Ovarian cancer is one of the most devastating cancers in women. A fundamental step toward improving detection and treatment of this lethal disease is to understand the mechanism of its initiation and progression. In this study we demonstrated the role of brain-derived neurotrophic factor (BDNF) in ovarian cancer initiation and progression, particularly, the high-grade serous ovarian carcinoma (HGSOC). BDNF was discovered in the brain as a growth factor and chemoattractant inducing the migration, survival, and differentiation of neurons. It is also secreted by the ovary into the follicular fluid and by the adipocytes in the omentum and peritoneum. BDNF suppresses anoikis, the apoptosis induced by lack of proper cell to extra-cellular matrix (ECM) attachment. BDNF has been associated with tumor progression in colon, breast, lung, and gastric cancers. In ovarian tumors both BDNF and its receptor tropomyosin receptor kinase B (TrkB) are expressed. Their overexpression is associated with poor survival. Fallopian tube epithelial cells (FTEs) are hypothesized to be the cell of origin of HGSOC. We used 3 immortalized human normal FTE cell lines to demonstrate the effects of BDNF on the survival, mobility, and adhesion of FTEs in vitro. CellTiter luminescent cell viability assays were conducted to evaluate the effects of BDNF on the short-term and long-term survival of FTEs in 3D culture conditions. Caspase-3 activity assays were used to quantify the extent of which BDNF inhibited anoikis in FTEs. Trans-well and 3D bioprinting migration assays were used to determine whether BDNF could promote the mobility of FTEs. The ECM-coated beads were co-cultured with FTEs in a 3D model and their attachment to ECM was quantified in order to evaluate the effects of BDNF on the cell adhesion. The BDNF-activated intracellular pathways were identified using Western blots, RNA microarray, RT-QPCR analyses. Our data demonstrated that TrkB was expressed by the FTEs in human and mouse fallopian tubes. BDNF significantly enhanced the survival of FTE cell lines in the serum-free 3D culture condition. Their enhanced survival was also evidenced by the decreased caspase-3 activity indicating the inhibition of anoikis. BDNF increased the ability of FTEs to migrate in the migrations assays. The BDNF-treated FTEs attached to the ECM-coated beads faster than the untreated cells. Western blots showed that BDNF activated the phosphorylation of TrkB, AKT, ERK, PLC-gamma1, and CREB. RNA microarray and QPCR data suggest that epithelial-mesenchymal transition (EMT), anti-oxidative stress, and ECM-related pathways were activated by BDNF leading to the enhanced survival, migration, and cell adhesion. These results revealed the potential role of BDNF to promote ovarian cancer initiation. Understanding this molecular pathway will lead to the development of more specific markers for early detection and better prevention and treatment strategies.

Citation Format: Min Kang, Kay Y. Chong, Tobias M. Hartwich, Oluwagbemisola O. Madarikan, Jonah Nucci, Sarah L. Cady, Yang Yang-Hartwich. The role of brain-derived neurotrophic factor in ovarian cancer initiation and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5220.