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Pflügers Archiv - European Journal of Physiology

, Volume 469, Issue 12, pp 1567–1577 | Cite as

TRPC6 channels modulate the response of pancreatic stellate cells to hypoxia

  • Nikolaj Nielsen
  • Kateryna Kondratska
  • Tobias Ruck
  • Benedikt Hild
  • Ilya Kovalenko
  • Sandra Schimmelpfennig
  • Jana Welzig
  • Sarah Sargin
  • Otto Lindemann
  • Sven Christian
  • Sven G. Meuth
  • Natalia Prevarskaya
  • Albrecht SchwabEmail author
Ion channels, receptors and transporters
Part of the following topical collections:
  1. Ion channels, receptors and transporters

Abstract

Pancreatic cancer is characterized by a massive fibrosis (desmoplasia), which is primarily caused by activated pancreatic stellate cells (PSCs). This leads to a hypoxic tumor microenvironment further reinforcing the activation of PSCs by stimulating their secretion of growth factors and chemokines. Since many of them elicit their effects via G-protein-coupled receptors (GPCRs), we tested whether TRPC6 channels, effector proteins of many G-protein-coupled receptor pathways, are required for the hypoxic activation of PSCs. Thus far, the function of ion channels in PSCs is virtually unexplored. qPCR revealed TRPC6 channels to be one of the most abundant TRPC channels in primary cultures of murine PSCs. TRPC6 channel function was assessed by comparing PSCs from TRPC6−/− mice and wildtype (wt) littermates. Cell migration, Ca2+ signaling, and cytokine secretion were analyzed as readout for PSC activation. Hypoxia was induced by incubating PSCs for 24 h in 1% O2 or chemically with dimethyloxalylglycine (DMOG). PSCs migrate faster in response to hypoxia. Due to reduced autocrine stimulation, TRPC6−/− PSCs fail to increase their rate of migration to the same level as wt PSCs under hypoxic conditions. This defect could not be overcome by the stimulation with platelet-derived growth factor. In line with these results, calcium influx is increased in wt but not TRPC6−/− PSCs under hypoxia. We conclude that TRPC6 channels of PSCs are major effector proteins in an autocrine stimulation pathway triggered by hypoxia.

Keywords

TRPC6 channel Pancreatic stellate cell Migration Tumor microenvironment Hypoxia 

Notes

Acknowledgements

This work was supported by the Marie Curie Initial Training Network IonTraC (FP7-PEOPLE-2011-ITN grant agreement no. 289648) and Deutsche Forschungsgemeinschaft, Cells-in-Motion Cluster of Excellence (EXC 1003—CiM), University of Münster, Germany, and DFG SCHW 407/17-1.

Compliance with Ethical Standards

Conflicts of Interest

At the time of the project SC and IK were employees of Bayer Pharma AG. It did not impact the study design nor data interpretation. Other authors do not have a conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Nikolaj Nielsen
    • 1
  • Kateryna Kondratska
    • 2
  • Tobias Ruck
    • 3
  • Benedikt Hild
    • 1
  • Ilya Kovalenko
    • 4
    • 5
  • Sandra Schimmelpfennig
    • 1
  • Jana Welzig
    • 1
  • Sarah Sargin
    • 1
  • Otto Lindemann
    • 1
  • Sven Christian
    • 4
  • Sven G. Meuth
    • 3
  • Natalia Prevarskaya
    • 2
  • Albrecht Schwab
    • 1
    Email author
  1. 1.Institute of Physiology IIWestfälische Wilhelms-Universität MünsterMünsterGermany
  2. 2.Inserm, U-1003, Equipe labellisée par la Ligue Nationale Contre le Cancer, Laboratory of Excellence, Ion Channels Science and TherapeuticsUniversité Lille 1Villeneuve-d’AscqFrance
  3. 3.Department of Neurology, Albert-Schweitzer-Campus 1, Building A10Westfälische Wilhelms-Universität MünsterMünsterGermany
  4. 4.Bayer-Pharma AGBerlinGermany
  5. 5.Cancer CenterUniversity of MichiganAnn ArborUSA

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