Abstract B7: Molecular signaling in the human fallopian tube: Insights into proliferation and p53 expression

Ovarian cancer is the most lethal gynecological malignancy in women. This is primarily due to patients presenting in late stage disease when the cancer has already metastasized. Contributing to this delayed diagnosis is uncertainty regarding the origin of ovarian cancer and what causes initial transformation. It has recently been hypothesized that the distal epithelia of the fallopian tube is the origin of transformation leading to ‘ovarian’ cancer, particularly the serous histotype. A potential precursor lesion to serous cancer, known as the ‘p53 signature’, has been identified in the fallopian tube. However, little is known about the normal human fallopian tube and what factor(s) might lead this potential precursor lesion to develop into serous ovarian cancer. In order to examine the role of the fallopian tube in the development of serous cancer, as well as potential initiation factors that might be involved in early disease, a novel three-dimensional (3D) culture method was utilized. This 3D culture supports growth within the normal tissue architecture and retains epithelia in contact with its stromal environment using alginate hydrogels. This system was utilized for examination of normal human fallopian tissue collected from women undergoing salpingectomy for both benign and malignant conditions. Donated tissues were treated with factors hypothesized to have a role in the onset of serous cancer for 2 and 7 days in culture. Insulin (5 ug/ml) was used to stimulate glycolysis, hydrogen peroxide (H2O2, 1 mM) was used as an oxidative stress mimetic, and the dominant female steroid hormones estrogen (10 nM) and progesterone (100 nM) were utilized to investigate hormone controlled cell growth. Resulting cultured tissues retained normal fallopian morphology as demonstrated by immunohistochemistry for cytokeratin-8 and E-cadherin. Additionally, both tubal epithelial sub-types (secretory and ciliated) were retained in culture (denoted by PAX8 and acetylated-tubulin staining, respectively). Fimbriae cultures were further analyzed for changes in proliferation, DNA damage, and importantly, induction of p53 expression, which is thought to be linked to the onset of serous cancer. Initial findings reveal ex vivo inducible p53 expression can be acquired. These hotspots of p53 expression are secretory cell enriched similarly to those seen in vivo, but are not always expressed concomitantly with γH2AX, a marker of DNA damage. Additionally, it was noted that oxidative stress (H2O2) and insulin significantly increased the rate of proliferation as compared to vehicle control. Conversely, the effect of the steroid hormones on proliferation was less notable, with progesterone treatment consistent with possible promotion of fallopian epithelial cell death. Characterization of biological function within early putative preneoplastic lesions is integral to ovarian cancer research. Without identifying the tissue of origin, current research may be focusing on genetic or protein changes that are different only because they are compared to the wrong normal tissue of origin. Further, targeted therapies might fail due to identification of targets that are not in the correct progenitor cell population. In order to evaluate the p53 signature as a potential precursor lesion to serous cancer, we must understand what induces p53 expression in the fallopian tube and why. Citation Format: Sharon L. Eddie, Suzanne M. Quartuccio, Jessica A. Shepherd, Rajul Kothari, Joanna E. Burdette. Molecular signaling in the human fallopian tube: Insights into proliferation and p53 expression. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B7.