Follicular Fluid Promotes Anoikis Resistance in TP53 Mutated Fallopian Tube Epithelial Cells in Ovarian Cancer

Abstract

Ovarian cancer is the most lethal gynecological disease and the high rate of mortality can be largely attributed to an inability to diagnose it in its early stages, stemming from a general lack of understanding of the disease's origins. In the formation of the disease, fallopian tube epithelial (FTE) cells—ovarian cancer progenitor cells—accrue a TP53 mutation and metastasize to the ovary or omentum. To survive in suspension in the peritoneal cavity, FTE cells must evade anoikis, a form of apoptosis that occurs when anchorage‐dependent cells become detached from the extracellular matrix (ECM). During ovulation, the oocyte‐releasing follicle discharges significant quantities of follicular fluid (FF), bathing the fimbria in reactive oxygen species, hormones, and growth factors. These microenvironmental factors are believed to have a synergistic effect with genetic mutations to initiate ovarian carcinogenesis. We have found that FF significantly (p<0.0001) increased resistance to anoikis in TP53‐mutated FTE cells, facilitating metastasis. This ubiquitous trend was observed in all FF patient samples (n=7). These assays employed flow cytometry with live/dead staining to quantify cell survival. To elucidate the mechanism governing this increase in survival of FTE cells, we fractioned FF by molecular weight, denatured proteins in FF, and added exogenous factors in anoikis assays. We discovered that hyaluronic acid (HA)—a glycosaminoglycan found in ECM—significantly (p=0.0017) increased survival of TP53‐mutated FTE, indicating its role as a constituent in the anoikis signaling cascade. FF protein denaturation results pointed to a mechanism that is likely multifaceted involving both protein and non‐protein components. By understanding the interplay of genetic mutations and microenvironmental factors, we hope to reveal the complete mechanism behind anoikis resistance to develop earlier detection mechanisms and preventative methods for ovarian cancer in its earliest stage.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.