title: Inhibition of the colony-stimulating-factor-1 receptor affects the resistance of lung cancer cells to cisplatin.
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 pro-tumorigenic properties of tumor-infiltrating immune components.
authors.affiliation: Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, USA.
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.affiliation: New York University Langone Medical Center, New York University, New York, USA.
authors.forename: Carmencita
authors.initials: C
authors.lastname: Lavilla
authors.affiliation: Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, USA.|University Campus Biomedico, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Canino
authors.affiliation: Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, USA.
authors.forename: Chandra
authors.initials: C
authors.lastname: Goparaju
authors.affiliation: Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Preiss
authors.affiliation: New York University Langone Medical Center, New York University, New York, USA.
authors.forename: Samrah
authors.initials: S
authors.lastname: Noreen
authors.affiliation: Translational Oncogenomics Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy.|Department of Oncology, Juravinski Cancer Center-McMaster University, Hamilton, Ontario, Canada.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Blandino
authors.affiliation: Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, USA.|Translational Oncogenomics Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cioce
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D052160:Benzothiazoles / Q000494:pharmacology / Q000627:therapeutic use; D063646:Carcinogenesis / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010766:Phosphorylation; D010848:Picolinic Acids / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D016186:Receptor, Macrophage Colony-Stimulating Factor
chemical_list: D000444:Aldehyde Dehydrogenase; D052160:Benzothiazoles; D002945:Cisplatin; D007093:Imidazoles; D017493:Leukocyte Common Antigens; D016173:Macrophage Colony-Stimulating Factor; D010848:Picolinic Acids; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; C568289:4-(2-(2-hydroxycyclohexylamino)benzothiazol-6-yloxy)pyridine-2-carboxylic acid methylamide; C000622186:CSF1R protein, human; D016186:Receptor, Macrophage Colony-Stimulating Factor; C000604309:JNJ-40346527; C516769:PTPRC protein, human
keywords: ALDH; CSF-1; CSF-1R; chemoresistance; lung cancer