Inhibition of the colony-stimulating-factor-1 receptor affects the resistance of lung cancer cells to cisplatin

Harvey I. Pass, Carmencita Lavilla, Claudia Canino, Chandra Goparaju, Jordan Preiss, Samrah Noreen, Giovanni Blandino, Mario Cioce

Research output: Contribution to journalArticle

Abstract

In the present work we show that multiple lung cancer cell lines contain cisplatin resistant cell subpopulations expressing the Colony-Stimulating-Factor-Receptor-1 (CSF-1R) and surviving chemotherapy-induced stress. By exploiting siRNA-mediated knock down in vitro and the use of an investigational CSF-1R TKI (JNJ-40346527) in vitro and in vivo, we show that expression and function of the receptor are required for the clonogenicity and chemoresistance of the cell lines. Thus, inhibition of the kinase activity of the receptor reduced the levels of EMT-associated genes, stem cell markers and chemoresistance genes. Additionally, the number of high aldehyde dehydrogenase (ALDH) expressing cells was reduced, consequent to the lack of cisplatin-induced increase of ALDH isoforms. This affected the collective chemoresistance of the treated cultures. Treatment of tumor bearing mice with JNJ-40346527, at pharmacologically relevant doses, produced strong chemo-sensitizing effects in vivo. These anticancer effects correlated with a reduced number of CSF-1Rpos cells, in tumors excised from the treated mice. Depletion of the CD45pos cells within the treated tumors did not, apparently, play a major role in mediating the therapeutic response to the TKI. Thus, lung cancer cells express a functional CSF-1 and CSF-1R duo which mediates pro-tumorigenic effects in vivo and in vitro and can be targeted in a therapeutically relevant way. These observations complement the already known role for the CSF-1R at mediating the protumorigenic properties of tumor-infiltrating immune components.

Original languageEnglish
Pages (from-to)56408-56421
Number of pages14
JournalOncotarget
Volume7
Issue number35
DOIs
Publication statusPublished - 2016

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Keywords

  • ALDH
  • Chemoresistance
  • CSF-1
  • CSF-1R
  • Lung cancer

ASJC Scopus subject areas

  • Oncology

Cite this

Pass, H. I., Lavilla, C., Canino, C., Goparaju, C., Preiss, J., Noreen, S., Blandino, G., & Cioce, M. (2016). Inhibition of the colony-stimulating-factor-1 receptor affects the resistance of lung cancer cells to cisplatin. Oncotarget, 7(35), 56408-56421. https://doi.org/10.18632/oncotarget.10895