title: Acidosis Promotes Metastasis Formation by Enhancing Tumor Cell Motility.
abstract: The tumor microenvironment is characterized by hypoxia, acidosis as well as other metabolic and biochemical alterations. Its role in cancer progression is increasingly appreciated especially on invasive capacity and the formation of metastasis. The effect of acidosis on metastasis formation of two rat carcinoma cell lines was studied in the animal model. In order to analyze the pH dependency of different steps of metastasis formation, invasiveness, cell adhesion and migration of AT-1 prostate cancer cells as well as possible underlying cell signaling pathways were studied in vitro. Acidosis significantly increased the formation of lung metastases of both tumor cell lines in vivo. In vitro, extracellular acidosis neither enhanced invasiveness nor affected cell adhesion to a plastic or to an endothelial layer. However, cellular motility was markedly elevated at pH 6.6 and this effect was sustained even when extracellular pH was switched back to pH 7.4. When analyzing the underlying mechanism, a prominent role of ROS in the induction of migration was observed. Signaling through the MAP kinases ERK1/2 and p38 as well as Src family kinases was not involved. Thus, cancer cells in an acidic microenvironment can acquire enhanced motility, which is sustained even if the tumor cells leave their acidic microenvironment e.g. by entering the blood stream. This increase depended on elevated ROS production and may contribute to the augmented formation of metastases of acidosis-primed tumor cells in vivo.
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle, Magdeburger Straße 6, 06112, Halle (Saale), Germany. anne.riemann@medizin.uni-halle.de.
authors.forename: A
authors.initials: A
authors.lastname: Riemann
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle, Magdeburger Straße 6, 06112, Halle (Saale), Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schneider
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle, Magdeburger Straße 6, 06112, Halle (Saale), Germany.
authors.forename: D
authors.initials: D
authors.lastname: Gündel
authors.affiliation: Institute of Physiology II, University of Münster, Münster, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Stock
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle, Magdeburger Straße 6, 06112, Halle (Saale), Germany.
authors.forename: M
authors.initials: M
authors.lastname: Gekle
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle, Magdeburger Straße 6, 06112, Halle (Saale), Germany.
authors.forename: O
authors.initials: O
authors.lastname: Thews
mesh_terms: D000138:Acidosis / Q000473:pathology*; D000818:Animals; D002279:Carcinoma 256, Walker / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D005260:Female; D006863:Hydrogen-Ion Concentration; D008297:Male; D009362:Neoplasm Metastasis; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D017382:Reactive Oxygen Species
keywords: Acidosis; MAP kinases; Metastasis formation; Migration; ROS