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.
Since clear cell/endometrioid ovarian cancers are frequently associated with endometriosis (a benign but painful gynecological disease), we propose that endometriosis is a precursor lesion leading to development of these rare subtypes of ovarian cancers. The proposed studies will investigate whether autophagy, a survival mechanism activated in response to oxidative stress (i.e., heme, elevated in endometriotic cysts whose breakdown product (iron) elicits cell transformation), modulates the transition from endometriosis to ovarian cancers. Since patients with clear cell ovarian cancers frequently have a poor prognosis, the proposed studies are important and will serve to fill in an important missing link to our understanding of the development of these endometriosis-associated ovarian cancers.
|Bauckman, Kyle; Haller, Edward; Taran, Nicholas et al. (2015) Iron alters cell survival in a mitochondria-dependent pathway in ovarian cancer cells. Biochem J 466:401-13|