title: Impact of the Tumor Microenvironment on the Expression of Inflammatory Mediators in Cancer Cells.
abstract: Hypoxia and extracellular acidosis are common features of solid malignant tumors. The aim of the study was to analyze whether these pathophysiological parameters affect the expression of inflammatory mediators in tumor cells. Therefore the mRNA expression of MCP-1 (monocyte chemotactic protein 1), iNOS and osteopontin was measured under hypoxic (pO2 1 mmHg) and acidotic (pH 6.6) conditions by qPCR in AT1 R-3327 prostate cancer cells. In addition, the underlying signaling cascades were analyzed by using inhibitors of the p38 and ERK1/2 MAP kinase pathways.Hypoxia led to a significant decrease of the expression of MCP-1 and osteopontin over the complete observation period of 24 h, whereas the iNOS expression after an initial reduction slightly increased. Acidotic conditions for up to 6 h increased the iNOS expression significantly which was functional as indicated by an elevated level of nitrate/nitrite formation by 30 %. Acidosis had almost no impact on the MCP-1 expression of tumor cells, whereas the osteopontin level tended to increase leading to a significantly elevated level after 24 h at pH 6.6. Inhibiting the p38 and ERK1/2 under control conditions revealed that the MAPKs play a significant role for the regulation of the expression of inflammatory mediators. MCP-1 expression could be lowered by inhibiting ERK1/2 whereas iNOS expression was dependent on both p38 and ERK1/2 MAPK. These results indicate that the adverse tumor microenvironment affects the expression of inflammatory mediators by tumors cells and may therefore modulate the immune response within the tumor tissue.
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle, Magdeburger Str. 6, 06114, Halle, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Riemann
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle, Magdeburger Str. 6, 06114, Halle, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ihling
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle, Magdeburger Str. 6, 06114, Halle, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Reime
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle, Magdeburger Str. 6, 06114, Halle, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Gekle
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle, Magdeburger Str. 6, 06114, Halle, Germany. oliver.thews@medizin.uni-halle.de.
authors.forename: O
authors.initials: O
authors.lastname: Thews
mesh_terms: D000818:Animals; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006863:Hydrogen-Ion Concentration; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D013997:Time Factors; D000072258:Tumor Hypoxia; D059016:Tumor Microenvironment; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018836:Inflammation Mediators; C506897:Spp1 protein, rat; D053495:Osteopontin; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C535149:Mapk1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D010100:Oxygen
keywords: Acidosis; ERK1/2; Hypoxia; Inflammatory mediators; Tumor