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.
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Thews O, Vaupel P (2015) Spatial oxygenation profiles in tumors during normo- and hyperbaric hyperoxia. Strahlenther Onkol 191:875–882
Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49:6449–6465
Mao Y, Poschke I, Kiessling R (2014) Tumour-induced immune suppression: role of inflammatory mediators released by myelomonocytic cells. J Intern Med 276:154–170
Seruga B, Zhang H, Bernstein LJ et al (2008) Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer 8:887–899
Riemann A, Ihling A, Thomas J et al (2015) Acidic environment activates inflammatory programs in fibroblasts via a cAMP-MAPK pathway. Biochim Biophys Acta 1853:299–307
Riemann A, Schneider B, Ihling A et al (2011) Acidic environment leads to ROS-induced MAPK signaling in cancer cells. PLoS One 6:e22445
Sauvant C, Nowak M, Wirth C et al (2008) Acidosis induces multi-drug resistance in rat prostate cancer cells (AT1) in vitro and in vivo by increasing the activity of the p-glycoprotein via activation of p38. Int J Cancer 123:2532–2542
McClellan JL, Davis JM, Steiner JL et al (2012) Linking tumor-associated macrophages, inflammation, and intestinal tumorigenesis: role of MCP-1. Am J Physiol Gastrointest Liver Physiol 303:G1087–G1095
Deshmane SL, Kremlev S, Amini S et al (2009) Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 29:313–326
Lala PK, Chakraborty C (2001) Role of nitric oxide in carcinogenesis and tumour progression. Lancet Oncol 2:149–156
Shevde LA, Samant RS (2014) Role of osteopontin in the pathophysiology of cancer. Matrix Biol 37:131–141
Riemann A, Wußling H, Loppnow H et al (2016) Acidosis differently modulates the inflammatory program in monocytes and macrophages. Biochim Biophys Acta 1862:72–81
Pedoto A, Nandi J, Oler A et al (2001) Role of nitric oxide in acidosis-induced intestinal injury in anesthetized rats. J Lab Clin Med 138:270–276
Campo GM, Avenoso A, D’Ascola A et al (2013) 4-mer hyaluronan oligosaccharides stimulate inflammation response in synovial fibroblasts in part via TAK-1 and in part via p38-MAPK. Curr Med Chem 20:1162–1172
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This study was supported by the BMBF (ProNet-T3 Ta-04) and the Wilhelm-Roux program of the Medical School, University Halle-Wittenberg, Germany.
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Riemann, A., Ihling, A., Reime, S., Gekle, M., Thews, O. (2016). Impact of the Tumor Microenvironment on the Expression of Inflammatory Mediators in Cancer Cells. In: Luo, Q., Li, L., Harrison, D., Shi, H., Bruley, D. (eds) Oxygen Transport to Tissue XXXVIII. Advances in Experimental Medicine and Biology, vol 923. Springer, Cham. https://doi.org/10.1007/978-3-319-38810-6_14
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DOI: https://doi.org/10.1007/978-3-319-38810-6_14
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