Understanding the origin and pathogenesis of epithelial ovarian cancer

描述(申请人提供)：卵巢癌是最致命的妇科癌症。死亡率高的主要原因是这种癌症在进展良好之前很少被发现。而且早期发现是困难的，因为人们对这种致命的癌症是如何开始和转移的知之甚少。尽管手术和化疗在过去20年中逐渐得到改善，但大多数对最初的化疗有效的卵巢癌女性患者会复发并最终死亡。因此，为了减少卵巢癌的死亡，及早发现癌症并更有效地治疗晚期卵巢癌至关重要。卵巢癌的早期发现和有效治疗需要更好地了解致命性卵巢癌的分子机制。作为我博士后培训的一部分，我开发了一个卵巢癌的基因工程小鼠模型，方法是有条件地禁用两个基因：编码microRNA生物合成关键酶的迪格尔基因和编码肿瘤抑制因子的PTEN基因。这些在卵巢和输卵管中都缺乏基因的突变小鼠患上一种高度侵袭性的转移性浆液性上皮癌，与人类卵巢癌非常相似。因此，这项NRSA应用程序将专注于表征和使用这些小鼠，以进一步了解女性卵巢癌。我的建议的总体假设是，在一个容易发生肿瘤的环境中，microRNA水平的总体下降促进了卵巢癌的发展。特异性的Aim1将用于卵巢上皮性癌的起源和早期肿瘤过程的研究。为了帮助识别卵巢癌的早期标记基因，将对这些突变小鼠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质。还将通过基因表达分析来研究这些小鼠的转移过程。此外，还将培养小鼠肿瘤细胞，以研究卵巢癌进展和转移的分子途径。总而言之，这些方法将产生治疗晚期卵巢癌的有用药物靶点。特定的Aim3将涉及建立更多的卵巢癌小鼠模型。由于大多数致命的卵巢癌患者携带p53肿瘤抑制基因的突变，因此p53基因的突变将被整合到已经缺乏Disher和PTEN基因的突变小鼠中。这种新的突变小鼠模型将被预测患上卵巢癌，在基因上与人类卵巢癌更相似。这项NRSA提案的主要目标将是使用基因工程小鼠模型来确定高转移性卵巢上皮癌的起源和分子途径。 公共卫生相关性：卵巢癌是导致女性癌症死亡的第五大常见原因。提出的NRSA研究的目标是发现新的有效药物靶点，使患有晚期卵巢癌的妇女受益。除了有助于更有效的治疗外，这项研究还将有助于发现有助于早期发现或筛查女性致命卵巢癌的新生物标记物。

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. PUBLIC HEALTH RELEVANCE: Ovarian cancer is the fifth most common cause of cancer death in women. The goals of the proposed NRSA research are to discover new effective drug targets that benefit women with advanced ovarian cancers. In addition to contributing to more effective treatment, this research will also help discover novel biomarkers useful for early detection or screening of deadly ovarian cancer in women.