Acidosis Promotes Metastasis Formation by Enhancing Tumor Cell Motility

  • A. RiemannEmail author
  • B. Schneider
  • D. Gündel
  • C. Stock
  • M. Gekle
  • O. Thews
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 876)


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.


Acidosis Metastasis formation Migration ROS MAP kinases 



This study was supported by the Deutsche Krebshilfe (Grants 106774/106906), the BMBF (ProNet-T3 Ta-04) and the Wilhelm-Roux program of the Medical School, Universität Halle-Wittenberg.


  1. 1.
    Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49:6449–6465PubMedGoogle Scholar
  2. 2.
    Gerweck LE, Seetharaman K (1996) Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res 56:1194–1198PubMedGoogle Scholar
  3. 3.
    Gatenby RA, Gawlinski ET, Gmitro AF et al (2006) Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res 66:5216–5223CrossRefPubMedGoogle Scholar
  4. 4.
    Giusti I, D’Ascenzo S, Millimaggi D et al (2008) Cathepsin B mediates the pH-dependent proinvasive activity of tumor-shed microvesicles. Neoplasia 10:481–488CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Moellering RE, Black KC, Krishnamurty C et al (2008) Acid treatment of melanoma cells selects for invasive phenotypes. Clin Exp Metastasis 25:411–425CrossRefPubMedGoogle Scholar
  6. 6.
    Rofstad EK, Mathiesen B, Kindem K, Galappathi K (2006) Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. Cancer Res 66:6699–6707CrossRefPubMedGoogle Scholar
  7. 7.
    Workman P, Aboagye EO, Balkwill F et al (2010) Guidelines for the welfare and use of animals in cancer research. Br J Cancer 102:1555–1577CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Riemann A, Schneider B, Ihling A et al (2011) Acidic environment leads to ROS-induced MAPK signaling in cancer cells. PLoS One 6:e22445CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Porporato PE, Payen VL, Pérez-Escuredo J et al (2014) A mitochondrial switch promotes tumor metastasis. Cell Rep 8:754–766CrossRefPubMedGoogle Scholar
  10. 10.
    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 123:2532–2542CrossRefPubMedGoogle Scholar
  11. 11.
    Estrella V, Chen T, Lloyd M et al (2013) Acidity generated by the tumor microenvironment drives local invasion. Cancer Res 73:1524–1535CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Robey IF, Baggett BK, Kirkpatrick ND et al (2009) Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Res 69:2260–2268CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, New York 2016

Authors and Affiliations

  • A. Riemann
    • 1
    Email author
  • B. Schneider
    • 1
  • D. Gündel
    • 1
  • C. Stock
    • 2
  • M. Gekle
    • 1
  • O. Thews
    • 1
  1. 1.Julius-Bernstein-Institute of Physiology, University of HalleHalle (Saale)Germany
  2. 2.Institute of Physiology II, University of MünsterMünsterGermany

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