 protein; improved; killings; mRNA Transcript Degradation; metastatic process; molecular marker; mouse model; mutant mouse model; neoplastic cell; novel; ovarian neoplasm; post-doctoral training; tumor; tumor progression; zygote

DESCRIPTION (provided by applicant): Ovarian cancer is the most deadly gynecologic cancer. The main reason for a high death rate is that this cancer is seldom detected until it is well advanced. And early detection is difficult because there is little known about how this deadly cancer begins and metastasizes. Although surgery and chemotherapy have gradually improved over the last 20 years, most women with ovarian cancer who successfully respond to initial chemotherapy relapse and eventually die. To reduce ovarian-cancer deaths, it is therefore essential to detect the cancer early and to more effectively treat advanced ovarian cancers. Early detection and effective treatment of ovarian cancer will require better understanding of the molecular mechanisms underlying deadly ovarian cancer. As part of my postdoctoral training, I have developed a genetically engineered mouse model of ovarian cancer by conditionally disabling the two genes: the DICER gene, encoding an essential enzyme for microRNA biosynthesis, and the PTEN gene, encoding a tumor suppressor. These mutant mice lacking both genes in the ovary and fallopian tube develop a highly aggressive metastatic serous epithelial cancer, which closely resembles human ovarian cancer. This NRSA application will therefore focus on characterizing and using these mice to further understand ovarian cancer in women. The general hypothesis of my proposal is that overall decrease of microRNA levels in a tumor-prone environment promotes development of ovarian cancer. Specific Aim1 will investigate the origin and early tumor process of epithelial ovarian cancer. To help identify early marker genes of ovarian cancer, gene-expression analyses will be performed on the ovarian tumor tissues sampled from these mutant mice. Specific Aim2 will define the metastatic nature of these mouse ovarian cancers that mirror human ovarian cancer. The metastatic process will be investigated in these mice also by gene-expression analyses. In addition, tumor cells from this mouse cancer will be cultured to study the molecular pathways of ovarian-cancer progression and metastasis. Together, these approaches will yield useful drug targets for treating advanced ovarian cancers. Specific Aim3 will involve creating additional mouse models of ovarian cancer. Because most patients with deadly ovarian cancers carry mutations in the p53 tumor-suppressor gene, a mutation in the p53 gene will be incorporated into the mutant mice that already lack the DICER and PTEN genes. This new mutant-mouse model would be predicted to develop ovarian cancer that is genetically more similar to human ovarian cancer. The primary goal of this NRSA proposal will be to define the origin and molecular pathways of highly metastatic epithelial ovarian cancer using genetically engineered mouse models.

描述（由申请人提供）：卵巢癌是最致命的妇科癌症。高死亡率的主要原因是，很少检测到该癌症直到良好的先进。早期发现很困难，因为对这种致命的癌症如何开始和转移鲜为人知。尽管在过去的20年中，手术和化学疗法逐渐改善，但大多数卵巢癌的女性成功地应对最初的化学疗法复发并最终死亡。为了减少卵巢癌死亡，必须尽早检测到癌症并更有效地治疗晚期卵巢癌。早期检测和有效治疗卵巢癌将需要更好地了解致命卵巢癌的分子机制。作为我的博士后训练的一部分，我通过有条件地禁用了这两个基因，开发了一种基因工程的卵巢癌小鼠模型：DICER基因，编码用于microRNA生物合成的必需酶和PTEN基因，编码肿瘤抑制剂。这些在卵巢和输卵管中缺乏基因的突变小鼠会形成高度侵略性的转移性浆液性上皮癌，与人类卵巢癌紧密相似。因此，这种NRSA应用将集中于表征和使用这些小鼠进一步了解女性的卵巢癌。我的提议的总体假设是，易于肿瘤环境中microRNA水平的总体降低会促进卵巢癌的发展。特定的AIM1将研究上皮卵巢癌的起源和早期肿瘤过程。为了帮助识别卵巢癌的早期标记基因，将对这些突变小鼠采样的卵巢肿瘤组织进行基因表达分析。特定的AIM2将定义这些反映人类卵巢癌的小鼠卵巢癌的转移性。这些小鼠也将通过基因表达分析研究转移过程。此外，该小鼠癌的肿瘤细胞将被培养，以研究卵巢癌进展和转移的分子途径。这些方法将共同产生用于治疗晚期卵巢癌的有用药物靶标。特定的AIM3将涉及创建其他小鼠卵巢癌模型。由于大多数致命卵巢癌患者在p53肿瘤抑制基因中携带突变，因此p53基因中的突变将掺入突变小鼠中，该突变小鼠已经缺乏dicer和pten基因。预计这种新的突变鼠模型会发展为遗传上与人类卵巢癌更相似的卵巢癌。该NRSA建议的主要目标是使用基因工程小鼠模型来定义高度转移性上皮卵巢癌的起源和分子途径。