title: 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 μmol/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 μmol/L) B16.F10 cells, resulting in significantly reduced lung metastasis-like lesions (-48.3%, P = 0.006). Prior application of 50 IU unfractionated heparin further reduced lung invasion (-81.6%, P = 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.
authors.affiliation: Tumor Biology Center Freiburg, Clinical Research, Dept. Lipids & Liposomes, Breisacher Str.117, D-79106 Freiburg, Germany. jantscheff@tumorbio.uni-freiburg.de
authors.forename: Peter
authors.initials: P
authors.lastname: Jantscheff
authors.forename: Martin
authors.initials: M
authors.lastname: Schlesinger
authors.forename: Juliane
authors.initials: J
authors.lastname: Fritzsche
authors.forename: Lenka A
authors.initials: LA
authors.lastname: Taylor
authors.forename: Ralph
authors.initials: R
authors.lastname: Graeser
authors.forename: Gregor
authors.initials: G
authors.lastname: Kirfel
authors.forename: Dieter O
authors.initials: DO
authors.lastname: Fürst
authors.forename: Ulrich
authors.initials: U
authors.lastname: Massing
authors.forename: Gerd
authors.initials: G
authors.lastname: Bendas
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary*; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D039041:Integrin alpha4beta1; D008244:Lysophosphatidylcholines; D019007:P-Selectin; D011994:Recombinant Proteins