Changes in ovarian tumours collected from a SKOV3 tumour xenograft model after treatment with placental extracellular vesicles

Abstract

Ovarian cancer (OC) is the third most common gynaecological cancer with a 6.6% incidence rate and is associated with a high mortality rate. Since the late 1990s, pregnancy has been consistently confirmed as a protective factor for ovarian cancer. Parous women are known to have a significantly reduced risk of developing ovarian cancer compared with nulliparous women. Dogma suggests the protective effect of parity is due to anovulation and hormone reduction during pregnancy, it cannot fully explain this pregnancy-related anti-tumour effect. The human placenta may play an important role in preventing ovarian cancer development as the studies reported that the cargo in placental extracellular vesicles (EVs) carry anti-tumour properties. A previous in vitro study found that the treatment of placental EVs significantly reduced the proliferation of SKOV-3 ovarian tumour cells. Furthermore, the SKOV-3 tumour xenograft model with which I am working illustrated a significant decrease in the volume of ovarian tumours in mice after being treated by both placental micro and nano placental EVs. Therefore, in this study, the underlying mechanisms involved in the ovarian tumour regression upon placental EVs treatment needed to be further investigated and studied. Various types of histological assays were performed to investigate the morphological and immunological changes in ovarian tumours after treatment with placental EVs grown in a mouse xenograft model. Signs of cellular necrosis were found in the ovarian tumours treated by placental EVs, but not in healthy organs suggesting that the placental EVs induced ovarian tumour regression is associated with the necrosis of ovarian tumour cells. Further investigation suggested the RIP1-RIP3-MLKL necroptosis pathway was not involved in ovarian tumour necrosis, suggesting that placental EVs induced ovarian tumour necrosis/regression is independent of RIP1-RIP3-MLKL signalling pathways in this SKOV-3 tumour xenograft model. However, reduced activation of the unfolded protein response (a response on endoplasmic reticulum) was seen in ovarian tumour tissues collected from mice that had been treated with both placental micro- and nano-EVs, suggesting ER stress pathway may be involved in necrosis in ovarian tumour tissues. In addition to the unfolded protein response, the number of CD169+ macrophages and NKp46+ NK cells were increased significantly in ovarian tumour tissues collected from mice that had been treated with placental micro-EVs. The positive correlation between CD169+ macrophages and NKp46+ NK cells, suggested that infiltration of CD169+ macrophages and NKp46+ NK cells in ovarian tumour tissues could be one reason for the reduction of ovarian tumour size in the SKOV-3 tumour xenograft model. Taken together, data presented in this study indicated that placental EVs have anti-ovarian tumour activity, that involved at least infiltration of CD169+ macrophages and NK cells and an increase in necrosis accompanied by an increased unfolded protein response.