Development of Animal Models (Transgenic Mice) for Ovarian Cancer

日本的卵巢癌死亡率呈逐年上升趋势，在这50年间增加了8倍以上。卵巢癌的早期诊断比较困难，因为卵巢癌患者没有症状或只是轻微症状，直到疾病进入晚期，如III/IV期，难以治疗。近年来，我们利用特异性角蛋白启动子，建立了大量高表达多种生长因子或癌基因的转基因小鼠，如转化生长因子α、c-src、c-erb B_2、胰岛素样生长因子-1和E_2F1。这些转基因小鼠产生了包括皮肤、前列腺癌、胆囊癌和子宫颈在内的各种上皮性肿瘤。在这些转基因小鼠中，角蛋白1、5、14和氯霉素作为启动子。然而，由于这些转基因小鼠的启动子在卵巢表面上皮细胞(OSE)中不表达，因此这些小鼠不可能与卵巢肿瘤的发生有关。本研究旨在建立卵巢癌的动物模型。首先，我们探索了有希望的候选分子作为与卵巢肿瘤相关的转基因小鼠的特异性启动子，发现角蛋白8(K8)在卵巢表面上皮细胞中特异表达。接下来，我们制备了K8、GFP(绿色荧光蛋白)转基因小鼠，以证实K8基因表达的分布和定位。最后，我们尝试制作了一些转基因小鼠，包括K8.IGF-1转基因小鼠、K8.E2F1转基因小鼠、K8.erbB2转基因小鼠和K8.src转基因小鼠。然而，这些项目仍在进行中，我们的初步数据显示，OSE的乳头状增生，被认为是卵巢舞蹈者的前驱病变，在erbB2转基因小鼠中观察到。

The mortality rate of ovarian cancer in Japan is increasing year by year, and more than 8 times in these 50 years. It is difficult to diagnose ovarian cancer in early stage, because patients with ovarian cancer have no symptoms or just mild symptoms until the disease is in an advanced stage such as stage III/IV and hard to treat. Therefore, ovarian cancer is sometimes called the "silent killer."Recently, we have established a lot of transgenic mice overexpressing various growth factors or oncogenes, such as TGF-α, c-src, c-erbB2, IGF-1, and E2F1, using specific keratin promoters. These transgenic mice developed various epithelial tomors including skin, prostate, gallbladder and uterine cervix. In these transgenic mice, keratin 1, 5, 14 and loricrin were used as promoters. However, there is no possibilities that these mice were associated with ovarian tumorigenesis, because these promoters of transgenic mice were not expressed in ovarian surface epithelium (OSE).In this study, we aimed at development of animal models for ovarian cancer. First, we explored the promising candidate molecules as a specific promoter for making transgenic mice associated with ovarian tumorigenesis, and found that keratin 8 (K8) was specifically expressed in ovarian surface epithelium. Next, we made K8,GFP (green fluorescent protein) transgenic mice to confirm the distribution and localization of K8 expression. Finally, we attempted to make some transgenic mice, K8.IGF-1 transgenic mice, K8.E2F1 transgenic mice, K8.erbB2 transgenic mice, and K8.src transgenic mice. However these projects are still on going, our preliminary data showed that papillary proliferation of OSE, considered as precursor lesions of ovarian dancer, was observed in erbB2 transgenic mice.