Dispersal of epithelial cancer cell colonies by lysophosphatidic acid (LPA)

Abstract

We describe a model system in which cancer cell colonies disperse into single, highly migratory cells in response to lysophosphatidic acid (LPA). Though LPA is known to stimulate chemotaxis and chemokinesis, a colony dispersal effect has not been reported, to our knowledge. Cancer colony dispersal by LPA is comprised of an ordered sequence of events: (1) stimulation of membrane ruffling and formation of lamellipodia, (2) dissolution of adherens junctions, (3) single cell migration in a mesenchymal-like morphology we term "ginkgo-leaf." The net result is dispersal of carcinoma cells from a compact colony. We analyzed these three steps using live-cell imaging and computer-assisted quantification and measured the following parameters: onset of lamellipodia formation, lamellipodia velocity, colony dispersal, trans-epithelial resistance, migrating cell number and speed. Because hepatocyte growth factor (HGF) was described as an epithelial scatter factor, we compared it to LPA in our system and found that HGF has no epithelial colony dispersal properties and that this effect is strictly related to LPA. Given its striking similarity to tumor cell budding observed in patients, we propose that LPA-colony dispersal may provide a cellular mechanism underlying cancer invasion and as such deserves further studies.

Cytoplasmic Domain Interactions of Syndecan-1 and Syndecan-4 with α6β4 Integrin Mediate Human Epidermal Growth Factor Receptor (HER1 and HER2)-dependent Motility and Survival

“…These findings suggest that this mechanism is activated in vivo either by overexpression of HER2 or kinase-activating mutations of the receptor, or by enhanced deposition of LN332. Modulation of LN332 expression by LPA may partly explain the tumorigenic activity of this lipid (46,77). Our data also suggest, however, that ␣6␤4 integrin binding to the LN332 is not required; thus, its primary role may be to act as a signaling scaffold when bound by the syndecans, rather than having a role in clustering the receptor complex by engaging the matrix.…”

Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Induces β-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma

“…LPA regulates a multitude of ovarian tumor cell responses, including proliferation, migration, and invasion (19,24,28). LPA is expressed as high as 80 M in the ascites fluid and serum of patients with ovarian cancer (24, 25, 49 -51), underlying the importance of understanding its pathophysiological role in ovarian cancer.…”

Alternatively spliced protein arginine methyltransferase 1 isoform PRMT1v2 promotes the survival and invasiveness of breast cancer cells

“…This assay measures the ability of epitheliallike tumor cells to detach from colonies in culture mimicking a migratory phenotype. 29,34,35 Specifically, colonies were classified based on morphology as compact, loose or scattered (Fig. 7C).…”