Lysophosphatidylcholine Pretreatment Reduces VLA-4 and P-Selectin–Mediated B16.F10 Melanoma Cell Adhesion In vitro and Inhibits Metastasis-Like Lung Invasion In vivo

Abstract

Lysophosphatidylcholine (LysoPC) is an important intermediate in degradation and biosynthesis of phosphatidylcholine (PC). Reduced plasma LysoPC levels observed in patients with advanced cancer indicate a deregulation of LysoPC metabolism in metastasis. Recent data showed strong antimetastatic effects of liposomes consisting of saturated PC in a murine pancreatic metastasis model. LysoPC, generated from saturated PC after accumulation of the liposomes in tumor tissue, might be contributing to these effects. Examining effects of high local concentrations of saturated LysoPC and investigating potential molecular mechanisms, fast removal of saturated LysoPC from medium by murine B16.F10 melanoma cells and radical shifts in tumor cell membrane fatty acid (FA) composition toward saturated FAs were observed in vitro. Scanning electron microscopy revealed remarkable morphologic surface changes of LysoPC-treated tumor cells, probably causing their impaired migratory ability on fibronectin. A LysoPC concentration exceeding a threshold of about 400 mmol/L, slightly above physiologic levels, strongly reduced VLA-4-mediated binding of B16.F10 cells to VCAM-1 as well as P-selectin-dependent interaction with activated platelets, although expression levels were not altered. These findings were reflected in a syngenic intravenous lung invasion model using repeatedly ex vivo LysoPC-treated (450 mmol/L) B16.F10 cells, resulting in significantly reduced lung metastasis-like lesions (À48.3%, P ¼ 0.006). Prior application of 50 IU unfractionated heparin further reduced lung invasion (À81.6%, P ¼ 0.043). Our work shows for the first time that saturated LysoPC in high concentrations reduces melanoma cell adhesion in vitro and hematogeneous dissemination in vivo by direct ex vivo tumor cell targeting.

Molecular MRI enables early and sensitive detection of brain metastases

“…In a melanoma model, both blockade and inhibition of VCAM-1 have been shown to significantly reduce liver metastasis (16,27). Similarly, disruption of the interaction between very late antigen-4, the natural ligand to VCAM-1, on tumor cells and endothelial VCAM-1 reduces both adhesion of metastatic renal cell cancer cells to endothelial cells in vitro (28) and incidence of lung metastases in vivo (29). Moreover, several human tumor cell lines that metastasize to the lung show greater expression of very late antigen-4 than nonmetastatic lines (30).…”

Probiotic pre-administration reduces mortality in a mouse model of cecal ligation and puncture-induced sepsis

“…Although LPCs are typically regarded as pro-inflammatory mediators, they were increased in inflammatory diseases (27,28). A previous series of studies have demonstrated a protective effect of LPCs against diseases, including type 2 diabetes (29), cancer (30) and inflammatory diseases (31).…”

Characterization of Phospholipid Molecular Species by Means of HPLC-Tandem Mass Spectrometry

“…In the vascular endothelium, LPC increased permeability and expression of proinflammatory mediators such as adhesion molecules and cytokines. However, saturated LysoPC in high concentrations reduced melanoma cell adhesion in vitro (Jantscheff et al, 2011). Certain lysophospholipids such as ether-linked lysophosphatidylcholine are acetylated by a specific acetyltransferase to form platelet activating factors (Hanahan, 1986).…”