Abstract
Epithelial ovarian cancer (EOC) metastasis occurs by exfoliation of cells and multicellular aggregates (MCAs) from the tumor into the peritoneal cavity, adhesion to and retraction of peritoneal mesothelial cells and subsequent anchoring. Elevated levels of lysophosphatidic acid (LPA) have been linked to aberrant cell proliferation, oncogenesis, and metastasis. LPA disrupts junctional integrity and epithelial cohesion in vitro however, the fate of free-floating cells/MCAs and the response of host peritoneal tissues to LPA remain unclear. EOC MCAs displayed significant LPA-induced changes in surface ultrastructure with the loss of cell surface protrusions and poor aggregation, resulting in increased dissemination of small clusters compared to untreated control MCAs. LPA also diminished the adhesive capacity of EOC single cells and MCAs to murine peritoneal explants and impaired MCA survival and mesothelial clearance competence. Peritoneal tissues from healthy mice injected with LPA exhibited enhanced mesothelial surface microvilli. Ultrastructural alterations were associated with restricted peritoneal susceptibility to metastatic colonization by single cells as well as epithelial-type MCAs. The functional consequence is an LPA-induced dissemination of small mesenchymal-type clusters, promoting a miliary mode of peritoneal seeding that complicates surgical removal and is associated with worse prognosis.
Highlights
Epithelial ovarian cancer (EOC) metastasis occurs by exfoliation of cells and multicellular aggregates (MCAs) from the tumor into the peritoneal cavity, adhesion to and retraction of peritoneal mesothelial cells and subsequent anchoring
We previously demonstrated that MCAs generated from epithelial- and mesenchymal-type ovarian cancer cells possess dramatically different phenotypes, ranging from loosely adhesive clusters to highly cohesive solid spheroids[24]
Four different lysophosphatidic acid (LPA) treatment regimens were implemented (Fig. 1B): (a) EOC cells grown as two-dimensional (2D) monolayers and subsequently seeded to grow threedimensionally (3D) in hanging drops were left untreated; (b) EOC cells were grown in monolayers without LPA and further treated with 80 μM LPA in hanging drops (‘2D − 3D+’); (c) EOC cells were grown in monolayers with 80 μM LPA and subsequently incubated without LPA in hanging drops (‘2D + 3D−); (d) EOC cells were treated with 80 μM LPA both in monolayers and hanging drops (‘2D + 3D−’)
Summary
Epithelial ovarian cancer (EOC) metastasis occurs by exfoliation of cells and multicellular aggregates (MCAs) from the tumor into the peritoneal cavity, adhesion to and retraction of peritoneal mesothelial cells and subsequent anchoring. EOC MCAs displayed significant LPA-induced changes in surface ultrastructure with the loss of cell surface protrusions and poor aggregation, resulting in increased dissemination of small clusters compared to untreated control MCAs. LPA diminished the adhesive capacity of EOC single cells and MCAs to murine peritoneal explants and impaired MCA survival and mesothelial clearance competence. Buildup of malignant ascitic fluid further expedites intraperitoneal transport as anoikis-resistant single cells and multicellular aggregates (MCAs, or spheroids) The latter colonize and retract the mesothelial monolayer of peritoneally-lined abdominal organs, anchor in the submesothelial extracellular matrix (ECM) and proliferate to form metastatic n odules[6,7,8]. As opposed to normal ovarian epithelial cells which do not produce LPA at levels significant enough to stimulate aberrant receptor activation[38], in EOC constitutive production of LPA by both ovarian cancer cells and mesothelial cells of the p eritoneum[38, 39] increases EOC cell adhesive, migratory and invasive properties, colony formation in vitro as well as tumorigenesis/metastasis in vivo[39,40,41]
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