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很少被发现，直到它是晚期。早期发现是困难的，因为人们对这种致命的癌症如何开始和转移知之甚少。虽然手术和化疗在过去20年中逐渐改善，但大多数成功应对初始化疗的卵巢癌患者复发并最终死亡。因此，为了减少卵巢癌死亡，必须及早发现癌症并更有效地治疗晚期卵巢癌。卵巢癌的早期发现和有效治疗需要更好地了解致命卵巢癌的分子机制。作为博士后培训的一部分，我通过有条件地禁用两个基因开发了一个卵巢癌的基因工程小鼠模型：DICER基因，编码microRNA生物合成的必需酶，和PTEN基因，编码肿瘤抑制因子。这些在卵巢和输卵管中缺乏这两种基因的突变小鼠发展成高度侵袭性的转移性浆液性上皮癌，其与人类卵巢癌非常相似。因此，NRSA的这项申请将专注于表征和使用这些小鼠来进一步了解女性卵巢癌。我的建议的一般假设是，在肿瘤易感环境中microRNA水平的总体下降促进了卵巢癌的发展。特异性Aim1将研究上皮性卵巢癌的起源和早期肿瘤过程。为了帮助鉴定卵巢癌的早期标记基因，将对从这些突变小鼠中取样的卵巢肿瘤组织进行基因表达分析。特异性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在这些小鼠中研究转移过程。此外，将培养这种小鼠癌症的肿瘤细胞，以研究卵巢癌进展和转移的分子途径。总之，这些方法将产生用于治疗晚期卵巢癌的有用的药物靶点。特定的Aim3将涉及创建额外的卵巢癌小鼠模型。由于大多数致命的卵巢癌患者携带p53肿瘤抑制基因突变，p53基因突变将被纳入已经缺乏DICER和PTEN基因的突变小鼠中。这种新的小鼠模型将被预测会发展出与人类卵巢癌在遗传上更相似的卵巢癌。这个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上皮性卵巢癌的起源和分子途径。

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.