Abstract A29: Effects of lysophosphatidic acid on ovarian cancer metastatic dissemination
Authors: Klymenko Yuliya , Bos Brandi , Campbell Leigh , Loughran Elizabeth , Liu Yueying , Kim Oleg , Nephew Kenneth P. , Stack M. Sharon 
Published: August 2018

Epithelial ovarian cancer (EOC) is typically detected after extensive intraperitoneal metastases, contributing to its status as the deadliest gynecologic malignancy. Metastasis occurs as tumor cells exfoliate from the primary tumor, permeate throughout the peritoneal cavity as single cells and multicellular aggregates (MCAs), adhering to the mesothelial layer of peritoneal tissues and subsequently inducing mesothelial retraction, submesothelial matrix invasion, and tumor mass proliferation. This process is often accompanied by accumulation of malignant ascites rich in lysophosphatidic acid (LPA), a bioactive lipid molecule that activates a subfamily of G-protein coupled receptors and is linked to aberrant cell proliferation, oncogenesis, and metastasis. It has been previously shown that LPA disrupts junctional integrity and epithelial cohesion of EOC cells in vitro, which may facilitate tumor cell extension from the primary carcinoma. However, the subsequent fate of free-floating cells/MCAs as well as the microenvironmental response of host tissues to abundant LPA levels remains unclear. Thus, the objective of the current study is two-fold: to elucidate the effects of LPA on cancer cell/MCA dynamics and peritoneal adhesivity, and to assess alterations in peritoneal tissue ultrastructure and susceptibility to metastatic anchoring upon LPA exposure. Using a novel ex vivo tissue explant assay, we report that LPA diminished the adhesive capacity of EOC cells to murine peritoneal explants in three different EOC cell lines. Further, EOC MCAs displayed significant changes in surface morphology with the loss of cell surface protrusions and poor cell aggregation, resulting in a higher number of disseminated small clusters compared to untreated control MCAs. Additionally, we found that peritoneal tissues from healthy mice injected intraperitoneally with LPA (versus those injected with phosphate-buffered saline or left untreated) demonstrated remarkably higher mesothelial surface microvilli density and length, as detected by scanning electron microscopy. Subsequent analysis of ex vivo peritoneal adhesion revealed notable attenuation of both single cell and MCA seeding to ultrastructurally modified peritoneal explants of LPA-injected mice. Taken together, these findings support the hypothesis that LPA modulates EOC metastatic dissemination and ultimate metastatic success through alterations in both ovarian cancer cell/MCA behavior (aggregation and peritoneal adhesivity) and the intraperitoneal microenvironment (changes in host mesothelial morphology and susceptibility to metastatic anchoring). These data call for future studies on the role of LPA in EOC metastatic progression using preclinical in vivo murine models of EOC metastasis to test with the prospective LPA-targeted interventions.

Citation Format: Yuliya Klymenko, Brandi Bos, Leigh Campbell, Elizabeth Loughran, Yueying Liu, Oleg Kim, Kenneth P. Nephew, M. Sharon Stack. Effects of lysophosphatidic acid on ovarian cancer metastatic dissemination. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A29.