Autocrine CSF-1R signaling drives mesothelioma chemoresistance via AKT activation

Cell Death Dis. 2014 Apr 10;5(4):e1167. doi: 10.1038/cddis.2014.136.

Abstract

Clinical management of malignant pleural mesothelioma (MPM) is very challenging because of the uncommon resistance of this tumor to chemotherapy. We report here increased expression of macrophage colony-stimulating-factor-1-receptor (M-CSF/CSF-1R) mRNA in mesothelioma versus normal tissue specimens and demonstrate that CSF-1R expression identifies chemoresistant cells of mesothelial nature in both primary cultures and mesothelioma cell lines. By using RNAi or ligand trapping, we demonstrate that the chemoresistance properties of those cells depend on autocrine CSF-1R signaling. At the single-cell level, the isolated CSF-1R(pos) cells exhibit a complex repertoire of pluripotency, epithelial-mesenchymal transition and detoxifying factors, which define a clonogenic, chemoresistant, precursor-like cell sub-population. The simple activation of CSF-1R in untransformed mesothelial cells is sufficient to confer clonogenicity and resistance to pemetrexed, hallmarks of mesothelioma. In addition, this induced a gene expression profile highly mimicking that observed in the MPM cells endogenously expressing the receptor and the ligands, suggesting that CSF-1R expression is mainly responsible for the phenotype of the identified cell sub-populations. The survival of CSF1R(pos) cells requires active AKT (v-akt murine thymoma viral oncogene homolog 1) signaling, which contributed to increased levels of nuclear, transcriptionally competent β-catenin. Inhibition of AKT reduced the transcriptional activity of β-catenin-dependent reporters and sensitized the cells to senescence-induced clonogenic death after pemetrexed treatment. This work expands what is known on the non-macrophage functions of CSF-1R and its role in solid tumors, and suggests that CSF-1R signaling may have a critical pathogenic role in a prototypical, inflammation-related cancer such as MPM and therefore may represent a promising target for therapeutic intervention.

MeSH terms

  • Autocrine Communication* / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / pathology
  • Drug Resistance, Neoplasm* / drug effects
  • Enzyme Activation / drug effects
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics
  • Flow Cytometry
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glutamates
  • Guanine / analogs & derivatives
  • Humans
  • Interleukins / pharmacology
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology*
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Mesothelioma / enzymology
  • Mesothelioma / genetics
  • Mesothelioma / metabolism*
  • Mesothelioma / pathology*
  • Pemetrexed
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptor, Macrophage Colony-Stimulating Factor / genetics
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism*

Substances

  • Glutamates
  • Interleukins
  • interleukin-34, human
  • Pemetrexed
  • Guanine
  • Macrophage Colony-Stimulating Factor
  • Receptor, Macrophage Colony-Stimulating Factor
  • Proto-Oncogene Proteins c-akt

Supplementary concepts

  • Mesothelioma, Malignant