Development of a new molecular target therapy for ovarian carcinoma based on the analyses of mechanisms for its peritoneal dissemination

卵巢癌是妇科恶性肿瘤死亡的主要原因。卵巢癌患者的不良预后与腹膜播散有关;腹膜播散是一种转移过程，其中癌细胞从原发肿瘤分离，附着在腹膜上，并在该部位重新生长。本研究的目的是在分析卵巢癌细胞腹膜转移的分子机制的基础上，开发一种新的分子靶向治疗方法。乳头状突起尖端的卵巢癌细胞实际上表达HIF-1 α，这与E-cadherin表达减少有关。体外实验表明，缺氧通过上调E-cadherin启动子的抑制子SNAIL的表达，抑制E-cadherin的表达，并增强其侵袭能力。这些发现表明，缺氧发挥 ...更多信息 在转移部位，我们将目光集中在小G T β RhoA上，它是来自腹水的各种生长信号的共同途径的候选者。RhoA在腹膜转移中的表达明显高于原发灶。通过用溶血磷脂酸（LPA）处理上调和激活Rho增加了癌细胞的侵袭力，并且用Rho的特异性抑制剂C3外切酶处理逆转了LPA处理的效果。使用裸鼠的离体模型显示腹膜传播在组成型表达Rho的卵巢癌细胞中更突出。此外，我们的初步研究表明，口服他汀类药物，Rho激活的潜在抑制剂，抑制卵巢癌细胞的腹膜传播。这些结果表明，RhoA是一个很好的分子靶点，在新的治疗卵巢癌腹膜转移。少

Ovarian carcinoma is the leading cause of gynecological cancer death. The poor prognosis for patients with ovarian cancer is related with peritoneal dissemination ; a metastatic process in which cancer cells detach from the primary tumor, attach to the peritoneum, and re-grow at the site. The objective of this study is to develop a new molecular target therapy, based on the analyses of the molecular mechanisms of peritoneal dissemination of ovarian cancer cells.In the metastatic process, since cancer cells become independent from the blood supply and exposed to hypoxia, we focused on the hypoxic environment and. Ovarian cancer cells in the tip of papillary projection actually expressed HIF-1 alpha, being associated with reduced expression of E-cadherin. In vitro experiment indicated that hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL that is a repressor of E-cadherin promotor, and also increases the invasive capacity. These findings suggest that hypoxia play … More s an important role in the dissemination of ovarian cancer cells in the primary lesion.In the metastaic sites, we focused on the small GTPase RhoA, that is the candidate of common pathway from various growth signals from the ascites. The expression of RhoA was significantly higher in the peritoneal dissemination than in the primary lesion. Up-regulation and activation of Rho by treatment with lysophospahtidic acid (LPA) increased the invasiveness of cancer cells, and treatment with C3 exoenzyme, a specific inhibitor of Rho, reversed the effect of LPA treatment. Ex vivo model using nude mice showed that peritoneal dissemination was more prominent in ovarian cancer cells expressing Rho constitutively. In addition, our preliminary study showed that oral administration of statins, potential inhibitor of Rho activation, suppressed the peritoneal dissemination of ovarian cancer cells. These findings indicate that RhoA is a good molecular target in the new therapy for peritoneal dissemination of ovarian carcinoma. Less