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Pericytes Suppress Brain Metastasis from Lung Cancer In Vitro

  • Takashi Fujimoto
  • Shinsuke Nakagawa
  • Yoichi MorofujiEmail author
  • Daisuke Watanabe
  • Kenta Ujifuku
  • Nobutaka Horie
  • Tsuyoshi Izumo
  • Masami Niwa
  • William A. Banks
  • Maria A. Deli
  • Takayuki Matsuo
Original Research

Abstract

Metastasis of lung cancer to the brain is associated with poor outcomes and limited therapeutic options. The blood–brain barrier (BBB) plays a major role in brain metastasis. However, little is known about the role of pericytes in brain metastasis formation. This study aimed to reveal the interaction between pericytes and cancer cells. We established in vitro BBB models with rat primary cultured BBB-related cells (endothelial cells, astrocytes, and pericytes) and investigated the relationship between BBB-related cells and metastatic cancer cell lines. We observed a significant decrease in transendothelial electrical resistance with metastatic cancer cells in monolayer and coculture models with astrocytes. In contrast, the coculture model with pericytes showed inhibition of the decrease in transendothelial electrical resistance with metastatic cancer cells. In addition, the expression of tight junction protein was preserved only in the coculture model with pericytes. The conditioned medium of pericytes with metastatic cancer cells suppressed the proliferation of the cancer cells significantly. This study revealed that brain pericytes are the major regulators of the resistance of the BBB to lung cancer metastasis to the brain. Pericytes exert an anti-metastatic effect and thus have potential for the preventive treatment of brain metastasis.

Keywords

Blood–brain barrier Pericytes Brain metastasis Lung cancer 

Notes

Acknowledgements

We thank Jun Aruga for critical review of the manuscript and helpful professional guidance. We also thank Mitchell Arico from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Authors’ Contributions

T.F. and Y.M. designed the study and wrote the initial draft of the manuscript. S.N contributed to analysis and interpretation of data, M.N. and M.D. were involved in planning, and also supervised the work. All other authors have contributed to data collection and interpretation, and critically reviewed the manuscript. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding

This study was funded by JSPS and HAS under the Japan-Hungary Research Cooperative Program (to Y.M. and M.D.) and, in part, by Grants-in-Aid for Scientific Research (C) 17K10840 (to Y.M.), (C) 15KK0349 (to Y.M.), and (C) 17K10839 (to K.U.).

Compliance with Ethical Standards

Conflict of interest

All authors have no conflicts of interest to disclose.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NeurosurgeryNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
  2. 2.Department of Medical PharmacologyNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
  3. 3.BBB LaboratoryPharmaCo-Cell Company Ltd.NagasakiJapan
  4. 4.VA Puget Sound Health Care System, Geriatric Research Education and Clinical CenterSeattleUSA
  5. 5.Division of Gerontology and Geriatric Medicine, Department of MedicineUniversity of Washington School of MedicineSeattleUSA
  6. 6.Biological Barriers Research Group, Institute of Biophysics, Biological Research CentreHungarian Academy of SciencesSzegedHungary

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