PPARγ and RXR ligands disrupt the inflammatory cross-talk in the hypoxic breast cancer stem cells niche

J Cell Physiol. 2014 Nov;229(11):1595-606. doi: 10.1002/jcp.24601.

Abstract

Cancer stem cells (CSCs) are affected by the local micro-environment, the niche, in which inflammatory stimuli and hypoxia act as steering factors. Here, two nuclear receptors (NRs) agonists, i.e. pioglitazone (PGZ), a ligand of peroxisome proliferator activated receptor-γ, and 6-OH-11-O-hydroxyphenanthrene (IIF), a ligand of retinoid X receptors, were investigated for their capability to interference with the cross-talk between breast CSCs and the niche compartment. We found that IIF potentiates the ability of PGZ to hamper the mammospheres-forming capability of human breast tumours and MCF7 cancer cells, reducing the expression of CSCs regulatory genes (Notch3, Jagged1, SLUG, Interleukin-6, Apolipoprotein E, Hypoxia inducible factor-1α and Carbonic anhydrase IX). Notably, these effects are not observed in normal-MS obtained from human breast tissue. Importantly, NRs agonists abolish the capability of hypoxic MCF7 derived exosomes to induce a pro-inflammatory phenotype in mammary glands fibroblasts. Moreover, NRs agonist also directly acts on breast tumour associated fibroblasts to downregulate nuclear factor-κB pathway and metalloproteinases (MMP2 and MMP9) expression and activity. In conclusion, NRs agonists disrupt the inflammatory cross-talk of the hypoxic breast CSCs niche.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / metabolism
  • Apolipoproteins E / metabolism
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology*
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases / metabolism
  • Cell Hypoxia / drug effects
  • Cell Survival / drug effects
  • Exosomes / drug effects
  • Exosomes / metabolism
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Ligands
  • MCF-7 Cells
  • Matrix Metalloproteinase 9 / metabolism
  • Models, Biological
  • NF-kappa B / metabolism
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / enzymology
  • Neoplastic Stem Cells / pathology*
  • PPAR gamma / metabolism*
  • Phenanthrenes / pharmacology
  • Pioglitazone
  • Receptor Cross-Talk* / drug effects
  • Retinoid X Receptors / agonists
  • Retinoid X Receptors / metabolism*
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / pathology
  • Stem Cell Niche* / drug effects
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Thiazolidinediones / pharmacology

Substances

  • 6-OH-11-O-hydroxyphenanthrene
  • Antigens, Neoplasm
  • Apolipoproteins E
  • Biomarkers, Tumor
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ligands
  • NF-kappa B
  • PPAR gamma
  • Phenanthrenes
  • Retinoid X Receptors
  • Thiazolidinediones
  • MMP9 protein, human
  • Matrix Metalloproteinase 9
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases
  • Pioglitazone