PPARγ and RXR Ligands Disrupt the Inflammatory Cross-talk in the Hypoxic Breast Cancer Stem Cells Niche

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.

Time-dependent PPARγ Modulation of HIF-1α Signaling in Hypoxic Pulmonary Artery Smooth Muscle Cells

“…To our knowledge, this is the first article to examine the effect of PPARγ activation on HIF-1α signaling in HPASMCs. PPARγ activation reduced expression of HIF-1α in cancer stem cells 46 and increased HIF-1α in breast cancer cells, 47 whereas both transcription factors were upregulated in cardiac hypertrophy. 48 We previously reported that RSG attenuated HIF-1α activation in hypoxic endothelial cells, 31 and pioglitazone similarly attenuated HIF-1α in skeletal muscle through effects on mitochondrial function.…”

EGFR inhibition by (-)-epigallocatechin-3-gallate and IIF treatments reduces breast cancer cell invasion

“…IIF also induced differentiation in several cancer cell lines, inhibited MMP-2 and MMP-9 and increased expression of their inhibitors (TIMP-1 and TIMP-2) [44]. Both ATRA and IIF down-regulated genes that supported the tumour stem cell phenotype maintenance (Slug, Notch-3 and Jagged-1) by blocking the NF-κB axis: these events were associated with re-expression of differentiation markers such as ERα and keratin-18 in breast carcinoma stem cells [45]. …”

Exosome: emerging biomarker in breast cancer

“…In breast cancer, hypoxia-mediated triggering of HIF-1α (Hypoxia inducible factors) enhanced exosomes secretion and lead to aggressive cell phenotype [67]. Breast cancer-derived exosomes produced under hypoxic conditions can also promote inflammatory crosstalk within the tumor niche to promote growth, which is decreased by activation of nuclear receptors within the cancer cell [68]. Besides, tumor cells made cancer cells significantly reduce the effectiveness of irradiation under hypoxic tumor microenvironments.…”