Mutagenic, surviving and tumorigenic effects of follicular fluid in the context of p53 loss: initiation of fimbria carcinogenesis

Abstract

Ovulation is the strongest risk factor for ovarian high-grade serous carcinoma (HGSC) that largely originates from the fallopian tube fimbriae and always carries loss-of-function mutations of TP53 in both early and late lesions. Mature ovarian follicle contains high level of reactive oxygen species (ROS). When released from ovulation, follicular fluid (FF) bathes the fimbriae and may lead to DNA double-strand break (DSB) and neoplastic transformation. In this study, we examined the mutagenic and tumorigenic activities of human pre-ovulatory FFs. A subset (6/11) of FFs was found with high levels of ROS whereas the antioxidant capacities were indifferent. These ROS(high) FFs induced intracellular ROS and DSBs in the secretory cell population of fimbriae epithelium. When p53 and Rb were turned down, the FF-exposed secretory cells overcame apoptosis and expanded the population carrying ROS and DSB. The cancer initiation and promotion effects of FF were further recapitulated in Trp53 (-/-) mice. When introduced into the mammary fat pad, ROS(high) but not ROS(low) FFs induced early-onset B-cell lymphoma. Cotreatment with physiological concentration of melatonin, a potent antioxidant, ameliorated the mutagenic and tumorigenic effect of ROS(high) FF in vitro and in vivo. The study revealed ROS and mitogens in mature ovarian follicles could initiate the transformation of fimbria epithelium in the context of p53 loss and melatonin is a potent preventive agent.

Cytidine deaminase Apobec3a induction in fallopian epithelium after exposure to follicular fluid

“…Exposure of fallopian epithelial cells to FF increased γH2A.X foci, confirming previous studies [17, 18]. However, γH2A.X increase could be independent of DNA damage, such as following activation of DNA-PKC/CHK2 in the absence of DNA damage [29].…”

“…This has led to the idea that FF may be tumorigenic, and that repetitive exposure of fallopian epithelial cells to this complex fluid may cause mutations and alterations leading to neoplastic transformation [10]. Three studies support the hypothesis that FF can cause DNA damage marks and cell proliferation in cultured fallopian epithelial cells [16–18]. In a mouse model, ovulation induced γH2A.X foci in oviductal epithelial cells in vivo after gonadotropin stimulation in a proliferation independent manner [16].…”

“…In another study, incubation of fallopian epithelial cells with FF for 24 hr significantly increased γH2A.X foci compared with culture medium alone [17]. The third study used human FF and immortalized human fallopian epithelial cells to show that individual FF stratified into two groups: one with high reactive oxygen species (ROS) that increased the number of cells positive for γH2A.X, and one with low ROS that did not increase γH2A.X [18]. Although these studies suggest FF is responsible for inducing DNA damage, studies designed to control for the plasma constituents in FF, and a hypothesis driving the DNA-damaging properties of FF are essential to understand early molecular changes that occur during fallopian carcinogenesis related to ovulation.…”

Iron overload and altered iron metabolism in ovarian cancer

“…Exposure of fallopian epithelium to follicular fluid leads to a small increase in cell proliferation along with IL-8 cytokine levels (Bahar-Shany et al, 2014). High ROS containing follicular fluid was capable of inducing early onset B-cell lymphoma in mammary fat pads in mice lacking p53 (Huang et al, 2015). …”

Follicular fluid has more to offer: Insulin-like growth factor axis on ovarian carcinogenesis

“…Previous studies have examined the link between ovulation and cancer development by examining fallopian tube follicular fluid (FF), which bathes fallopian tubes after each ovulation and is a required process during ovulation [6,7]. They found that FF in high concentrations could cause significant DNA damage, double-stranded breaks, and TP53 nuclear accumulation that created an immunostaining pattern similar to that seen in p53 signature.…”