The Influences of RARγ on the Behavior of Normal and Cancer Stem Cells

Retinoic acid receptor (RARγ) mRNA is expressed spatially and temporally during mouse embryogenesis and largely within stem and progenitor cells, indicating a role in organ formation. RARγ agonism promoted the maintenance of hematopoietic stem cells, and blocked stem cell development as shown for hematopoiesis, zebrafish development, and chondrogenesis. Transgene expression enhanced the generation of induced pluripotent stem cells, indicating a role in ground-state pluripotency. RARγ is oncogenic in acute myeloid leukemia, cholangiocarcinoma, and colorectal, head and neck, hepatocellular, ovarian, pancreatic, prostate, and renal cancers. RARγ agonism or overexpression enhanced the proliferation of cancer cells. Conversely, antagonism or inhibition of all-trans retinoic acid synthesis led to the death of cancer cells including cancer stem cells. The pathways regulated by RARγ, via canonical activation and repression of gene expression, include Wnt/β-catenin and Notch signaling. RARγ also acts as a co-factor to Smad3 and reduced or enhanced TGFβ-driven and Smad3-mediated events when liganded and non-liganded, respectively. Collectively the findings support the view that RARγ plays a crucial role in controlling stem and progenitor cell behavior.