title: Extracellular S100A4 affects endothelial cell integrity and stimulates transmigration of A375 melanoma cells.
abstract: High extracellular S100A4 level proves a specific characteristic of some cancer cases, including malignant melanoma. Concerning the latter, extracellular S100A4 in an autocrine manner was shown to promote prometastatic activation of A375 cells by interaction with the receptor for advanced glycation endproducts (RAGE). We hypothesized that interaction of extracellular S100A4 with RAGE in a paracrine manner will affect endothelial cell (EC) integrity thus further promoting melanoma metastasis. We investigated the influence of recombinant and cell (A375)-derived S100A4 on junction protein expression and EC (hCMEC/D3) integrity by measuring transendothelial electrical resistance (TEER). Decrease of TEER and diminished expression of both occludin and VE-cadherin revealed the loss of EC integrity. Transmigration of transgenic A375 cells (A375-hS100A4/A375-hRAGE) through the EC monolayer was significantly higher compared to wild-type A375 cells, and was substantially decreased by sRAGE. A pilot study in mice, intracardially injected with A375-hS100A4 or A375-hRAGE cells, showed lower survival rates and a higher incidence of metastases compared to wild-type A375 cells. Tumor development was mostly located in the brain, bones, and ovaries. These findings provide further evidence on extracellular S100A4 as paracrine mediator of prometastatic endothelial dysfunction involving its interaction with RAGE.
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department Radiopharmaceutical and Chemical Biology, Dresden, Germany; Technische Universität Dresden, Department of Chemistry and Food Chemistry, Dresden, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Herwig
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department Radiopharmaceutical and Chemical Biology, Dresden, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Belter
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department Radiopharmaceutical and Chemical Biology, Dresden, Germany; Technische Universität Dresden, Department of Chemistry and Food Chemistry, Dresden, Germany. Electronic address: j.pietzsch@hzdr.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D019899:Paracrine Communication; D000071999:S100 Calcium-Binding Protein A4 / Q000493:pharmacokinetics*
chemical_list: D000071999:S100 Calcium-Binding Protein A4; C077591:S100A4 protein, human
keywords: Prometastatic endothelial dysfunction; Receptor for advanced glycation endproducts (RAGE); S100 proteins; Soluble RAGE (sRAGE); Transendothelial electrical resistance (TEER); hCMEC/D3