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

描述（由申请人提供）：提出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导致的分子改变。有趣的是，这些过程也可能有助于类卵巢癌/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（PIK 3CA/ARID 1A）有关，通常位于卵巢癌附近，并与氧化应激标志物增加有关。自噬是一种在氧化应激下激活的生存机制，可促进肿瘤的发生发展，可能是一种理想的治疗靶点。自噬在子宫内膜异位症相关卵巢癌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其可能参与子宫内膜异位症的转化。我们认为，持续暴露于活性氧（引起铁升高的卵巢囊肿）改变自噬通量，从而调节从子宫内膜异位症卵巢癌的过渡。在目标1中，我们将检验自噬在卵巢癌（典型和非典型）病变和卵巢透明细胞/类卵巢癌组织中发生改变的假设。在目的2中，我们将检验以下假设：在活化的PIK 3CA/K-Ras的存在下，通过自噬来调节凋亡细胞的转化潜力。如果目标成功，我们将（1）提高我们对这种转变的理解，（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.