Transition from Endometriosis to Ovarian Cancer: Role of Iron-Induced Autophagy

描述(申请人提供)：据认为，子宫内膜异位症是一种良性妇科疾病，是由于持续暴露于局部氧化应激和炎症过程而导致的分子改变。有趣的是，这些过程也可能有助于子宫内膜样癌/透明细胞卵巢癌的发展。事实上，非典型卵巢子宫内膜异位症(被认为是“癌前病变”)与突变(PIK3CA/ARID1A)有关，通常位于卵巢癌附近，并与氧化应激标志物增加有关。自噬是一种对氧化应激做出反应而激活的生存机制，它促进了肿瘤的发展，可能是治疗的理想靶点。自噬在子宫内膜异位症相关卵巢癌发生发展中的作用尚不清楚；然而，这种生存机制与氧化应激之间的联系表明它可能参与了子宫内膜异位症的转化。我们认为，持续暴露于活性氧物种(由子宫内膜异位囊肿铁升高引起)改变自噬通量，从而调节从子宫内膜异位症向卵巢癌的转变。在目标1中，我们将检验自噬从子宫内膜异位(典型和非典型)病变到卵巢透明细胞/子宫内膜样癌组织改变的假设。在目标2中，我们将验证一种假设，即在激活的PIK3CA/K-RAS存在的情况下，异位内膜细胞的转化潜力是通过自噬来调节的。如果目标成功，我们将(1)提高我们对这一转变的理解，(2)确定新的靶点，以减轻这些卵巢癌的负担。

DESCRIPTION (provided by applicant): It is proposed that endometriosis, a benign gynecological disease, results from molecular alterations due to persistent exposure to local oxidative stress and inflammatory processes. Interestingly, these processes may also contribute to the development of endometrioid/clear cell ovarian cancers. Indeed, atypical ovarian endometriosis (considered "precancerous" lesions) are associated with mutations (PIK3CA/ARID1A), are often located adjacent to the ovarian cancer, and associated with increased oxidative stress markers. Autophagy, a survival mechanism activated in response to oxidative stress, promotes tumorigenic development and may be an ideal target for therapy. The role of autophagy in the development of endometriosis-associated ovarian carcinomas is unknown; however, the links between this survival mechanism and oxidative stress suggests its possible involvement in endometriosis transformation. We propose that persistent exposure to reactive oxygen species (induced by iron elevated in endometriotic cysts) alters autophagic flux thereby regulating the transition from endometriosis to ovarian cancer. In Aim 1, we will test the hypothesis that autophagy is altered from endometriotic (typical and atypical) lesions and to ovarian clear cell/endometrioid carcinoma tissues. In Aim 2, we will test the hypothesis that the transformation potential of endometriotic cells in the presence of activated PIK3CA/K-Ras is modulated via autophagy. If the aims are successful, we will (1) improve our understanding of this transition and (2) identify new targets to diminish the burden of these ovarian cancers.