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，这种癌症直到很晚期才被发现。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。虽然手术和化疗在过去的20年里逐渐得到改善，但大多数卵巢癌患者在最初的化疗成功后会复发并最终死亡。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。作为我博士后培训的一部分，我通过有条件地禁用两个基因，开发了一种卵巢癌基因工程小鼠模型：DICER基因，编码microRNA生物合成的必需酶，PTEN基因，编码肿瘤抑制因子。这些缺乏卵巢和输卵管基因的突变小鼠发展为高度侵袭性转移性浆液上皮癌，与人类卵巢癌非常相似。因此，NRSA的应用将集中在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，在肿瘤易发的环境中，microRNA水平的整体降低促进了卵巢癌的发展。特异性Aim1将探讨上皮性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，将对这些突变小鼠的卵巢肿瘤组织进行基因表达分析。特异性Aim2将确定这些小鼠卵巢癌的转移性质，这些小鼠卵巢癌反映了人类卵巢癌。转移过程也将通过基因表达分析在这些小鼠中进行研究。此外，该小鼠肿瘤细胞将被培养以研究卵巢癌进展和转移的分子途径。总之，这些方法将产生治疗晚期卵巢癌的有用药物靶点。具体目标将包括创建更多的卵巢癌小鼠模型。因为大多数致命的卵巢癌患者携带p53肿瘤抑制基因突变，p53基因的突变将被合并到已经缺乏DICER和PTEN基因的突变小鼠中。据预测，这种新的突变小鼠模型将发展为与人类卵巢癌基因更相似的卵巢癌。本NRSA提案的主要目标是利用基因工程小鼠模型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.