RESUMO
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.
Assuntos
Neoplasias da Mama/patologia , Inflamação/patologia , Células-Tronco Neoplásicas/patologia , PPAR gama/metabolismo , Receptor Cross-Talk , Receptores X de Retinoides/metabolismo , Nicho de Células-Tronco , Antígenos de Neoplasias/metabolismo , Apolipoproteínas E/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/enzimologia , Anidrase Carbônica IX , Anidrases Carbônicas/metabolismo , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/metabolismo , Ligantes , Células MCF-7 , Metaloproteinase 9 da Matriz/metabolismo , Modelos Biológicos , NF-kappa B/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/enzimologia , Fenantrenos/farmacologia , Pioglitazona , Receptor Cross-Talk/efeitos dos fármacos , Receptores X de Retinoides/agonistas , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Nicho de Células-Tronco/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia , Tiazolidinedionas/farmacologiaRESUMO
This article explores examples of successful and unsuccessful regenerative medicine on human epithelia. To evaluate the applications of the first regenerated tissues, the analysis of the past successes and failures addresses some pending issues and lay the groundwork for developing new therapies. Research should still be encouraged to fill the gap between pathologies, clinical applications and what regenerative medicine can attain with current knowledge.